Human Fungal Pathogens of Mucorales and Entomophthorales

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Leonel Mendoza1,2, Raquel Vilela2,3,4, Kerstin Voelz5,6, Ashraf S. Ibrahim7,8, Kerstin Voigt9, and Soo Chan Lee10

1Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48424-1031 2Biomedical Laboratory Diagnostics, Michigan State University, East Lansing, Michigan 48424-1031 3Faculty of Pharmacy, Federal University of Minas Gerais (UFMG), Minas Gerais, CEP33400000 Belo Horizonte, Brazil 4Belo Horizonte Brazil; Superior Institute of Medicine (ISMD), Minas Gerais, CEP33400000 Belo Horizonte, Brazil 5Institute of Microbiology and Infection & School of Biosciences, University of Birmingham, Birmingham B15 2TT, United Kingdom 6The National Institute of Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom B15 2WB 7Division of Infectious Diseases, Harbor–University of California Los Angeles Medical Center, St. John’s Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California 90502 8David Geffen School of Medicine at UCLA, Los Angeles, California 90095 9Jena Microbial Resource Collection, Leibniz Institute for Natural Product Research and Infection Biology and University of Jena, Faculty of Biology and Pharmacy, Institute of Microbiology, Neugasse 25, 07743 Jena, Germany 10Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710 Correspondence: [email protected]

In recent years, we have seen an increase in the number of immunocompromised cohorts as a result of infections and/or medical conditions, which has resulted in an increased incidence of fungal infections. Although rare, the incidence of infections caused by fungi belonging to

www.perspectivesinmedicine.org basal fungal lineages is also continuously increasing. Basal fungal lineages diverged at an early point during the evolution of the fungal lineage, in which, in a simpliﬁed four-phylum fungal kingdom, Zygomycota and Chytridiomycota belong to the basal fungi, distinguishing them from Ascomycota and Basidiomycota. Currently there are no known human infections caused by fungi in Chytridiomycota; only Zygomycotan fungi are known to infect humans. Hence, infections caused by zygomycetes have been called zygomycosis, and the term “zygomycosis” is often used as a synonym for “mucormycosis.” In the four-phylum fungal kingdom system, Zygomycota is classiﬁed mainly based on morphology,including the ability to form coenocytic (aseptated) hyphae and zygospores (sexual spores). In the Zygomycota, there are 10 known orders, two of which, the Mucorales and Entomophthorales, contain species that can infect humans, and the infection has historically been known as zygomy-

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L. Mendoza et al.

cosis. However, recent multilocus sequence typing analyses (the fungal tree of life [AFTOL] project) revealed that the Zygomycota forms not a monophyletic clade but instead a polyphyletic clade, whereas Ascomycota and Basidiomycota are monophyletic. Thus, the term “zygomycosis” needed to be further speciﬁed, resulting in the terms “mucormycosis” and “entomophthoramycosis.” This review covers these two different types of fungal infections.

MUCORALES AND MUCORMYCOSIS germinate to form a sporangium at the apex culminating in sexual meiospores. The forma- ucoralean fungi reproduce both sexually tion of zygospores requires two compatible and asexually. The asexual sporangio- M mating types, and it takes aconsiderable amount spores are formed in a globe-like structure called of time for the zygospores to germinate (re- the sporangium on the apex of sporangiophore viewed in Lee et al. 2010). Therefore, the asexual (Fig. 1). The sporangiospores then disperse and, sporangiospores may serve as the major source on appropriate conditions, germinate to pro- of dissemination and infection. duce a mycelial complex. Most of the pathogenic Mucormycosis is an infection caused by Mucorales are heterothallic, and in their sexual fungi that belong to the Mucorales order. In- development, hyphae of the two different mat- fection sites include the lungs, rhinocerebral ing types [(2) and (þ)] sense each other and spaces, sinuses, soft tissue, skin, gastrointestinal undergo fusion to form zygospores, which later tract, and bloodstream (Dromer and McGinnis 2003; Ibrahim and Spellberg 2006). The predicted economic burden in the U.S. health care system caused by mucormycosis is $100,000 per case (Ibrahim et al. 2008a). Although mucormycosis has long been considered a rare fungal infection, advances in medical care and an increasingly aging population have resulted in a recent increase in the incidence (Roden et al. 2005; Chayakulkeeree et al. 2006; Lanternier and Lortholary 2009; Roilides et al. 2009; Kon- toyiannis et al. 2010; Petrikkos et al. 2012). Enhanced management of susceptible individuals with predisposing conditions (e.g., diabe- www.perspectivesinmedicine.org tes, iron overload, immune-suppressive therapy, cancer, and trauma injury [Chayakulkeeree et al. 2006]) has improved patient prognosis while potentially allowing for the establishment of opportunistic mucormycosis. Consequent- ly, mucormycosis is the second-most-common mold infection in hematological malignancy Figure 1. Morphology of Mucor circinelloides (left) and transplant patients, and the mortality rates and Rhizopus oryzae (right). (A) Sporangia form at are unacceptably high, with .90% mortality in the apices of sporangiophores and contain the asex- disseminated infections (Ribes et al. 2000; Ro- ual sporangiospores. (B) Zygospores formed during den et al. 2005; Lanternier et al. 2012b). mating. (Figures adapted from Li et al. 2011 [left] and The etiologic agents of mucormycosis in- Gryganskyi et al. 2010 [right], respectively.) (C)Hy- phae in the brains of infected mice. The tissue spec- clude Rhizopus spp., Mucor spp., Lichtheimia imens were stained with Gomori’s methenamine sil- (previouslyAbsidia)spp.,Cunninghamella,Rhi- ver at 48 h postinfection. Scale bars, 50 mm(A); 100 zomucor,and Apophysomyces spp.,among others mm(B,C). (Chayakulkeeree et al. 2006; Ibrahim and Spell-

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HFPs of Mucorales and Entomophthorales

berg 2006; Neblett Fanfair et al. 2012). Among However, treatment with the iron-chelat- 50 mucormycosis cases in solid organ trans- ing agent deferoxamine in dialysis patients or plant recipients, Mucor spp. accounted for 37% repeated blood transfusions in bone marrow of cases, followed by Rhizopus spp. (35%) and transplant patients with myelodysplastic syn- Mycocladus (synonym of Lichtheimia) (13%) drome can also lead to iron overload and high- (Singh et al. 2009). In a European survey of 230 ly fatal (80%) mucormycosis (Boelaert et al. cases, Rhizopus spp. accounted for 24% of cases, 1988, 1989, 1991; Maertens et al. 1999). Defer- followed by Mucor spp. (22%) and Lichtheimia oxamine-treated guinea pigs challenged with spp. (14%) (Petrikkos 2008). In a survey of 75 Rhizopus spp. show increased susceptibility and cases in India, Rhizopus spp. (69%) were the reduced survival (Van Cutsem and Boelaert most common, followed by Apophysomyces spp. 1989; Boelaert et al. 1993). Interestingly, defer- (19%) (Chakrabarti et al. 2009). Overall, Rhizo- oxamine acts in the context of Rhizopus in- pus spp. and Mucor spp. are considered the most fection as a siderophore and transfers iron prevalent causal agents of mucormycosis. molecules from transferrin to the fungus by receptor-mediated interaction, thus supporting fungal growth (Boelaert et al. 1993, 1994; de Host Factors in Mucormycosis Locht et al. 1994). Diabetes mellitus is one of the major risk fac- Furthermore, individuals with suppressed tors, affecting 36%–88% of all patients with immunity (e.g., because of transplantation, mucormycosis (Joshi et al. 1999; Nithyanandam malignancies, HIV,steroids, or neutropenia) are et al. 2003; Roden et al. 2005). Although a hy- at increased risk of developing mucormyco- perglycemic state itself can be a predisposing sis, with high mortality rates of 68%–100% factor for disease development (Helderman et (Roden et al. 2005; Chayakulkeeree et al. al. 1974; Nithyanandam et al. 2003), Mucorales 2006). These patients often present with defects infections are particularly prevalent and ful- in innate immunity, particularly of phagocytic minant in connection with diabetic ketoacido- effector cell functions. For example, 15% of sis (DKA) or other forms of acidosis (Artis patients in this group who develop mucormy- et al. 1982; Nithyanandam et al. 2003). During cosis have severe neutropenia (Chayakulkeeree DKA, the concentration of ketones in the pa- et al. 2006; Ibrahim et al. 2012). In addition, tient’s blood increases, leading to acidification. impaired macrophage or neutrophil function The decrease in pH increases the availability because of corticosteroid therapy might also of free iron, an essential growth factor for Mu- significantly increase susceptibility to Mucor- corales. Indeed, Rhizopus species exhibit poor ales infections (Ribes et al. 2000). www.perspectivesinmedicine.org growth in normal iron-deprived serum but en- In healthy individuals, phagocytes induce hanced growth under elevated iron levels in vi- differential immune responses depending on tro (Artis et al. 1982; Boelaert et al. 1993). In the fungal morphological structure. Murine normal human serum, iron is bound to carrier bronchoalveolar macrophages inhibit germina- proteins (e.g., transferrin, ferrin, or lactoferrin) tion of Rhizopus oryzae spores and thus pre- to limit toxic effects while at the same time func- vent the formation of invasive hyphal forms tioning as a host defense mechanism by iron (Waldorf et al. 1984a; Waldorf 1989; Jorens et deprivation (nutritional immunity) (Weinberg al. 1995). Although macrophages are unable to 1974; Howard 1999). During acidosis the bind- kill fungal spores, macrophages, monocytes, and ing affinity of the iron-binding glycoprotein human neutrophils can damage and kill fungal transferrin is reduced, leading to the release hyphae without prior phagocytic uptake by of iron into the bloodstream (Ibrahim et al. means of oxidative stress and cationic peptides 2008d). The loss of the growth-inhibitory func- (Chinnand Diamond 1982;Diamond and Clark tion of iron-overloaded serum can be rescued 1982; Diamond et al. 1982; Levitz et al. 1986; with the iron chelators deferasirox and deferi- Waldorf 1989). Interestingly, fungal morpholo- prone (Ibrahim et al. 2006, 2007). gy also affects the chemotactic potential of R.

