Trends in Microbiology
Volume 28, Issue 11, November 2020, Pages 922-933
Journal home page for Trends in Microbiology

Review
Fungal Pathogens: Shape-Shifting Invaders

https://doi.org/10.1016/j.tim.2020.05.001Get rights and content

Highlights

  • Fungal pathogens grow in different shapes that influence their ability to disseminate an infection. For example, small spores (conidia) penetrate deep into the lung, budding cells that are about the size of a red blood cell disseminate in the bloodstream, and long hyphal filaments grow invasively into solid tissues.

  • Some fungi undergo shape shifting in the host to form larger cells, or clusters of cells, that are too big to be eaten (phagocytosed) by leukocytes.

  • Other fungi form small yeasts that have developed strategies for surviving inside the phagosome where they are safe from attack by other immune cells. This also allows them to disseminate throughout the host in a Trojan horse mechanism.

  • Fungal shape shifting can also enhance growth in the host by creating interconnected networks of hyphal filaments (mycelia) that promote sharing of nutrients.

Fungal infections are on the rise due to new medical procedures that have increased the number of immune compromised patients, antibacterial antibiotics that disrupt the microbiome, and increased use of indwelling medical devices that provide sites for biofilm formation. Key to understanding the mechanisms of pathogenesis is to determine how fungal morphology impacts virulence strategies. For example, small budding cells use very different strategies to disseminate compared with long hyphal filaments. Furthermore, cell morphology must be monitored in the host, as many fungal pathogens change their shape to disseminate into new areas, acquire nutrients, and avoid attack by the immune system. This review describes the shape-shifting alterations in morphogenesis of human fungal pathogens and how they influence virulence strategies.

Section snippets

Fungal Pathogens Alter Cell Shape as Part of Their Virulence Strategy

Most fungi play beneficial roles in the environment but a small subset can cause lethal infections in humans [1]. These pathogenic species grow in a wide range of different morphologies that provide distinct advantages for virulence [2., 3., 4.] (Figure 1, Key Figure). Many fungal pathogens grow as yeast (see Glossary) which are about the size of a red blood cell and are therefore well suited for bloodstream dissemination. By contrast, molds (multicellular chains of filamentous hyphal cells)

Cryptococcus: Yeasts That Cloak Themselves in a Protective Capsule and Shift into Giant Cells

Cryptococcus neoformans is one of the best studied fungi because it is a major cause of lethal fungal infections worldwide due to its ability to infect AIDS patients. The related species Cryptococcus gattii has also gained attention recently for causing clusters of infections in seemingly healthy individuals [1,4,7]. Cryptococcus species grow by budding (Figure 2A) and by forming filamentous cells in nature, but they shift primarily into the budding mode of replication in the host [8]. To get

Histoplasma capsulatum: A Dimorphic Fungal Pathogen That Grows as Hyphal Filaments in the Environment and Shifts to Yeast in the Host

In spite of its species name, Histoplasma capsulatum does not form a capsule. It is part of a group known as thermally dimorphic fungi because it forms filamentous hyphae at low temperatures in the environment but shifts to yeast growth at the elevated temperature of the human body [24,25]. Infection is often initiated when hyphal filaments transition to forming structures known as conidiophores that release small asexual conidia (spores) that are subsequently inhaled into the lung [26]. Thus,

Aspergillus fumigatus: Inhaled Conidia Transform into Invasive Hyphae That Further Shift into an Interconnected Mycelial Network

Filamentous hyphal growth has several virulence advantages, including the ability to invade tissues; the large size of hyphae also prevents phagocytosis. Aspergillus fumigatus, the primary focus of this section, is one of the most common lethal fungal pathogens [31]. It has been a particularly severe problem in immunocompromised individuals, such as bone marrow transplant patients [1]. For comparison, we also describe Rhizopus oryzae, which differs from A. fumigatus in that it forms

Multimorphic Candida Species Form Cell Aggregates and Biofilms

Candida species are distinct from most other fungal pathogens in that they are commensal organisms that colonize the skin or gastrointestinal (GI) tract. Thus, rather than inhaling conidia, patients are usually infected by endogenous organisms that, under conditions such as immune deficiency or biofilm formation, are able to overwhelm host defenses and disseminate. Candida species are also distinct in that most are multimorphic in the host where they transition between budding and filamentous

Coccidioides Species Form Giant Spherules in the Host Containing Hundreds of Endospores

