This is a free sample of content from Human Fungal Pathogens. Click here for more information on how to buy the book. The Spectrum of Fungi That Infects Humans Julia R. Ko¨hler1, Arturo Casadevall2, and John Perfect3 1Division of Infectious Diseases, Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 2Departments of Microbiology and Immunology and Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, New York, New York 10461 3Division of Infectious Diseases, Duke Medical Center, Durham, North Carolina 27710 Correspondence: [email protected] Few among the millions of fungal species fulfill four basic conditions necessary to infect humans: high temperature tolerance, ability to invade the human host, lysis and absorption of human tissue, and resistance to the human immune system. In previously healthy individu- als, invasive fungal disease is rare because animals’sophisticated immune systems evolved in constant response to fungal challenges. In contrast, fungal diseases occur frequently in immunocompromised patients. Paradoxically, successes of modern medicine have put in- creasing numbers of patients at risk for invasive fungal infections. Uncontrolled HIV infection additionally makes millions vulnerable to lethal fungal diseases. A concerted scientific and social effort is needed to meet these challenges. ungal infections today are among the most by which living humans became substrates for Fdifficult diseases to manage in humans. fungi. Given the tremendous wealth of recent Some fungi cause disease in healthy people, but findings on fungal evolution, phylogenetics, ge- most fungal infections occur in individuals al- nomics, development, and pathogenesis, this ready experiencing serious illness, and frequent- overview will necessarily omit much work criti- ly jeopardize the success of the newest medical cal to our understanding of fungi, which the advances in cancer care, solid organ and hema- other articles in this collection will focus on in topoietic stem cell transplantation, neonatal detail. medicine, autoimmune disease therapies, trau- Among the estimated 1.5–5.0 million fun- ma and intensive care, and sophisticated sur- gal species on planet Earth (O’Brien et al. 2005), gery. In fact, these medical advances themselves only several hundred cause disease in humans, often make their beneficiaries vulnerable to and very few are able to affect healthy people. fungal disease. Treatment can involve breaching Animals coevolved with fungi, and the sophis- normal immune functions, or susceptible pa- ticated and potent human immune system arose tients, such as extremely premature newborns from the constant challenge posed by the mi- who survive long enough to become infected by crobial world. Fungal pathogens likely adapted a fungus. their pathogenic repertoire to other animal The following discussion intends to touch prey—mammals, insects, and even unicellular on highlights of the evolutionary developments amoebae—before encountering and attacking Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a019273 1 © 2015 by Cold Spring Harbor Laboratory Press. All rights reserved. This is a free sample of content from Human Fungal Pathogens. Click here for more information on how to buy the book. J.R. Ko¨hler et al. humans. But unlike plants, insects, and ecto- plant pathogens that can infect neutropenic thermic vertebrates (animals whose body tem- patients. As filamentous Fusarium spp. produce perature fluctuates with their surroundings), cells resembling yeast in the human host, which mammals are highly resistant to invasive fungal readily float within the bloodstream, a hallmark diseases, and evolution of endothermy and of their dissemination is development of nu- homeothermy enhanced antifungal immunity merous metastatic foci in the skin, presumably (Robert and Casadevall 2009; Bergman and because the skin is the coolest organ. The devel- Casadevall 2010). The remarkable resistance of opment of metastatic lesions in warm organs mammals to fungal pathogens has been hypoth- distant from the primary focus, like spleen and esized to be responsible for emergence of mam- kidneys, is much more unusual in fusariosis. In mals as the dominant land species, when pro- contrast, invasive infections with human tem- liferation of fungi at the end of the Cretaceous perature-adapted Candida spp., which also use era created a “fungal filter” that selected for this yeast to disseminate through the bloodstream, animal group (Casadevall 2005, 2012). frequently lead to innumerable metastatic foci For a fungus, parasitizing a human is a de- in deep organs. manding strategy. Four criteria must be fulfilled. Morphogenesis is an important virulence (1) It