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oryzae on neutrophils. Although inactive spores and have repeatedly been implicated in break- do not induce neutrophil migration, active through infections in patients under prophy- spores and hyphae present a potent chemotactic latic voriconazole treatment (Kontoyiannis et signal (Waldorf and Diamond 1985). After en- al. 2000, 2005; Imhof et al. 2004; Marty et al. countering R. oryzae hyphae, human polymor- 2004; Siwek et al. 2004; Roden et al. 2005; Trifi- phonuclear neutrophils activate the expression lio et al. 2007). R. oryzae preexposure to vorico- of Toll-like receptor 2 and NF-kBpathway– nazole significantly decreased survival rates in related genes (Chamilos et al. 2008b). Addi- Drosophila and murine infection models of mu- tionally, Dectin-1-dependent activation of in- cormycosis. Mice infected with pretreated R. terleukin 23 production by human dendritic oryzae showed higher fungal burdens in the cells induces proinflammatory Th17 responses lungs, increased angioinvasion, enhanced in- (Chamilos et al. 2010). flammation, and pronounced tissue damage In contrast, macrophages from diabetic or (Lamaris et al. 2009). However, the mechanism corticosteroid-treated mice fail to inhibit spore by which voriconazole elevates R. oryzae viru- germination (Waldorf et al. 1984a,b). Neutro- lence is currently not understood. phils from diabetic patients with hyperglycemia and DKA retain the ability to damage Host–Pathogen Interactions in Mucormycosis fungal hyphae but show reduced responses to R. oryzae chemotactic factors (Chinn and Dia- Mucorales–host interactions during infection mond 1982). This might interrupt downstream are characterized by severe angioinvasion with signaling and the activation of appropriate vessel thrombosis and necrosis (Ibrahim et al. downstream cytokine responses. 2005b, 2012; Ben-Ami et al. 2009). Necrotic tis- Intact skin as a mechanical barrier for entry sue can restrict the access of phagocytic effec- of Mucorales spores is an important defense tor cells or antifungals to infected areas, likely mechanism against infections. The breakdown prohibiting fungal clearing and contributing of the skin barrier by burns or local trauma to the organism’s hematogenous dissemination injuries has been recognized as a common risk via penetration of endothelial cells and the ex- factor for developing mucormycosis. Particu- tracellular matrix of blood vessels (Ibrahim et al. larly in recent years, clusters of infections with 2012). R. oryzae ungerminated spores, but not unusual Mucorales members (e.g., Apophyso- germinated spores or hyphae, attach to the ma- myces spp. and Saksenaea spp.) have been iden- trix proteins laminin and type IV collagen in tified in the context of environmental disasters vitro (Bouchara et al. 1996). However, R. oryzae such as the Joplin, Missouri tornado in 2011 spores and germ tubes can adhere to human www.perspectivesinmedicine.org (Etienne et al. 2012; Neblett Fanfair et al. 2012) umbilical vein endothelial cells and cause cell and combat-related trauma (Evriviades et al. damage by a phagocytosis-dependent mecha- 2011; Warkentien et al. 2012). In these settings, nism (Ibrahim et al. 2005b). Strikingly,cell dam- injury often occurs as a result of extreme natural age does not depend on infection with viable forces or explosive blasts resulting in deep- R. oryzae spores (Ibrahim et al. 2005b), which seated tissue implantation of Mucorales spores must be considered in clinical practice. The glu- from environmental sources. Additionally, no- cose-regulated protein GRP78, a member of the socomial Mucorales infections have been re- Hsp70 chaperone family, was identified as the ported in relation to surgical wound dressings receptor for invasion and damage of endothelial (Gartenberg et al. 1978; Mead et al. 1979). cells (Liu et al. 2010). Hyperglycemia and ele- Other risk factors for mucormycosis in- vated iron concentration, conditions mimicking clude intravenous drug abuse, malnutrition, DKA, increase GRP78 expression and R. oryzae premature birth, and long-term application uptake by and subsequent damage of endothe- of the broad-spectrum antifungal voriconazole lial cells (Liu et al. 2010). Additionally, DKA (Chayakulkeeree et al. 2006). Mucorales are re- mice express more GRP78 in target organs sistant to voriconazole (Dannaoui et al. 2003) than normal mice. Recently, the Mucorales li-

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HFPs of Mucorales and Entomophthorales

gand that binds to GRP78 was identified as sis-predisposing factors. For example, in DKA CotH, acell surface protein unique to Mucorales patients, hyperglycemia and acidemia should be (Gebremariam et al. 2014). Collectively, these corrected. Similarly, stopping or reducing im- findings likely explain the susceptibility of dia- munosuppressive therapy, particularly cortico- betic patients and individuals with iron overload steroids, should be strongly considered when to mucormycosis. Anti-GRP78 or anti-CotH the diagnosis of mucormycosis is made. Finally, antibodies were protective in R. oryzae–infected iron administration to patients with active mu- DKA mice (Liu et al. 2010; Gebremariam et al. cormycosis (e.g., treatment with deferoxamine) 2014) and might offer a new therapeutic strategy should be avoided, as iron exacerbates infection for disease management. in animal models (Abe et al. 1990; Ibrahim et al. The size of spores is also known to con- 2007). Iron can also be liberated during blood tribute to virulence (Li et al. 2011). In a het- transfusion as a result of hemolysis, so a conser- erologous wax moth larva mucormycosis mod- vative approach to red blood cell transfusions is el, large multinucleate spores exhibit higher advisable. virulence compared with small mononucleate Blood vessel thrombosis and resulting tis- spores, which is likely caused by the ability of sue necrosis are a hallmark of mucormycosis larger spores to germinate more rapidly than and can result in poor penetration of antifungal smaller spores. This is further supported by agents to the site of infection. Therefore, surgi- the observation that larger spores can germi- cal debridement of the infected and necrotic nate inside macrophages, whereas macrophages tissue should be performed on an urgent basis can contain smaller spores on phagocytosis. to improve outcome. Among patients with pul- These findings coincide with examples of fungal monary mucormycosis, surgical treatment plus cell size dimorphism contributing to virulence. antifungal therapy greatly improves outcome For example, the human-pathogenic basidio- compared with the use of antifungal therapy mycete Cryptococcus neoformans often produces alone (Tedder et al. 1994). Moreover, surgery mononucleate but polyploid giant/titan cells, was found to be an independent variable pre- which are less susceptible to the host immune dicting a favorable outcome in patients with system (Okagaki et al. 2010; Zaragoza et al. mucormycosis (Roden et al. 2005). Retrospec- 2010). In addition, Coccidioides immitis, an as- tive data support the use of intraoperative fro- comycetous human pathogen, generates signif- zen sections to delineate the margins of infected icantly enlarged multinucleate spherules that tissues, with sparing of tissues lacking evidence enable the fungus to escape the host immune of infection (Langford et al. 1997). system (Huppert et al. 1982; Hung et al. 2007). www.perspectivesinmedicine.org Antifungal Monotherapy Treatment of Mucormycosis Primary antifungal therapy for mucormycosis Four factors are critical to eradicate mucormy- should be based on a polyene antifungal agent. cosis, including the following: (1) early diagno- Amphotericin B deoxycholate (AmB) is the sis; (2) reversal of the underlying predisposing only antifungal agent approved for the treat- factors, if possible; (3) surgical debridement ment of mucormycosis (Kwon-Chung and Ben- when possible; and (4) appropriate antifungal nett 1992; Spellberg et al. 2005; Sugar 2005). therapy. Early diagnosis is critical because small, Mucorales are relatively resistant to AmB, which focal lesions can often be surgically excised be- necessitates the administration of high doses of fore they progress to involve critical structures the drug that are often associated with nephro- or disseminate. Moreover, early initiation of toxicity. However, lipid formulations of AmB polyene therapy within 5 d of diagnosis has can be administered at higher doses because been associated with improvement in survival they are significantly less nephrotoxic, which (Chamilos et al. 2008a). Equally important is makes them likely to be more effective than the correction or control of the mucormyco- AmB(Walshetal.1999;Ibrahimetal.2003;Reed

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et al. 2008). Liposomal amphotericin B (LAmB) concerns about the reliability of achieving ade- is preferred to amphotericin B lipid complex quate in vivo levels of orally administered po- for infections with central nervous system in- saconazole (Ullmann et al. 2006; Krishna et al. volvement based on retrospective survival data 2007a,b,c). Consequently, posaconazole mono- (Gleissner et al. 2004) and evidence of superior therapy cannot currently be recommended as brain penetration in animal models (Groll et al. primary treatment of mucormycosis. In con- 2000; Ibrahim et al. 2008c). In support of these trast, available clinical data from open-label sal- ﬁndings, a retrospective series in patients with vage studies suggest that posaconazole is a rea- rhino-orbital-cerebral mucormycosis receiving sonable option for patients with mucormycosis amphotericin B lipid complex as primary ther- who are refractory to or intolerant of polyenes apy found that these patients had inferior out- (Greenberg et al. 2006; van Burik et al. 2006). comes compared with patients receiving either Posaconazole is also commonly used as “step- AmB or LAmB (Reed et al. 2008). There is no down” therapy among stable patients who have clear advantage of either agent for non–central initially responded to a polyene; however, no nervous system infections. prospective studies have explored this thera- Although itraconazole is considered to be peutic approach. Recent data also demonstrated the ﬁrst marketed azole drug with some in vitro activity of an investigational azole, isavucona- activity against Lichtheimia (Sun et al. 2002), its zole, against Mucorales in vitro (Guinea et al. role in managing mucormycosis is limited be- 2008; Verweij et al. 2009) and in vivo (Luo et al. cause of a lack of activity against Rhizopus spp., 2013a). These data suggest that isavuconazole is the most common pathogens isolated from likely to play a role in managing patients with clinical cases. Fluconazole and the second-gen- mucormycosis in the future. eration broad-spectrum antifungals triazole Finally, R. oryzae has a 1,3-b-glucan syn- and voriconazole are not active against Mu- thase, the target enzyme for echinocandins corales in vitro (Sun et al. 2002). As mentioned (Ma et al. 2009), and this enzyme can be in- above, the prophylactic and therapeutic use of hibited by these agents (Ibrahim et al. 2005a). voriconazole in transplant patients has been as- However, this class of antifungal agents has sociated with breakthrough-disseminated mu- minimal activity against agents of mucormy- cormycosis (Blin et al. 2004; Imhof et al. 2004; cosis when tested in vitro or in experimental Kobayashi et al. 2004; Marty et al. 2004; Kon- mucormycosis (Diekema et al. 2003; Espinel- toyiannis et al. 2005; Oren 2005). In fact, a re- Ingroff 2003; Ibrahim et al. 2005a). cent study showed that in vitro pretreatment of Mucorales with voriconazole, AmB, or caspo-

www.perspectivesinmedicine.org Antifungal Combination Therapy fungin acetate increased the virulence of these organisms in murine and Drosophila models of In murine experimental mucormycosis, poly- mucormycosis (Lamaris et al. 2009). In con- ene–posaconazole combination therapy is not trast, posaconazole is the only Food and Drug superior to polyene monotherapy for mu- Administration–approved azole with broad in cormycosis in mice (Ibrahim et al. 2009), and vitro activity against Mucorales (Dannaoui et al. no comparative data are available for combi- 2003; Spreghini et al. 2010). However, posaco- nation therapy in humans. Therefore, there is nazole is efﬁcaciously inferior to AmB for the no basis for recommending polyene–posaco- treatment of murine mucormycosis and is not nazole combination therapy. Despite the mod- superior to placebo for the treatment of murine est activity of echinocandins against Mucorales infection with R. oryzae (Rodriguez et al. 2008; (Diekema et al. 2003; Espinel-Ingroff 2003; Ibrahim et al. 2009; Luo et al. 2013b). Similar Ibrahim et al. 2005a), the use of this group of results were reported for mice infected with antifungals in combination with lipid formula- Mucor circinelloides (Salas et al. 2012). This tions of AmB improves the outcome of mucor- could be a result of unfavorable pharmaco- mycosis in mice (Spellberg et al. 2005; Ibrahim kinetic/pharmacodynamic data that have raised et al. 2008b). Human data also support the use

