Human Fungal Pathogens of Mucorales and Entomophthorales
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Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Human Fungal Pathogens of Mucorales and Entomophthorales 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- Editors: Arturo Casadevall, Aaron P. Mitchell, Judith Berman, Kyung J. Kwon-Chung, John R. Perfect, and Joseph Heitman Additional Perspectives on Human Fungal Pathogens available at www.perspectivesinmedicine.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a019562 Cite this article as Cold Spring Harb Perspect Med 2015;5:a019562 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press 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 poly- phyletic 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 predict- ed economic burden in the U.S. health care sys- tem caused by mucormycosis is $100,000 per case (Ibrahim et al. 2008a). Although mucor- mycosis has long been considered a rare fungal infection, advances in medical care and an in- creasingly 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 individ- uals with predisposing conditions (e.g., diabe- www.perspectivesinmedicine.org tes, iron overload, immune-suppressive thera- py, 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- 2 Cite this article as Cold Spring Harb Perspect Med 2015;5:a019562 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press 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 re- ceptor-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