must be able to grow at a high tempera- factor related to fungal locomotion. Although ture, at or above 37˚C. (2) It must be able to fungal hyphae can pierce tissue barriers owing reach the tissues it will parasitize, by penetrating to the turgor pressure at their tips, yeast can host tissue barriers, or by circumventing them readily disseminate to distant sites in a large through small airborne cells that enter air-filled animal. Fungi that infect healthy humans do spaces of lungs and sinuses directly. (3) It must so almost exclusively in their yeast form. But be able to digest and absorb components of for most fungi, the ability to assume various human tissues. (4) Finally, it must be able to shapes is critical for infecting humans, because withstand the human immune system. many enter the body in the form of small, round Virulence factors can be divided into as- airborne dispersal propagules, sporangiospores pects of physiology that allow a fungus to fulfill or conidia, which are produced from hyphal these four criteria. Growth at high temperature cells. In the oceans, fungi originated as unicel- is a stringent criterion, because land-colonizing lular, oval cells propelled by flagella, so growth fungi likely evolved in association with plants as a round or oval cell was a fundamental fungal (Humphreys et al. 2010), whose nighttime tem- trait. Lucking et al. (2009), in their comparison perature must be cool enough to minimize the of fossil and molecular dating systems of fungal ratio of carbon-expending respiration to car- evolution, state that “all dating estimates show bon-assimilating photosynthesis. Casadevall that the evolution of filamentous fungi oc- and colleagues have discussed how the stable curred much later than the origin of the fungal elevated temperature of endothermic (warm- lineage itself, suggesting that for a long time blooded) animals may have been one of the after their origin, fungi were heterotrophic, uni- most potent developments in antifungal immu- cellular, flagellate, aquatic organisms.” An op- nity (Robert and Casadevall 2009; Bergman and tion for the hyphal form, whose adaptive utility Casadevall 2010; Garcia-Solache and Casadevall is shown by convergent evolution of hyphae in 2010). The energy cost of the human fever re- fungi and oomycete water molds (Money et al. sponse to infection, which is tightly regulated by 2004), may have evolved when fungi colonized cytokines like TNF-a, represents another testi- land as plant symbionts (Redecker et al. 2000; mony to the evolutionary importance of tem- Heckman et al. 2001; Lucking et al. 2009). perature as a major host defense against fungi. Morphogenesis also contributes to protection The role of fungal heat intolerance is il- against amoeboid cell predation. Filamentous lustrated by the different clinical scenarios of forms of Cryptococcus neoformans are resistant disseminated Fusarium infection versus dissem- to amoeba (Neilson et al. 1978), and incubation inated candidiasis. Fusarium spp. are important of Histoplasma capsulatum and Blastomyces 2 Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a019273 © 2015 by Cold Spring Harbor Laboratory Press. All rights reserved. This is a free sample of content from Human Fungal Pathogens. Click here for more information on how to buy the book. The Spectrum of Fungi That Infects Humans dermatitidis yeast with amoeba at 37˚C triggers tween lineages of a single species. In contrast, transition to filamentous growth (Steenbergen many species that grow at 37˚C can readily in- et al. 2004). fect a severely immunocompromised patient. Tremendous variability of cell forms and Last, coordinating the processes to fulfill the ability to switch between them continues these four criteria of pathogenicity demands a in extant fungal phyla, and few lineages have complex network of sensing and signaling sys- completely lost a round or a filamentous cell tems, which inform the fungal cell of external form. A highly successful human-host-associat- conditions and set in motion its appropriate ed fungus, Candida albicans, is notable for the responses. Loss of virulence was shown many facility and frequency with which it switches times in many fungal pathogens, when just between a broad spectrum of growth forms in a single element of a sensing and signaling the host, between round yeast, elongated pseu- network was genetically or pharmacologically dohyphae, and filamentous hyphae (Sudbery disturbed, such as mechanosensor, calcineurin, et al. 2004). Adhesion molecules are virulence protein kinase A, MAP kinase, Tor, and high factors related to fungal locomotion strategies osmolarity signaling pathways (Rohde and Car- because a hypha