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of lipid-formulation AmB and echinocandins, Given the rarity of the disease and the negative albeit from a small retrospective study. Combi- outcome from the phase 2 randomized clinical nation therapy with lipid formulations of AmB trial, a large phase 3 trial to elucidate the role of plus caspofungin was associated with signifi- iron chelators in treating mucormycosis will be cantly improved outcomes for rhino-orbital-ce- difficult to conduct. Alternatively, we believe rebral mucormycosis in diabetic patients com- that patients with a disease as fatal as mucormy- pared with polyene monotherapy (Reed et al. cosis would opt for an experimental treatment 2008). Because the data are very limited, further that might work if they are honestly informed of clinical studies are necessary to determine the the risks and benefits. usefulness of echinocandin combination thera- Some case reports have suggested a success- py in patients with mucormycosis. Echinocan- ful outcome in managing mucormycosis with dins should be administered at standard, Food hyperbaric oxygen as an adjunct therapy. Hy- and Drug Administration–approved doses, be- perbaric oxygen might be useful for treating cause dose escalation results in paradoxical loss mucormycosis in conjunction with standard of efficacy in preclinical models (Ibrahim et al. therapy because higher oxygen pressure im- 2005a, 2008a). proves the killing ability of neutrophils (Couch et al. 1988). Additionally, high oxygen pressure inhibits the germination of fungal spores and Iron Chelation Therapy and Other growth of mycelia in vitro (Robb 1966). Simi- Novel Approaches larly, case reports have described survival of pa- Unlike deferoxamine, which predisposes patients with mucormycosis treated with adjunct tients to mucormycosis via a xenosidero- recombinant granulocyte colony–stimulating phore-mediated iron supply mechanism (Boe- factor and granulocyte macrophage colony– laert et al. 1993), the iron chelator deferasirox stimulating factor or with recombinant interfer- is fungicidal for clinical isolates of Mucorales on-g in conjunction with lipid formulations (Ibrahim et al. 2007). In DKA mice with dis- of AmB (Gonzalez et al. 1997; Kullberg and seminated mucormycosis, combination defera- Anaissie 1998; Ma et al. 2001; Mastroianni sirox–LAmB therapy resulted in synergistic im- 2004; Abzug and Walsh 2004). Granulocyte col- provement of survival rates and reduced fungal ony–stimulating factor–mobilized granulocyte burden in the brain (Ibrahim et al. 2007). Based transfusions have been increasingly used for on these animal data, deferasirox was used suc- refractory mycoses, including mucormycosis cessfully as salvage therapy in several patients (Slavin et al. 2002; Grigull et al. 2006). with mucormycosis, including rhino-orbital- In pathogenic fungi, the Ca2þ/calmodulin- www.perspectivesinmedicine.org cerebral mucormycosis (Spellberg et al. 2009). dependent serine/threonine phosphatase calci- Unfortunately, a randomized, double-blind, neurin is involved in morphogenesis and viru- phase 2 safety clinical trial of adjunctive defer- lence and is a promising target for antifungal asirox therapy (plus LAmB) found excess mor- drugs (reviewed in Chen et al. 2010). The calci- tality in the patients treated with deferasirox neurin pathway is conserved throughout eu- (Spellberg et al. 2012). However, patients in karyotes. Calcineurin consists of two subunits: the deferasirox–LAmB arm were more likely the catalytic A subunit, which has phophatase than placebo patients to have active malignancy, activity; and the regulatory B subunit, which neutropenia, or corticosteroid therapy and less binds to the A subunit for activation of the com- likely to have received additional antifungals, plex. The calcineurin inhibitors FK506 and cy- making the results of this pilot trial less conclu- closporine A synergistically inhibit the growth sive (Donnelly and Lahav 2012). The negative of Mucorales in combination with other anti- result of the phase 2 study came despite the fungal drugs (Dannaoui et al. 2009; Narreddy continuing anecdotal success of the use of de- et al. 2010; Thakur and Revankar 2011). Effica- ferasirox as an adjunct therapy against mucor- cious outcomes were observed for combination mycosis (Soman et al. 2012; Ribeiro et al. 2013). therapy with posaconazole and FK506 in both

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Drosophila and murine cutaneous mucormyco- in higher fungi) at maturity. Asexual repro- sis model systems (Lewis et al. 2013). Another duction occurs by spores formed in sporocarps, study found that FK506 treatment enforces which are multispored sporangia or uni/few- M. circinelloides to grow as its less virulent yeast spored sporangiola that develop in soil or form, rather than its invasive hyphal form (Lee on organic material above ground (Benjamin et al. 2013). In addition, when compared with 1979; Benny et al. 2001). Sporangia develop a other immunosuppressants, FK506 treatment visible, variously shaped columella (a bulbous results in lower rates of mucormycosis among vesicle at the sporangiophore apex), which al- solid organ transplant patients, which further ways protrudes into the sporangium. The exis- suggests that calcineurin inhibitors may control tence of a visible, well-developed columella in mucormycosis (Singh et al. 2009). multispored sporangia counts as the trademark of the Mucorales as a phylogenetically coher- ent (monophyletic) order (Fig. 1) (reviewed in Genomes of Mucorales—Characteristics Voigt 2012; for a phylogenetic overview, see of Mucoralean Genomes: Rhizopus, Mucor, Hoffmann et al. 2013). and Lichtheimia (ex Absidia) Because of the recent appearance of ge- Members of the Mucorales, the most prominent nomic sequences from various zygomycetous order of the fungi formerly described as Zygo- fungi, a comprehensive genome analysis is in mycota, belong to the one of the most ancient progress from the zygomycetes (Entomoph- terrestrial fungal lineages. Morphological traits thorales, Mucorales, and Mortierellales) (Table preserved in amber resemble those observed 1). Large-scale genome projects (e.g., Fungal today, indicating their evolutionary success Genomics Program, 1000 Fungal Genomes (Speranza et al. 2010). Calculations of the diver- Project [1KFG], and Mycocosm performed by gence time of the zygomycetes (here used collo- the U.S. Department of Energy’s Joint Genome quially for zygosporic fungi; formerly termed Institute [DOE-JGI], as well as the Fungal Ge- Zygomycota) from the other fungal lineages us- nome Initiative and the Origins of Multicellu- ing molecular clock estimates suggest the ﬁrst larity Project, which are both carried out at the occurrence of zygomycetous fungi on Earth in Broad Institute of Massachusetts Institute of the Precambrian era, 1200–1400 millionyears Technology and Harvard University) produced ago (Heckman et al. 2001; Blair 2009). More a total of 10 genomes of the mucoralean fungi; conservative estimations place their divergence among those, seven are from human-patho- at 800 million years ago (Fig. 2) (Berbee and genic opportunists. The genomes from M. circi- Taylor 2001). Thus, zygomycetous fungi and nelloides f. lusitanicus strain CBS277.49 (Gen- www.perspectivesinmedicine.org their most prevalent order, the Mucorales, were Bank accession number of the genome project: certainly important elements of ancient terres- PRJNA46717), Phycomyces blakesleeanus strain trial ecosystems (Krings et al. 2013). During this NRRL1555 [(2) mating type; PRJNA61391], long evolutionary history, they became ubiqui- Rhizopus delemar (ex R. oryzae type II strains, tously distributed worldwide and evolved vari- which produce fumaric-malic acid) strain ous modes of nutrition ranging from saprobic RA99-880 (PRJNA13066), and Lichtheimia cor- to facultatively parasitic in fungi and plants and ymbifera strain JMRC:FSU:9682 (PRJEB3978) are occasionally endophytic in plants, eventually completed (ﬁnalized or permanent draft; Table2). becoming an important group of opportunistic, systemic infection–causing pathogens of hu- Rhizopus: The Most Important Genus within mans. the Human-Pathogenic Mucorales The thalli of the Mucorales are composed of substrate mycelium, which is usually extremely The genus Rhizopus is the type genus of the robust and develops vigorously growing aerial family Rhizopodaceae K. Schum. 1984 and hyphae. Fertile hyphae are septate (microporic) develops sporangiophores forming an umbel. and never doliporic (which is exclusively found Each branch forms a secondary umbel that

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Sordaria Neurospora Aspergillus Histoplasma Saccharomyces Candida Schizosaccharomyces Coprinopsis Schizophyllum Suillus Mixia Puccinia Ustilago Funneliformis Glomus Scutellaspora Syncephalis Coemansia Chaetocladium Parasitella Mucor mucedo Blakeslea M. circinelloides Actinomucor Pilobolus Backusella Rhizopus Absidia Cunninghamella Phycomyces Thermomucor Lichtheimia Rhizomucor Fennellomyces Lentamyces Umbelopsis Catenaria Allomyces Entomophthora Orpinomyces Anaeromyces Chytriomyces Mortierella Dissophora Gallus Homo Drosophila Bombyx Hydra Zea Arabidopsis 3000.0 2500.0 2000.0 1500.0 1000.0 500.0 0.0

Figure 2. Timing of fungal divergences using BEAUTi and BEASTassuming a Basidiomycota–Ascomycota split 1200 + 108 million years ago (Heckman et al. 2001). Node bars indicate 95% highest posterior density intervals of node heights. Calculation of diverging times was performed using BEAUTi v1.7.1 and BEAST v1.6.2 (Drum- mond et al. 2012). A reduced 18S rDNA alignment (51 taxa, 1195 characters) was used as input for BEAUTi. BEAUTi was run choosing the substitution model GTR with empirical base frequencies, GTR þ I as site

www.perspectivesinmedicine.org heterogeneity model, and six g categories. The clock model was set to lognormal relaxed clock, estimate turned on. Calibration was performed by assuming a split of Ascomycota and Basidiomycota occurring 1208 + 108 million years ago with normal distribution (Heckman et al. 2001). The generated xml ﬁle was run in BEAST over the CIPRES portal (www.phylo.org). Sampled reasonable trees were summarized with the TreeAnnotater from the BEAST package.

branches dichotomously, one branch termi- tolerant, rhizoid-forming, multispored-sporan- nating in a sporangium and the other in ster- giate Mucor-like fungi. Molecular phylogenetic ile spines, building the rhizoids, which are char- analyses revealed a split into three clades: a ther- acteristic for the genus and abundant among mophilic Rhizopus microsporus group (growth members of the genus (reviewed in Voigt up to 45˚C), a subthermotolerant Amylomy- 2012). Species of the genus Rhizopus are sap- ces–R. oryzae species complex group (growth robes in soil and have importance as biotrans- at 37˚C–40˚C), and a mesophilic Rhizopus sto- forming and food-fermenting agents. Addition- lonifer group (growth below 37˚C). The sub- ally, they can cause disease in plants, animals, thermophilic R. oryzae is the primary cause of and humans. They are predominantly thermo- mucormycosis, hence, a logical initiation point

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Table 1. Zygomycetous genome sequencing projects (as of December 30, 2013) Complete

Order Finished Permanent draft Incompletea Targeteda Entomophthorales 1 0 4 0 Mortierellales 0 1 2 0 Mucorales 4 0 17 0 Source: Entompohthorales: GOLD (Genomes Online Database) at www.genomesonline.org; Mucorales and Mortierellales: NCBI (National Center for Biotechnology Information) at www.ncbi.nlm.nih.gov/genome. aOnly whole-genome sequencing projects.

for the first genome project within the Muco- enzymes, which are essential for fungal cell in- rales. The genome sequence of R. delemar strain tegrity and are absent in mammalian hosts, re- 99-880 (also termed RA 99-880), isolated from a veal potential targets for novel and R. oryzae– fatal case of mucormycosis, was determined by specific diagnostic and therapeutic treatments the Broad Institute (PRJNA13066) (Ma et al. (Ma et al. 2009). R. oryzae comprises a morpho- 2009). This strain was isolated in 1999 from a logically and physiologically heterogenous spe- brain abscess of a diabetic patient who devel- cies complex encompassing the sibling species oped fatal rhinocerebral mucormycosis. The R. oryzae sensu stricto and R. delemar. Phyloge- highly repetitive 45.3-Mb genome assembly netic analyses of genes encoding rDNA, internal contains abundant transposable elements, com- transcribed spacer (ITS), lactate dehydrogenase prising 20% of the genome. The original pro- B, actin, translation elongation factor-1a, and tein prediction reported by Ma et al. comprised genome-wide amplified fragment length poly- 13,895 protein-coding genes, which was verified morphisms resolved the same two exclusive to encode a total of 17,459 proteins (based on clusters, corresponding with the production of the Fungal Genome Collection of the University organic acid as an effective taxonomic character- of Nebraska, Lincoln, School of Biological Sci- ences and Center for Plant Science Innovation Table 2. Completed genome sequencing projects at em-x8.unl.edu/canderson/FungalGenome from the Mucorales and the Entomophthorales, the Collection). The order and genomic arrange- zygomycetous orders with potential to cause ment of the duplicated gene pairs and their mycoses in humans (as of December 30, 2013) common phylogenetic origin provided evidence Finished for an ancestral whole-genome duplication

www.perspectivesinmedicine.org GOLD- NCBI NCBI- event (Ma et al. 2009). The whole-genome du- a plication resulted in the duplication of nearly all ID accession ID subunits of the protein complexes associated Mucorales Gi01096 PRJNA61391 61391 with the respiratory electron transport chains, Gi00506 PRJNA13066 13066 - PRJNA46717 46717 V-ATPase, and ubiquitin–proteasome systems, b as well asthe expansion of multiple gene families - PRJEB3978 - Entomophthorales - C. coronatusc - related to cell growth and signal transduction and secreted aspartic protease and subtilase pro- Source: GOLD at www.genomesonline.org, NCBI at www.ncbi.nlm.nih.gov/genome, and ENA (European Nu- tein families, which are known fungal virulence cleotide Archive) at www.ebi.ac.uk/ena. factors. The duplication of the ergosterol bio- aNumbers for the NCBI-ID refer to NCBI project synthetic pathway (e.g., lanosterol 14a-demeth- identiﬁcation numbers (IDs). ylase [Erg11], the major azole target) was pos- bENA submission of the genome of the mucoralean tulated to contribute to the variable responses fungus Lichtheimia corymbifera JMRC:FSU:9682 to be released in 2014. of R. oryzae to different azole drugs, including cThe genome of the entomophthoralen fungus Coni- voriconazole and posaconazole (Vitale et al. diobolus coronatus JMRC:FSU4392 to be released in 2014 2012). Expanded families of cell-wall synthesis (unpublished and not yet submitted).

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istic. These studies grouped the species complex cies within the genus Mucor with aerial hyphae, into two sibling species: R. oryzae sensu stricto which sense and grow toward light (positively (also known as R. arrhizus) and R. delemar, cor- phototropic). M. circinelloides is ubiquitously relating with lactic acid and fumaric–malic acid distributed and saprobic in soil. Its dispersal oc- production, respectively (Abe et al. 2007). Re- curs through the air, soil, and food. Similar to classification of strains in the fumaric–malic other human-pathogenic Mucorales, M. circi- acid group as R. delemar, and, therefore, reclas- nelloides is an emerging opportunistic pathogen sification of the genome strain R. oryzae 99-880 that causes deep and systemic mucormycosis into R. delemar, was proposed (Gryganskyi et al. in immunocompromised humans. The spore 2010). More genome projects on R. oryzae were size is linked to virulence, and the plasticity of initiated on strains 99-892 (PRJNA186020), the sex locus and adaptations in pathogenicity B7407 (PRJNA184879), HUMC 02 (PRJNA have occurred during speciation of the M. circi- 186018), NRRL13440 (PRJNA186013), and nelloides complex (Li et al. 2011). M. circinel- NRRL21396 (PRJNA186015), with the latter loides exhibits hyphal growth in aerobic condi- two being classified as type 1. In addition tions but switches to multibudded yeast growth to the genome projects on the R. delemar–R. under anaerobic or high-CO2 conditions. The oryzae species complex representing the sub- calcineurin pathway orchestrates the yeast–hy- thermophilic Rhizopus group, further genome phal and spore size dimorphic transitions that projects were initiated on two strains of R. mi- contribute to virulence of this common zygo- crosporus (ATCC52813 and CCTCCM201021) mycete fungal pathogen (Lee et al. 2013). and R. stolonifer strain B9770 (PRJNA184886), The genome of M. circinelloides f. lusitanicus representing the thermophilic and the meso- CBS277.49 (PRJNA46717) was published as a philic groups, respectively (classification in ac- first draft in March 2009 and as a second assem- cordance to Voigt 2012). R. microsporus is tra- bly form in December 2009. In total, 10,930 and ditionally used for brewing alcoholic beverages 11,719 genes were structurally and functionally and fermented foods in China (Wang et al. annotated in the first and second versions of 2013) but is also an important causative agent the draft assembly, respectively, and the annota- of mucormycosis (de Hoog et al. 2000). The tion releases have a genome size of 36.5 Mb (ge- 45,666,236-bp (ca. 45.7-Mb) draft genome se- nome.jgi.doe.gov/Mucci2/Mucci2.info.html). quence of R. microsporus var. chinensis CCT The first version of the genome assembly from CCM201021 (PRJNA179339), isolated from M. circinelloides f. circinelloides strain 1006PhL the leaven Daqu, was determined, annotated, was released in April 2013 by the Broad Institute and released in February 2013 (Wang et al. (PRJNA172437). The genome size is 36.55 Mb, www.perspectivesinmedicine.org 2013). The genome of R. microsporus var. mi- and the GC content is 39.5%. Of atotal of 12,410 crosporus ATCC52813 (PRJNA205957) was re- predicted genes, 12,227 were functionally an- leased in August 2013 as part of the 1KFG proj- notated to proteins (based on information ect. With the exception of the genome from from www.ncbi.nlm.nih.gov/genome/?term¼ R. delemar strain 99-880, all other genomes of Mucorþcircinelloidesþf.þcircinelloides). Rhizopus spp. are incomplete. The size and GC content of the Rhizopus genomes are always Lichtheimia: Non-Rhizopus/Mucor-Like around 45 Mb and 36.9%, respectively. Human-Pathogenic Opportunists The genus Lichtheimia is the type genus of the M. circinelloides: Genome Initiatives of the family Lichtheimiaceae K. Hoffm., G. Walther& Second Most Common Causative Agent of K. Voigt (Hoffmann et al. 2009). Colonies of Emerging Mucormycosis Lichtheimia rapidly grow at temperatures be- M. circinelloides, the type genus of the order tween 37˚C and 42˚C and are predominantly Mucorales, and belonging to the family Muco- thermotolerant until a maximum of 55˚C. raceae Dumort. 1822, develops as any other spe- The hyphae of the substrate mycelia form char-

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L. Mendoza et al.

acteristic tree-like structures among the growth 61391) was finished and released by DOE-JGI front and giant cells, which are never found in in September 2006 (first version) and March any of the other pyriform sporangiate absidia- 2010 (second version). The latest version con- ceous fungi, formerly classified in the genus tains atotal of 16,528 predicted proteins (Fungal Absidia (Hoffmann et al. 2009). Lichtheimia Genome Collection of the University of Ne- spp. are ubiquitously distributed and are sapro- braska, Lincoln, School of Biological Sciences bic decomposers in soil and decaying organic and Center for Plant Science Innovation at matter (e.g., compost, silage, and fermented em-x8.unl.edu/canderson/FungalGenome food), but they have also become of increasing Collection/GenomeSummary). In addition to importance as causative opportunistic agents of NRRL1555 [UBC2 (2)], a wide variety of systemic mycoses in humans. They represent the strains, 20 in total [UBC21 (þ), A893, A905, second and third most common cause of mu- A909, B2, B16, C6, C21, C47, C68, C107 (þ), cormycosis in Europe and worldwide, respec- C109, C110, C149, C307, L151, L153, L157, tively (Roden et al. 2005; Skiada et al. 2011; L161, and L163], are currently sequenced at Lanternier et al. 2012a,b). The genus Lichthei- the DOE-JGI (based on information in GOLD mia encompasses six thermotolerant species: L. at www.genomesonline.org). corymbifera, L. ramosa, L. ornata, L. hyalospora, Within the 1KFG, the genomes of Backusella L. sphaerocystis (Alastruey-Izquierdo et al. circina FSU941 (genome size of 48.65 Mb, 2010), and L. brasiliensis (Santiago et al. 2014). genome.jgi.doe.gov/Bacci1/Bacci1.info.html) The former three are known to be clinically rel- and Umbelopsis ramanniana (genome size of evant (Schro¨dl et al. 2012). Pulmonary Lichthei- 23.08 Mb; genome.jgi-psf.org/Umbra1/Umb mia infections following solid organ transplan- ra1.home.html) were released in July and Sep- tation seem to be associated with a higher risk of tember 2013, respectively. Based on information developing disseminated disease (Sun et al. in GOLD, a variety of genome projects on Rhi- 2009). To gain insight into the genomic differ- zomucor spp. (R. miehei CBS182.67 [Gi17195] ences between these groups of pathogens, the and R. pusillus CBS183.67 [Gi17196]) were ini- type strain of L. corymbifera (JMRC:FSU:9682 tiated by the McGill University and Genome ¼ CBS 429.75 ¼ ATCC46771) was sequenced Quebec Innovation Centre. Both species play and compared to published genomes of other important roles in food fermentation as oppor- fungi comprising several phyla. Comparative tunistic human pathogens (de Hoog et al. 2000). genomics studies on Lichtheimia reveal a large evolutionary distance to all fungal genomes ENTOMOPHTHORAMYCOSIS: THE published until now, providing evidence for ZOOPATHOGENIC FUNGI OF THE www.perspectivesinmedicine.org the hypothesis that L. corymbifera has indepen- ENTOMOPHTHOROMYCOTA dently evolved its ability to infect humans by General Characteristics and Brief developing specific pathogenesis mechanisms Historical Review (Schwartze et al. 2014). If these differences are reflected in the genome, the mechanism may be The mammalian-pathogenic species of the En- revealed through the analysis of the genome of tomophthoromycota comprise members in the the thermotolerant but not human-pathogenic genera Basidiobolus and Conidiobolus (McGin- species L. hyalospora, for which the first assem- nis 1980; Khan et al. 2001; Kwon-Chung 2012). bly version was released by DOE-JGI in the The species of these genera are the etiologic 1KFG project in July 2013 (genome.jgi.doe. agents of entomophthoramycosis, an infection gov/Lichy1/Lichy1.home.html). of humans and lower animals that is restricted to the subcutaneous tissues and rarely involves other organs (Fromentin and Ravisse 1977; Further Mucorales Genome Initiatives McGinnis 1980). They are characterized by the The genome (53.9 Mbp in size) of P. blakeslee- production of a variety of spores in nature anus NRRL1555 [(2) mating type; PRJNA and in vitro, a property that has been used for

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the taxonomic separation of species, but in the The investigators recovered a strain of Basidio- past it has also fueled taxonomic controversies bolus ranarum from two children with subcu- (Kwon-Chung 2012; Gryganskyi et al. 2013). taneous infection. Numerous other cases have The mammalian-pathogenic species within the been diagnosed since the initial report (Mc- Entomophthoromycota are characterized by Ginnis 1980). Disseminated and intestinal in- the production of slow-growing tumoral-like fections caused by Basidiobolus have been also masses in the infected tissues that in some cases reported (Gugnani 1999). Subcutaneous infec- remain indolent for years. The area most com- tions involving Conidiobolus coronatus were first monly affected by Conidiobolus species is the observed in 1961 by Bridges et al. (1962) in four face (generally around the nose) (McGinnis horses in Texas, and in humans 4 years later 1980), whereas Basidiobolus species are fre- (Bras et al. 1965). However, the first case of quently found on limbs, the intestinal tract, human nasofacial involvement without culture and rarely in other body areas. was recorded by Blanche´ et al. in 1961. The first The majority of the fungi causing entomo- recorded cases of Conidiobolus incongruus in phthoramycosis develop short or long, broad humans took place in 1970 (Gilbert et al. (ribbon-type), sparsely septated hyphae in 1970), and the recovered organism was properly the infected host tissues and produce different identified by King and Jong (1976). Conidiobo- types of asexual spores in culture (McGinnis lus lampragues was first recognized as an etio- 1980; Kwon-Chung 2012). The sexual spores logic agent of entomophthoramycosis in a have also been found in recently isolated strains horse with subcutaneous infection (Humber from clinical cases of the disease, but they are et al. 1989) and more recently in sheep and usually lost after several subcultures (Kwon- humans (Vilela et al. 2010; Kimura et al. 2011). Chung 2012). A typical feature of these pathogens in the infected host’s tissues is the produc- Systematic Position and Nomenclature tion of a red-colored reaction around the invading hyphae known as the Splendore–Hoeppli Recent phylogenetic studies of fungi previously phenomenon (Kimura et al. 2011; Kwon-Chung placed within the obsolete phylum Zygomycota 2012). Interestingly, this phenomenon has been (Kwon-Chung 2012) indicated that the zoo- also encountered in mammalian tissues infected pathogenic genera Basidiobolus and Conidio- by parasites (Miller and Campbell 1984; Ki- blous are now considered members of the newly mura et al. 2011) and around the hyphae of created monophyletic phylum Entomophthor- the fungal-like mammalian-pathogenic oomy- omycota (Gryganskyi et al. 2013). The Ento- cetes Pythium insidiosum and Lagenidium spp. mophthoromycota comprises three classes: www.perspectivesinmedicine.org (Miller and Campbell 1982; Mendoza and Vilela Basidiobolomycetes (Basidiobolus spp.), Neozy- 2013). This phenomenon has previously been gitomycetes (Neozygitis spp.), and Entomoph- used to separate the genera Basidiobolus and thoromycetes (Conidiobolus spp., Completoria Conidiobolus from other fungi in the absence spp., Entomophthora spp., and others). The pro- of culture (Guarro et al. 1999; Gugnani 1999; posed taxonomic and phylogenetic changes Kwon-Chung 2012). However, this practice is placed the genus Basidiobolus within the class inappropriate because the above-mentioned Basidiobolomycetes, order Basidiobolales, fam- zoopathogenic oomycetes also develop a similar ily Basidiobolaceae (Humber et al. 1989; Kwon- reaction in the tissues of their infected hosts Chung 2012; Gryganskyi et al. 2013), whereas (Mendoza and Vilela 2013). the genus Conidiobolus is placed within the Van Overeem reported the first known case class Entomophthoromycetes, order Entomo- of an infection caused by a member of the En- phthorales, family Ancylistaceae (Gryganskyi tomophthoromycota in 1925 in Indonesia from et al. 2013). Under this new nomenclature, the a fistular ulcerated lesion on a horse limb. The old terminology—phycomycosis, rhinophyco- second case occurred in humans and was also mycosis, zygomycosis, rhinozygomycosis, and diagnosed in Indonesia (Kian Joe et al. 1956). others—used to name the diseases caused by

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Basidiobolus and Conidiobolus species is no in fungal infections in insects or in apparent longer supported (Kwon-Chung 2012). How- association with amphibians and reptiles with- ever, the epithets “basidiobolomycosis,” “coni- out active disease (Groff et al. 1991). The species diobolomycosis,” and “rhinoconidiolomycosis” in this phylum are commonly found in plant do not contradict the new classification and will detritus, where they could associate with insects probably remain in use. or mammals by producing forcibly ejected Vilela et al. (2010) conducted the first phy- sticky conidia that attach to the cuticle of insects logenetic analysis of the pathogenic Conidiobo- or to the skin of mammals. They are among the lus spp. using 18S rDNA sequences, a study con- most aggressive pathogens of insects and invade firmed a few months later (de Paula et al. 2010). the whole insect body; the infecting fungus then In their analysis, DNA sequences from three bursts through its exoskeleton and produces strains of C. coronatus clustered with Conidio- more sticky conidia at the ends of single spo- bolus firmipilleus; in turn, this cluster was a sis- rangiophores (King 1983; Werner et al. 2012). ter group with strong bootstrap support to Amphibians and reptiles could come in contact C. incongruus and Conidiobolus brefeldianus. C. with these fungal species by ingesting infected lampragues clustered in a long branch to Con- or colonized insects; the fungi thus become part idiobolus osmodes, Conidiobolus pumilus, Coni- of the creature’s intestinal flora. Few reports of diobolus rhysosporus, and Conidiobolus throm- amphibians affected by these species have been boides. B. ranarum was used as an outgroup in published (Groff et al. 1991). B. ranarum has the analysis. This result suggests that C. corona- been recovered from the intestinal content of tus and C. incongruus share more phylogenetic frogs and lizards and from their dung (Drech- similarities with each other than with C. lamp- sler 1956). C. coronatus and C. incongruus have ragues. Nie et al. (2012) and Jensen et al. (1998), been isolated from plant detritus and insects using 18S small-subunit rDNA and 28S rDNA (King and Jong 1976; Jensen et al. 1998). C. sequences and additional Conidiobolus species, incongruus was also found as a nosocomial reported that C. coronatus formed a well-sup- agent from a case of systemic entomophthora- ported sister cluster to C. firmipilleus, a finding mycosis (Walsh et al. 1994). C. lampragues has in agreement with previous studies (Vilela et al. only been recovered so far from infected mam- 2010). Unfortunately, this phylogenetic study mals, but it probably colonizes decaying vege- did not include more pathogenic species. Thus, tables and may also be present in soil of the areas a more comprehensive study including both of endemicity (de Paula et al. 2010; Vilela et al. saprophytic and zoopathogenic species is neces- 2010; Skiada et al. 2012). sary to better understand this interesting group Both Conidiobolus spp. and Basidiobolus www.perspectivesinmedicine.org of pathogens in the Entomophthoromycota. spp. are thermophilic fungi. Thus, these species Based on allelic variation, recent genomic are more commonly found in tropical and sub- analysis of B. ranarum showed that the nuclear tropical humid areas. When conditions of high genome is probably diploid with a putative ge- humidity, sunlight, and high temperatures exist, nome size of 700 Mb (Henk and Fisher 2012). their single sticky conidia are ejected and then The study found also redundancy in its elonga- attach to the skin of passing insects or animals, tion factors overlapping the paralog EF-1a. The including mammals. Entomophthoramycosis investigators speculate that genome duplication has been recorded in the subcutaneous and is an important feature favoring the preserva- intestinal tissues of apparently healthy or im- tion of overlapping genes in B. ranarum (Henk munocompromised hosts and less frequently and Fisher 2012). has been found to cause systemic infections (McGinnis 1980; Kwon-Chung 2012). Thus, it is believed that the species of these fungi can Ecology and Epidemiology only reach the subcutaneous tissue of their in- The ecological niche of the species in the phy- fected hosts through open skin or through small lum Entomophthoromycota has been studied abrasions in the intestinal tract (McGinnis

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HFPs of Mucorales and Entomophthorales

1980). The infection has been more frequently particular strain as a smooth zygospore produc- reported in the tropical and subtropical areas of er; reports of mammals affected by this species Asia, Africa, and the Americas (Martinson and appeared in the 1980s (Vismer et al. 1980). In Clark 1967; Londero et al. 1979; Kelly et al. 1980; 1962, Benjamin proposed another species, Ba- Gugnani 1999). sidiobolus microspores, based on the development of multiple sharp elongate “microspores” Taxonomic Description of the Mammalian from globose conidia and stretched zygospores. Pathogens Basidiobolus and Conidiobolus B. microspores is the only species that can be Species properly differentiated from other species because of its unique broad base and fine elongate Basidiobolus spp. replicative “microspores” on top of primary co- Since the introduction of the genus Basidiobolus nidia (Benjamin 1962). by Eidam in 1886, the description of the zoopa- The use of classical tools during the descrip- thogenic species in this genus has been always tion of the strain isolated from the first human contentious. Eidam used the described strain case caused by Basidiobolus spp. proved that B. ranarum as the type species for the genus; traditional methodologies are inaccurate (Kian thus, it has priority over other epithets suggest- Joe et al. 1956; McGinnis 1980; Kwon-Chung ed later (Eidam 1886). Based on the production 2012). Kian Joe et al. (1956) described undulat- of zygospores and other characteristics, Eidam ed outer cell walls of zygospores, and thus the introduced two new species: B. ranarum (zygo- strain was identified as B. ranarum. However, spores with undulating and smooth outer cell some had challenged their observations because walls) and B. lacerate (smooth zygospores sim- some figures were not clear, and the strain seems ilar to those of B. ranarum). In the original to display both undulated outer cell walls and description, Eidam noted that B. ranarum was mostly smooth outer cell walls of zygospores the first saprophytic organism recovered from (McGinnis 1980). Drechsler studied the same frog excrement, whereas B. lacerate was isolated strain and, based on the presence of smooth in lizard excrement. This fact and differences in zygospores, determined (Drechsler 1956) that morphological features convinced Eidam that it was very similar to Basidiobolus meristospo- both isolates were unrelated, and thus he de- rus (Thasnakorn et al. 1969). Numerous studies scribed them as different species. A study per- on the original isolate from the first human formed later by Levisohn and others on the two cases of basidiobolomycosis had suggested Basidiobolus species introduced by Eidam con- that the species B. haptosporus (Drechsler cluded that the appearance of the outer cell wall 1947; Srinivasan and Thirumalachar 1965), Ba- www.perspectivesinmedicine.org of the B. lacerate zygospores was identical to that sidiobolus heterosporus (Srinivasan and Thiru- of B. ranarum and, therefore, it “should bear the malachar 1965), B. lacerate (Eidam 1886), name B. ranarum” (Levisohn 1927; Fitzpatrick B. meristosporus (Drechsler 1956), and similar 1930; Drechsler 1956). species should be all treated as synonyms of The Streptomyces-like odor and the capaci- B. ranarum (McGinnis 1980; Gugnani 1999). ty to grow at different temperatures was a fea- B. microsporus, on the other hand, can be prop- ture first described by Drechsler in some strains erly separated from B. ranarum (Benjamin of Basidiobolus spp., characteristics also used to 1962). separate Basidiobolus species (Drechsler 1953; The cell cycle of the family Basidiobolaceae Greer and Friedman 1966; McGinnis 1980). is complex. Members of the family developed However, these physiological characteristics different types of phenotypic structures de- are variable among species, and some strains pending on their environmental conditions. possess one or more of these features, making They can also be readily recovered in culture their identification more difficult (Gugnani from contaminated environmental sources as 1999). In 1947, Drechsler introduced the species well as from clinical cases of basidiobolomyco- Basidiobolus haptosporus and described this sis (Srinivasan and Thirumalachar 1965; Skiada

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L. Mendoza et al.

et al. 2012). The genus Basidiobolus is not a cultured in special media, forming globose, traditional pathogen of insects but some species dividing, septate cells similar to those observed can be easily recovered from the intestinal con- in the unicellular algae (see Fig. 3Af, within the tents of amphibians and reptiles (Eidam 1886). circled part at the top). These structures are Based on this fact, some have hypothesized that known as “palmella” because of their morpho- some species could affect insects or perhaps that logical resemblance to algal cells (Levisohn insects only act as host carriers of Basidiobolus 1927). species, especially mites (Ingold 1934; Werner In laboratory culture (Fig. 3A) and in na- et al. 2012). The mechanism of conidium ejec- ture, the development of a colony from existing tion is different from that of Conidiobolus (In- conidia and/or meristospores could lead to the gold 1934; Yafetto et al. 2008). In Basidiobolus commencement of the sexual stage. Zygospore spp. (Fig. 3A), the formation of a uninucleate production is initiated by the formation of septa “ballistoconidium” on top of a simple conical in adjacent hypha (Fig. 3Ag), both of which columella is observed before ejection (Fig. 3Aa). develop small protuberances at the site of zygo- At maturity, a subconidial vesicle develops that spore formation (Fig. 3Ag–j and Fig. 4B,C). becomes turgid because of the pressure exerted Parallel beaks are formed, in which a nucleus by the accumulation of liquid within this re- migrates and divides on each side (Eidam gion (Fig. 3Ab). Under appropriate environ- 1886). One of the two nuclei at the tip of the mental conditions (light, humidity, and oth- beak eventually disintegrates, and the other mi- ers), the pressure results in weakness at the grates back into the mother hyphal cell. Mean- base of the elastic subconidial structure, which while, the hypha closes and the formed beaks is forcibly ejected along with the conidium (Fig. enlarge in size; a pore is then formed that allows 3Ac) (Dykstra 1994). The structure remains at- the second nucleus to enter the enlarged forma- tached to the ejected conidium during the ex- tion (Fig. 4E). Fusion of the nuclear structures pulsion, but could be detached after landing occurs, forming a zygospore with prominent (Ingold 1934; Yafetto et al. 2008). Ingold found cell walls (Fig. 4C). Mature zygospores (25– that the distance that Basidiobolus conidia trav- 50 mm) may have undulate and/or smooth eled was between 1 and 2 cm (Ingold 1934). cell walls (Kian Joe et al. 1956; Gugnani 1999); Thus, the ejected primary conidia (see Basidio- both types of cell walls have been recorded in the bolus conidia release below) could attach to same strain (McGinnis 1980). Thus, this taxo- mites, other invertebrates, and mammals (Fig. nomic characteristic could lead to misidentifi- 3A, center). Some conidia can be ingested by cation. Within the zygospore, meiosis occurs to other invertebrates, such as beetles, and the bee- form four haploid nuclei, of which only one www.perspectivesinmedicine.org tles in turn can then be ingested by vertebrate survives. At germination, the zygospore could animals such as amphibians or reptiles (Ingold develop coenocytic hyphae or sporangiphores 1934; Gugnani 1999). Once in the intestinal from which ballistoconidia could be formed, tract of these animals, the primary conidia di- and the life cycle is repeated. Figure 3A depicts vide by fission into several cells (sometimes the life cycle of Basidiobolus spp. .50) that are termed meristospores (Fig. 3Af ) and can be released in the feces of their Conidiobolus spp. vertebrate hosts. Meristospores can survive extreme environmental conditions for several Species of the genus Conidiobolus have been iso- months. Meristospores are then released within lated from dead insects, decaying leaves, keratin, the excrement of their vertebrate hosts, and living ferns, rotten vegetables, and soil (Kwon- they produce coenocytic mycelia and simple Chung 2012; Nie et al. 2012). The genus name sporangiphores, in which new ballistic conidia was introduced by Brefeld in 1884 (Brefeld will form (Fig. 3Ad). Elongated secondary bal- 1884). Two species, Conidiobolus utriculosis and listoconidium can become large cells that con- Conidiobolus minor, were proposed in this study, tinue to replicate by binary fission when sub- with C. utriculosis as the type species for the

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HFPs of Mucorales and Entomophthorales

A Basidiobolus ranarum

Gut of amphibians and reptiles f f Amphibian dung in nature d Insects g Plant detritus Mammals small skin cuts h c e Invading hyphae Splendore–Hoeppli i phenomenon

b Basidiobolomycosis

In vitro culture a j

B Conidiobolus spp. g

Insects Nature

e Plant detritus h d

Mammals small skin cuts c f i

Invading hyphae Splendore–Hoeppli phenomenon

www.perspectivesinmedicine.org j b

Conidiobolomycosis

In vitro culture k

a l

Figure 3. The life cycles of the representative species that cause entomophthoramycosis. (A) The life cycle of Basidiobolus ranarum. The life cycle starts after a single sporangiophore (a and b) forcibly ejects a conidium (c and d) or after the formation of an elongated sticky “capilliconidium” with a terminal sticky beak (e). Insects or other animals, including mammals, could come into contact with these sticky conidia. Some reptiles and amphibians feed from insects carrying these spores, and a new cycle begins inside their gut ( f ). Levisohn (1927) observed that a single conidium divided and could produce .50 small spores (meristospores), which could survive in dry environments. (Legend continues on following page.)

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L. Mendoza et al.

genus. Unlike the genus Basidiobolus, numerous in culture by the development of spherical yel- species (around 33 species [Nie et al. 2012]) have lowish zygospores, 15–40 mm in diameter. Each been described; some have been recovered from contains numerous globules on maturation dead insectsand mites and others are parasites of (Figs. 3Bj and 5D). The large size and the mul- mammals, including C. coronatus (Walker et al. tiple globules within the zygospore of C. in- 1992; Fischer et al. 2008; Yang et al. 2010), C. congruus are the features that can be used to incongruus (Walsh et al. 1994; Temple et al. differentiate the species from C. lampragues, 2001), and C. lampragues (Vilela et al. 2010; Ki- which produces smaller zygospores (12–18 mm mura et al. 2011). Because of their distinctive in size) that contain homogeneous single phenotypic features, most agree on the proper globules (Fig. 5E). C. incongruus can also de- identification among the mammalian-patho- velop single or multiple secondary multiplica- genic speciesthat cause conidiobolomycosis. Vi- tive conidia similar to those of C. coronatus (Fig. lela et al. described major morphological char- 5B,C). C. lampragues has been recovered from acteristics displayed by mammalian-pathogenic humans, horses, and sheep (Humber et al. 1989; Conidiobolus spp. in culture (Vilela et al. 2010) de Paula et al. 2010; Vilela et al. 2010; Kimura that could be used as a guide to properly char- et al. 2011). Single and secondary conidia sim- acterize the isolates. ilar to those of C. coronatus and C. incongruus According to this proposal, the mammali- have been also found in C. lampragues (Fig. 5F). an-pathogenic species could be separated as fol- However, multiplicative conidia surrounding a lows: (1) C. coronatus develops villose conidia primary conidium, similar to those shown in (Fig. 3Bf ) especially on water agar cultures from Figures 3Bc and 4G, have not been encountered solitary sporangiophores (Figs. 3Ba,b,g and 4F, in C. lampragues. Conidiobolus spp. that are lower part and in the inset). The other two spe- pathogenic to mammals develop conidia at the cies, C. incongruus and C. lampragues, do not apices of primary sporangiophores that are then produce villose conidium. This unique conidi- forcibly discharged. These conidia (Fig. 3Bd) um is characterized by its spherical shape with are globose to pyriform and have species-specif- numerous short filament-like projections that ic morphological features. For instance, C. in- may or may not cover the entire surface (Fig. congruus develops conidia with sharp pyriform 4F, lower part and in the inset). Conidia of papilla (Fig. 5A,C), whereas in C. coronatus (Fig. C. coronatus can also produce secondary conidia 4F) and C lampragues (Fig. 5F,G),this protuber- by replication that cover the surface of the pri- ance is smooth. mary conidia, known as multiplicative conidia Although the life cycle of Conidiobolus spp. (Figs. 3Bc and 4G). The secondary conidia are (Fig. 3B) is similar to that of Basidiobolus (Fig. www.perspectivesinmedicine.org smaller than primary conidia. In addition, the 3A), key differences exist. Conidiobolus spp. de- development of zygospores is absent in C. coro- velop a different type of asexual conidia (King natus. (2) C. incongruus can be readily identified 1983). For example, C. coronatus produces at

Figure 3. (Continued.) After being released into the environment, they develop short mycelia and produce single sporangiophores; alternatively, the nuclei in the same hyphae could exchange genetic material and develope zygospores (g–j). They can also develop into structures called palmella, which resemble green algae. Mammals inhabiting areas of endemicity can contact B. ranarum propagules through trauma and develop zygomycosis (center). (B) The life cycle of the pathogenic Conidiobolus species. A single conidiophore develops terminal conidia (a and b), which are forcibly ejected (d) using a mechanism different from that in the genus Basidiobolus (see taxonomy) and geminate (g). Most species that are pathogenic to mammals can develop replicative conidia (c and e), but the “villose” conidia ( f ) can only be found in C. coronatus. These conidia could develop more sporangiophores or repeat the cycle, or the nuclei of the same coenocytic hyphae could form a septum and develop into a zygospore (h–l ). Drawings of k and l are examples of C. lampragues and C. incongruus zygospores, respectively.

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HFPs of Mucorales and Entomophthorales

or multinucleate conidia that are produced at the apices of simple solitary sporangiophores, which emerge from vegetative coenocytic hyphae (Fig. 3Ba). Conidiobolus spp. eject their conidia by the cell wall invagination pressure exerted at the base of the sporangiophore, which causes a sudden eversion of this portion of the cell wall (Fig. 3Bb). The conidia on the sporangiophore of Conidiobolus spp. have a strong phototropism that stimulates their release (King 1983). The eversion of the conidial cell wall in contact with the sporangiophore results in the species-speciﬁc morphology of conidial papilla (Fig. 3Bd). The formation of zygospores occurs in the same hyphae, as illustrated in Fig. 3Bh–l; “k” shows a C. lampragues zygospore, and “l” depicts the zygospore of C. incongruus. Figure 4. Mycological and clinical aspects of Basidio- bolus ranarum.(A) A culture of B. ranarum on 2% Sabouraud dextrose agar after 4 d incubation at 37˚C. Note the small colonies formed by forcibly ejected conidia growing around the edges of the culture. (B) Coenocytic hypha of B. ranarum forming the ﬁrst septum and the elongation across the plane in which the future zygospore will develop. (C) Three mature zygospores with thick walls and their prominent beaks. Note the Splendore–Hoeppli phenomenon around the empty, round hyphal structures in a histological section (D, arrows). (E) Single replicative conidium formation in Conidiobolus coronatus.(F) C. coronatus conidiawith atypical basal papilla, which marks the residual section formed after ejection. The inset of panel F shows a villose conidium. (G) C. coronatus multiplicative secondary conidia around

www.perspectivesinmedicine.org a single conidium. The left portion of panel G shows a sporangiophore before conidium discharge. The inset depicts two multiplicative conidia. (H ) The eosinophilic inﬂammatory response and longitudinal sectioned hyphae of C. coronatus surrounded by an eosinophilic reaction. The presence of numerous Figure 5. Mycological characteristics of Conidiobolus eosinophils (arrows) is noted. (I) A young boy with incongruus.(A) Three C. incongruus conidia with bilateral rhinofacial infection caused by C. coronatus. characteristic sharp papillae. (B) An example of mul- Note the scar of the biopsy performed for diagnostic tiple replicative conidia of C. incongruus.(C)Aco- purposes. (Courtesy of Rafael Isa-Isa and Roberto nidium with a sharp papilla and a single secondary Arenas.) Scale bars, 25 mm(B); 10 mm(C); 18 mm replicative conidium. (D) Characteristic thick-walled (D); 15 mm(E,G); 23 mm(F); 19 mm(H ). zygospores of C. incongruus containing multiple hyaline globular structures in their cytoplasm. (E) Mul- tiple zygospores of C. lampragues with homogeneous cytoplasm. (F and G) C. lampragues conidia with least four types of asexual conidia (King 1977). smooth papillae and the formation of a hypha from Some members of the genus (except C. corona- a primary conidium, respectively. Scale bars, 14 mm tus) readily develop zygospores (sexual spores). (A); 20 mm(B); 15 mm(C,F); 28 mm(D); 17 mm The life cycle starts with the formation of uni- (E); 17 mm(G).

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Pathogenesis and Clinical and Pathological ture), a pathogen that mainly affects the subcu- Features taneous tissues and the intestinal tract of sus- Pathogenesis ceptible hosts and less frequently internal organs (Dworzack et al. 1978; Gugnani 1999; The infection of mammalian species with the Kwon-Chung 2012). The first published case members of Entomophthoromycota begins of Basidiobolus infection occurred in an Indo- with the attachment of an ejected sticky spore nesian horse, causing an ulcerative subcutane- into or near an open wound. The use of plants ous infection in one of the horse’s limbs (Van for play or to cover body parts has been impli- Overeem 1925). Kian Joe et al. diagnosed the cated as a possible mode of infection acquisition first cases of basidiobolomycosis in humans 31 (Gugnani 1999). The route of intestinal infec- years later, again in Indonesia (Kian Joe et al. tion caused by Basidiobolus spp. is more likely 1956). The cases were described as swelling the ingestion of food containing pathogenic masses in the subcutaneous pectoral region on propagules. As the pathogen is known to invade 4- and 8-yr-old boys (Kian Joe et al. 1956). The the intestines and adjacent tissues (de Aguiar infection started 6 mo earlier as small nodules et al. 1980; Khan et al. 2001), the presence of (papules) that slowly progressed to cover most small cuts in the mucosal surface of the intestine of the thoracic area. Remarkably, the patients is a more likely scenario for pathogen access to did not have fever or pain, and their general the intestinal mucosa. Once the conidia attach conditions were considered good. These cases to open surfaces and are stimulated by host tem- can be used to illustrate the typical clinical fea- perature, they germinate and penetrate open tures encountered in most subcutaneous basi- skin or small cuts on the mucosal surface (Fig. diobolomycosis cases, with the enlargement of 3A,B, life cycle). Susceptible hosts stimulated by regional lymph nodes sometimes mimicking release of antigens from germinating conidia Burkitt’s lymphoma (Bittencourt et al. 1982). trigger a local inflammatory response com- The anatomical distribution of the lesions in- posed of neutrophils, active macrophages, and cludes upper and lower limbs, thorax, and ab- eosinophils (Th2) but the pathogens seem to domen, and more rarely the neck, trunk, and survive this initial attack and further spread to face (Koshi et al. 1972; Gugnani 1999). The skin adjacent tissues. Detection of interleukin 10, on the subcutaneous tumor-like masses does interleukin 4, and tumor necrosis factor a, all not indent when pressure is applied. The disease cytokines related to the Th2 immunogenic re- occurs predominantly in male children (1–20 sponse to B. ranarum infection, tend to con- year old) and less frequently in adults. Histor- firm the presence of a typical Th2 response in ically, in some African countries, the male-to- www.perspectivesinmedicine.org the infected tissues triggered by members of female ratio of basidiobolomycosis patients was the Entomophthoromycota (Khan et al. 2001). 3:1, whereas in other countries it was as high The production of eosinophilic material around as 3:2 (Blanche´ et al. 1961). Basidiobolomyco- the invading hypha (Splendore–Hoeppli phe- sis has been also recorded in horses (Miller nomenon) is apparently formed by the de- and Campbell 1982) and dogs (Miller 1985). granulation of eosinophils and mast cells over Although the subcutaneous form of the disease both Basidiobolus and Conidiobolus invading could slowly spread to adjacent tissues, it is con- hyphae, in the same manner as previously re- sidered a benign disease with a high morbidity ported in infections caused by Lagenidium spp. but low mortality rate (Edington 1964; Gugnani and P.insidiosum (Gugnani 1999; Mendoza and 1999). However, in unusual cases with the Newton 2005; Mendoza and Vilela 2013). involvement of internal anatomical sites, the clinical signs are difficult to interpret; the intestinal form of basidiobolomycosis is one such Clinical and Pathological Features example. Basidiobolomycosis. Basidiobolomycosis is Although subcutaneous basidiobolomyco- caused by B. ranarum (see above nomencla- sis is relatively easy to recognize, the intestinal

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form is difficult to diagnose because the symp- rial known as the Splendore–Hoeppli phenom- toms are nonspecific. Moreover, there are no enon (see above). Fibrotic tissue containing nu- distinct risk factors and it does not occur in merous eosinophilic micro-abscesses and giant a specific age group (Khan et al. 2001). Some cells can be found. A characteristic feature of intestinal basidiobolomycosis cases have been the infection is the presence of longitudinal diagnosed in apparently healthy hosts, whereas and transversal 4- to 12-mm B. ranarum hyphae others have been recorded in patients with pre- surrounded by an eosinophilic hyaline material disposing factors or problems with the immune at the center of the eosinophilic micro-abscess- system (Khan et al. 2001; Kimura et al. 2011). es (Owen et al. 1985; Gugnani 1999). Infiltra- The first case of intestinal basidiobolomycosis tion of blood vessels by this pathogen is uncom- was reported by Onuigbo and Gugnani (1976). mon; in contrast, members of the Mucorales After this report, several other cases have been are consistently found in the lumen of blood diagnosed without culture, using the distinc- vessels and cause vascular thrombosis (Ribes tive Splendore–Hoeppli phenomenon as a et al. 2000). clue for diagnosis. The first patient with intestinal basidiobolomycosis confirmed by culture Conidiobolomycosis was published 6 years later (Schmidt et al. 1986) after the report of de Aguiar et al. (1980). Some Although .33 Conidiobolus spp. have been de- of the clinical symptoms related to B. ranarum scribed, only three have been reported as agents intestinal infection previously reported by oth- of conidiobolomycosis in humans and lower ers include (1) epigastric abdominal pain; (2) animals: C. coronatus, C. incongruus, and C. low fever; (3) bloody mucous diarrhea; and lampragues. Infections caused by Conidiobolus (4) the presence of tumor-like masses in the spp. are largely restricted to the subcutaneous stomach and intestinal tissues and sporadic in- tissues of the face, typically around the nose, volvement of the regional lymph nodes, liver, and rarely on other anatomic areas (Fig. 4I) and pancreas (Onuigbo and Gugnani 1976; (Onuigbo and Gugnani 1976). However, dis- de Aguiar et al. 1980; Pasha et al. 1997). In- semination to internal organs has been reported testinal basidiobolomycosis could mimic in- (Onuigbo and Gugnani 1976; Walshet al. 1994). flammatory bowel disease, colon carcinoma, The clinical location of the lesions caused Crohn’s disease, and intestinal mucormycosis by B. ranarum and Conidiobolus spp. tends (Onuigbo and Gugnani 1976; Bittencourt to differ. The main clinical and pathological et al. 1982; Pasha et al. 1997; Gugnani 1999; characteristics of each species are highlighted Hassan et al. 2013). In addition, unusual cases below. www.perspectivesinmedicine.org of B. ranarum affecting lungs (Bittencourt et al. 1980), lymph nodes (Kamalam and Thambiah C. coronatus 1979), maxillary sinus and palate (Dworzack et al. 1978), and muscles (Kamalam and Tham- The classical clinical features of C. coronatus in- biah 1982) have been also recorded. Secondary fection were first described in a man with rhi- bacterial infection of the ulcerated tissue is nofacial swelling in south Cameroon (Blanche´ common. et al. 1961). It is now apparent that C. coronatus Biopsied tissue of the tumor-like masses infection in mammals is often observed in the must be collected for histopathology and the nasal area of susceptible hosts (Isa-Isa et al. clinical laboratory. Histological sections of the 2012); this is a characteristic also present in in- affected tissue stained with hematoxylin and fections caused by the other two Conidiobolus eosin show the typical inflammatory reaction, spp. that infect humans, horses, and sheep including numerous eosinophils, mast cells, (Hernandez et al. 2007; Fischer et al. 2008; Ki- neutrophils, and lymphocytes. Some eosino- mura et al. 2011). Bridges et al. (1962) reported phils seem to fuse their granules to the invading cases of horses developing tumor-like masses hyphae, forming an eosinophilic hyaline mate- around the nares causing obstruction of the na-

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sal passages. Since the initial reported cases, nu- weight loss (Humber et al. 1989). At necropsy, merous additional cases have been reported an 8-cm mass was found in the rear palate and in horses (Mendoza and Alfaro 1985). Interest- near the pharyngeal area. Numerous small mas- ingly, small masses, termed “kunkers” by some, ses (kunkers) were also found in both guttural are recovered only from the tissues of infected pouches (see section on Laboratory Diagnosis horses (Mendoza and Alfaro 1985); these soft below). The clinical features of the first cases of masses have not been described in humans. conidiobolomycosis caused by C. lampragues Most diagnosed human cases of C. coronatus in sheep were published by Riet-Correa et al. infection are in African adults; however, cases (2008) in Paraiba, Brazil. The proper identifi- have also been reported in Asia and Latin Amer- cation of the etiology using molecular and tax- ica (Bittencourt et al. 1979; Yanget al. 2010; Isa- onomic tools was described in a later report Isa et al. 2012). Cases of conidiobolomycosis (Vilela et al. 2010). The description of C. lamp- in the United States and Australia have been ragues in sheep from Mato Grosso, Brazil, was diagnosed mainly in horses and dogs (Miller published shortly after (de Paula et al. 2010). and Campbell 1982). The affected anatomical areas were the rhino- In humans, C. coronatus infection starts facial and rhinopharyngeal areas. The clinical with a small subcutaneous nodule, caused by signs of rhinofacial conidiobolomycosis were invading hyphae, in the rhinofacial area that prominent swelling of the nostrils and face, dys- slowly invades the adjacent tissues and becomes pnea, and bilateral serosanguineous discharge bilateral, affecting both sides of the nose (Fig. (Riet-Correa et al. 2008). Sheep with the rhi- 4I). The swelling can spread to the cheek, eyes, nopharyngeal form of the disease developed upper lip, pharynx, and sinus. Thus, nasal ob- mechanical obstruction of the nasal cavities, struction, rhinorrhea, epistaxis, and weight loss swelling of the nose, and serosanguinous dis- are common features of the disease (McGinnis charge. Some of the affected sheep showed 1980; Yang et al. 2010; Isa-Isa et al. 2012). In exophthalmia, keratitis, and corneal ulceration severe chronic cases, bacterial sinusitis is an (Riet-Correa et al. 2008). Dense yellow exudates unwelcome complication of the infection. In- were observed on the turbinate bones, paranasal fected hosts may be exposed to environmental sinus, soft palate, orbital cavity, and pharynges. C. coronatus propagules through small cuts in The regional lymph nodes and muscular tissues the skin (see the section on Ecology and Epide- were also involved. P.insidiosum was also found miology above). Cases of C. coronatus systemic to affect the rhinopharyngeal tissue of Brazilian involvement have also been recorded (Walker sheep, indicating that an accurate differential et al. 1992). diagnosis is essential for appropriate manage- www.perspectivesinmedicine.org ment of the infection. The only human case of C. lampragues in- C. lampragues fection was diagnosed in a 61-year-old Japanese Few reports of conidiobolomycosis caused by worker with relapsed lymphoma and severe C. lampragues have been so far recorded, with neutropenia as a result of chemotherapy (Ki- the majority occurring in animals (Humber mura et al. 2011). The patient developed bilat- et al. 1989; Vilela et al. 2010) and one dissemi- eral lung infiltration and other complications, nated case in a human (Kimura et al. 2011). The including pancreatitis, and finally died of respi- first diagnosed case of C. lampragues infection ratory failure. At necropsy ribbon-like hyphae was in an Arabian mare from Louisiana (Hum- were detected in the bladder, heart, kidneys, ber et al. 1989). The typical clinical features of lungs, spleen, urethra, and thyroid gland. In his- C. coronatus (affliction of nasal passages) infec- topathology twotypes of hyphaewere described: tion reported earlier by Bridges et al. (1962) a type resembling the Mucorales and dichoto- in horses in Texas were also observed in the mous septate hyphae resembling Aspergillus spp. Louisiana case. The case reported by Humber C. lampragues was isolated in culture from the et al. described episodes of epistaxis and severe infected tissues. Surprisingly, the hyphae in the

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HFPs of Mucorales and Entomophthorales

infected tissues did not show the typical Splen- Laboratory Diagnosis dore–Hoeppli phenomenon characteristic of Serology, Wet Mount, and Culture the entomophthoraceous fungi, attributable in part to the immune status of the host. Although Standardized serological tests for the diagnosis C. lampragues infection in animals was found of basidiobolomycosis and conidiobolomycosis to affect the rhinofacial and rhinopharyngeal are not available. However, several studies using areas, the only human case of infection by C. immunodiffusion showed that, whereas some lampragues involved internal organs similar to antigens extracted from B. ranarum cross-react- systemic cases reported in C. coronatus (Walker ed with the antigens of Conidiobolus spp. and et al. 1992) and C. incongruus infection (Bitten- P. insidiosum, others were specific (Yangco et al. court et al. 1979; Walsh et al. 1994). 1986; Kaufman et al. 1990). Moreover, antibodies against Basidiobolus and Conidiobolus from infected patients were detected using western C. incongruus blot and enzyme-linked immunosorbent assay C. incongruus has been recovered from facial analyses, suggesting that these serological assays and systemic infections in humans, sheep, and could be used as a diagnostic tool (Mendoza deer (Carrigan et al. 1992; Ketterer et al. 1992; et al. 1992; Khan et al. 2001). Madson et al. 2009). The first recorded case of A fresh section of biopsied tissue must be C. incongruus infection in humans was diag- submitted to the clinical laboratory for culture nosed by Gilbert et al. in 1970, but the recovered and microscopic evaluation. The biopsy speci- organism was properly identified 6 yr later men must be cut into 2 mm 2 mm blocks by King and Jong (1976). C. incongruus in- and then placed on a slide glass with one drop fections have been diagnosed in both appar- of 10% KOH. The microscopic visualization of ently normal and immunocompromised hosts ribbon-type sparsely septate hypha covered by a (Walsh et al. 1994; Wuppenhorst et al. 2010). hyaline material is indicative of a presumptive An important difference between C. incongruus infection by members of the Entomophthoro- and the other pathogenic Conidiobolus species mycota. Likewise, a 2-mm block of biopsied is the clinical presentation of the infection. The tissue must be implanted onto 2% Sabouraud majority of diagnosed cases, some fatal, show dextrose agar plates and incubated at 37˚C and systemic involvement of several internal organs 25˚C. After 24–48 h of incubation at 37˚C, (Busapakum et al. 1983; Ketterer et al. 1992; small glabrous colonies are usually detected Hernandez et al. 2007). Since the first report, at around the implanted tissues (Fig. 3A). As the least three more patients have been diagnosed colony ages, numerous ballistoconidia, ejected www.perspectivesinmedicine.org with orbitofacial and orofacial conidiobolomy- from sporangiophores, can be observed on the cosis (Eckert et al. 1972; Busapakum et al. 1983; surface of the agar and attached to the inner side Al-Hajjar et al. 1996), and nine systemic cases of the culture plate lid. The presence of zygo- involving one or more organs have been report- spores with undulate and smooth cell walls can ed (Eckert et al. 1972; Busapakum et al. 1983; be readily found. The development of zygo- Walsh et al. 1994; Hernandez et al. 2007; Wup- spores on 2% Sabouraud dextrose agar plates penhorst et al. 2010). C. incongruus infection is necessary for proper identification of B. rana- has been also diagnosed in sheep, causing rhino- rum in culture (Fig. 4A,C). facial infection (Ketterer et al. 1992), and in a Conidiobolus spp. can be identified in cul- deer, causing systemic dissemination (Madson ture following the diagram proposed by Vilela et al. 2009). Thus, C. incongruus more com- et al. (2010). According to the chart, the pres- monly causes disseminated infections and sel- ence of villose conidia is the main criterium to dom causes localized infection, a clinical fea- separate C. coronatus from the other two path- ture in contrast to that of C. coronatus (Walker ogenic species (Fig. 4F,inset). C. incongruus can et al. 1992; Walshet al. 1994; Wuppenhorst et al. be readily identified by the development of 2010). typical zygospores that can be easily differenti-

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L. Mendoza et al.

ated from those produced by C. lampragues. Management C. incongruus develops larger zygospores (15– Successful treatment outcome is directly cor- 40 mm) with numerous globules (Fig. 5D), related to an early diagnosis. In chronic infec- whereas C. lamparagues zygospores are smaller tions caused by Conidiobolus spp. and Basidio- (12–18 mm) and display a single globule within bolus spp., the formation of fibrotic tissues the zygospore (Fig. 5E). around the eosinophilic micro-abscesses influ- ences the contact of antifungals and KI (potas- Histopathology sium iodide) with the invading hyphae (Table 3) (Gugnani 1999). Thus, decreasing levels of The histopathological characteristics of ba- the antifungals trimethoprim–sulfamethoxa- sidiobolomycosis and conidiobolomyosis in zole and/or KI in the infected areas reduce the infected tissues are similar (Fig. 4D,H). The action of the chemotherapeutic agent (Fomu- main characteristic is the formation of an eo- fod and Antia 1971; Yangco et al. 1984; Nazir sinophilic halo around the hyphae after hema- et al. 1997). The limiting factors of oral KI in- toxylin and eosin staining (Splendore–Hoeppli clude the following: (1) gastric intolerance, (2) phenomenon) mostly found at the center of thyroid metabolic disturbances, and (3) drug proliferative eosinophilic micro-abscesses (Fig. hypersensitivity. However, oral KI (40 mg/kg 4D,H). Hyaline coenocytic or sparsely septated daily) for 4–6 wk has been successful in some hyphae 5–12 mm in diameter are usually pre- cases of facial conidiobolomycosis (Kamalam sent as long ribbon-type hyphae (Fig. 4H) or and Thambiah 1982; Nazir et al. 1997; Krishnan as smallround structures, with the hyphae trans- et al. 1998). versely sectioned (Fig. 4D, arrows). In early in- Sensitivity studies have shown in vitro fection, the presence of an acute inflamma- multidrug resistance in most Conidiobolus spp. tory response with neutrophils, eosinophils, recovered from both humans and animals, and lymphocytes can also be found (Fig. 4H, including C. lampragues (Kimura et al. 2011; arrows). In chronic lesion fibrosis, eosinophils, Choon et al. 2012; Tondolo et al. 2013). In histiocytes, and multinucleated giant cells are contrast, in vitro studies of B. ranarum showed also encountered. Although the lack of the inhibitory and fungicidal susceptibility to mi- eosinophilic material around the invading hy- conazole and ketoconazole (400 mg daily) (Vil- phae has been reported in immunocom- lasco et al. 1966; Saka et al. 2010) and some promised hosts, the Splendore–Hoeppli phe- clinical response to AmB, itraconazole (200 mg nomenon is an important histopathological per day), and fluconazole (Randhawa et al. characteristic of the mammalian-pathogenic 1994). However, treatment with AmB alone www.perspectivesinmedicine.org Basidiobolus spp. and Conidiobolus spp. (Ki- has given unsatisfactory results (Khan et al. mura et al. 2011). This feature has been used 2001). B. ranarum infection has been treated to differentiate infections caused by members of the Mucorales and Entomophthoromycota (McGinnis 1980; Kwon-Chung 2012). However, Table 3. The most common factors interfering with cases such as those reported by Kimura et al. and the therapeutic outcome of infections caused by those caused by Mucorales must be interpreted Conidiobolus and Basidiobolus species with caution because the morphological fea- 1. Extensive, chronic lesions tures of their hyphae are identical. Moreover, 2. Extensive fibrosis eosinophilic material around the invading hy- 3. Host immunity phae is also present around the hyphae of 4. Surgical resection or debridement in critical the infected tissues in mammalian-pathogenic anatomical areas oomycetes (P.insidiosum and Lagenidium spp.), 5. Late diagnosis of the infection affecting the differential diagnosis of ento- 6. Low host tolerance to some drugs (i.e., mophthoramycosis (Miller and Campbell 1984; amphotericin B and KI) Mendoza and Vilela 2013). 7. Inadequate drug levels at site of infection

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with KI as a single daily dose of 30 mg/kg body Abzug MJ, Walsh TJ. 2004. Interferon-g and colony-stimu- weight for 5 mo to 1 yr (Gugnani 1999). Regard- lating factors as adjuvant therapy for refractory fungal infections in children. Pediatr Infect Dis J 23: 769–773. less, most antifungals and KI have been used to Alastruey-Izquierdo A, Hoffmann K, de Hoog GS, Rodri- treat basidiobolomycosis with some success guez-Tudela JL, Voigt K, Bibashi E, Walther G. 2010. (Gugnani 1999). Surgery and debridement of Species recognition and clinical relevance of the zygomy- the affected tissues can also be successful, espe- cetous genus Lichtheimia (syn. Absidia Pro Parte, Myco- cladus). J Clin Microbiol 48: 2154–2170. cially when combined with chemotherapy Al-Hajjar S, Perfect J, Hashem F, Tufenkeji H, Kayes S. 1996. (Prabhu and Patel 2004). Orbitofacial conidiobolomycosis in a child. Pediatr Infect Although spontaneous resolution has been Dis J 15: 1130–1132. documented for some B. ranarum infections Antonelli M, Vignetti P, Dahir M, Mohammed M, Favah AA. 1987. Entomophthoromycosis due to Basidiobolus (Burkitt et al. 1964; Atonelli et al. 1987), suc- in Somalia. Trans R Soc Trop Med Hyg 81: 86–187. cessful management of basidiobolomycosis is Artis WM, Fountain JA, Delcher HK, Jones HE. 1982. A usually directly associated with the chronic mechanism of susceptibility to mucormycosis in diabetic status of the lesion (Table 3). Several cases, in- ketoacidosis: Transferrin and iron availability. Diabetes 31: 1109–1114. cluding the intestinal form of the disease, have Ben-Ami R, Luna M, Lewis RE, Walsh TJ, Kontoyiannis DP. been successfully treated with KI (Kamalam 2009. A clinicopathological study of pulmonary mucor- and Thambiah 1979; Nazir et al. 1997). Howev- mycosis in cancer patients: Extensive angioinvasion but er, patients unresponsive to KI should continue limited inﬂammatory response. J Infect 59: 134–138. Benjamin RK. 1962. A new Basidiobolus that form micro- treatment with ketoconazole (Nazir et al. 1997; spores. Aliso 5: 223–233. Gugnani 1999), trimethoprim–sulfamethoxa- Benjamin RK. 1979. The whole fungus: II. In Proceedings of zole (Fomufod and Antia 1971), or itraconazole the 2nd International Mycological Conference (ed. Ken- (200 mg daily). Although C. coronatus is sus- drick B), pp. 573–616. National Museum of Natural Sci- ences, National Museums of Canada, and the Kananaskis ceptible to AmB, the prognosis of this infection Foundation, Environmental Sciences Centre of the Uni- is always reserved. Most antifungal drugs and versity of Calgary, Kananaskis, Alberta, Canada. KI have resulted in unsatisfactory outcomes in Benny GL, Humber RA, Morton JB. 2001. Zygomycota: most cases of conidiobolomycosis over the past Zygomycetes. In The Mycota, Vol. VIIA: Systematics and evolution (ed. McLaughlin DJ, et al.), pp. 113–146. 40 years (Yangco et al. 1984). Surgery and Springer, Berlin. debridement have been also used in cases of Co- Berbee M, Taylor J. 2001. Fungal molecular evolution: Gene nidiobolus spp. infection, resulting in some suc- trees and geological time. In The Mycota, Vol. VIIA: cess. Complete cure of the infection had been Systemics and evolution (ed. McLaughlin DJ, et al.), pp. 229–245. Springer, Berlin. achieved in some patients, mostly those with Bittencourt AL, Ayala MAR, Ramos EAG. 1979. A new form early diagnosis (Kelly et al. 1980; Nazir et al. of abdominal zygomycosis different from mucormycosis: 1997; Krishnan et al. 1998; Gugnani 1999). Report of two cases and review of the literature. Am J Trop

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Human Fungal Pathogens of Mucorales and Entomophthorales

Leonel Mendoza, Raquel Vilela, Kerstin Voelz, Ashraf S. Ibrahim, Kerstin Voigt and Soo Chan Lee

Cold Spring Harb Perspect Med published online November 6, 2014

Subject Collection Human Fungal Pathogens

Evolutionary Perspectives on Human Fungal Thermally Dimorphic Human Fungal Pathogens−− Pathogens Polyphyletic Pathogens with a Convergent John W. Taylor Pathogenicity Trait Anita Sil and Alex Andrianopoulos Black Molds and Melanized Yeasts Pathogenic to Mechanisms of Antifungal Drug Resistance Humans Leah E. Cowen, Dominique Sanglard, Susan J. Anuradha Chowdhary, John Perfect and G. Sybren Howard, et al. de Hoog Fungal Pathogens: Survival and Replication Treatment Principles for Candida and within Macrophages Cryptococcus Andrew S. Gilbert, Robert T. Wheeler and Robin C. Laura C. Whitney and Tihana Bicanic May Innate Defense against Fungal Pathogens The Human Mycobiome Rebecca A. Drummond, Sarah L. Gaffen, Amy G. Patrick C. Seed Hise, et al. Antifungal Pharmacokinetics and Treatment Principles for the Management of Mold Pharmacodynamics Infections Alexander J. Lepak and David R. Andes Dimitrios P. Kontoyiannis and Russell E. Lewis Human Fungal Pathogens of Mucorales and Adaptive Immunity to Fungi Entomophthorales Akash Verma, Marcel Wüthrich, George Deepe, et Leonel Mendoza, Raquel Vilela, Kerstin Voelz, et al. al. Functional Profiling of Human Fungal Pathogen The Candida Pathogenic Species Complex Genomes Siobhán A. Turner and Geraldine Butler Alexi I. Goranov and Hiten D. Madhani Aspergillus fumigatus and Related Species Fungal Morphogenesis Janyce A. Sugui, Kyung J. Kwon-Chung, Praveen Xiaorong Lin, J. Andrew Alspaugh, Haoping Liu, et R. Juvvadi, et al. al.

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