Coccidioides immitis and Coccidioides posadasii are found in the soil in arid regions of the southwestern USA and northwestern Mexico [60]. Although Coccidioides spp. are thermally dimorphic fungi, evolutionarily related to Histoplasma, they undergo very distinct morphological shifts. In soil, they grow as hyphal filaments and then alternating cells in the hyphae transform into arthrospores, which persist in the soil (Figure 5A). When the soil is disturbed, aerosolized arthrospores infect

Concluding Remarks

This review covers a sampling of the major human pathogens, but there is still much to be learned about shape-shifting fungi (see Outstanding Questions). We have only a limited view of fungal morphology in the host from histology. However, fungal strains that produce fluorescent proteins are making it possible to identify new morphological shape transitions in different host niches and after stress conditions such as hypoxia and antifungal therapy [73]. There are also many more fungi with

Acknowledgments

This work was supported by Public Health Service grants from the National Institutes of Health awarded to J.B.K. (R01GM116048 and R01AI047837) and A.M.N. (R01GM072540). We thank the members of our laboratories for their helpful comments on the manuscript.

Glossary

Ascus
a cell structure, containing sexual spores, produced following meiosis by ascomycete fungi.
Capsule
a protective layer, composed of polysaccharide chains, that surrounds the cell wall.
Conidia
asexual spores produced by molds; they are also called conidiospores.
Cyst
a term used to describe an ascus that contains the spores (ascospores) that form after mating of Pneumocystis jirovecii. This term is a holdover from when P. jirovecii was thought to be a parasite. (DNA sequencing revealed that it

References (75)

  • J. Roesler et al.

    Redundant ability of phagocytes to kill Aspergillus species

    J. Allergy Clin. Immunol.

    (2011)
  • D. Kadosh

    Regulatory mechanisms controlling morphology and pathogenesis in Candida albicans

    Curr. Opin. Microbiol.

    (2019)
  • J.N. Witchley

    Candida albicans morphogenesis programs control the balance between gut commensalism and invasive infection

    Cell Host Microbe

    (2019)
  • S.H. Liang

    Hemizygosity enables a mutational transition governing fungal virulence and commensalism

    Cell Host Microbe

    (2019)
  • G. Wall

    Candida albicans biofilm growth and dispersal: contributions to pathogenesis

    Curr. Opin. Microbiol.

    (2019)
  • K.D. Young

    Bacterial morphology: why have different shapes?

    Curr. Opin. Microbiol.

    (2007)
  • J.P.M. Araujo et al.

    Zombie-ant fungi emerged from non-manipulating, beetle-infecting ancestors

    Curr. Biol.

    (2019)
  • G.D. Brown

    Hidden killers: human fungal infections

    Sci. Transl. Med.

    (2012)
  • Z. Li et al.

    Morphology changes in human fungal pathogens upon interaction with the host

    J. Fungi (Basel)

    (2017)
  • J.R. Kohler

    Fungi that infect humans

    Microbiol. Spectr.

    (2017)
  • L.P. Erwig et al.

    Interactions of fungal pathogens with phagocytes

    Nat. Rev. Microbiol.

    (2016)
  • D.C. Yang

    Staying in shape: the impact of cell shape on bacterial survival in diverse environments

    Microbiol. Mol. Biol. Rev.

    (2016)
  • R.C. May

    Cryptococcus: from environmental saprophyte to global pathogen

    Nat. Rev. Microbiol.

    (2016)
  • Y. Zhao

    Life cycle of Cryptococcus neoformans

    Annu. Rev. Microbiol.

    (2019)
  • Z.A. Wang

    Unraveling synthesis of the cryptococcal cell wall and capsule

    Glycobiology

    (2018)
  • M.L. Littman

    Capsule synthesis by Cryptococcus neoformans

    Trans. N. Y. Acad. Sci.

    (1958)
  • M. Feldmesser

    Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection

    Microbiology

    (2001)
  • T.R. Kozel et al.

    Inhibition of phagocytosis by cryptococcal polysaccharide: dissociation of the attachment and ingestion phases of phagocytosis

    Infect. Immun.

    (1976)
  • A. Campuzano et al.

    Innate immunity against Cryptococcus, from recognition to elimination

    J. Fungi (Basel)

    (2018)
  • O. Zaragoza

    Basic principles of the virulence of Cryptococcus

    Virulence

    (2019)
  • S.T. Denham et al.

    Mechanisms of pulmonary escape and dissemination by Cryptococcus neoformans

    J. Fungi (Basel)

    (2018)
  • K.E. Fernandes

    Phenotypic variability correlates with clinical outcome in Cryptococcus isolates obtained from Botswanan HIV/AIDS patients

    mBio

    (2018)
  • L.H. Okagaki

    Cryptococcal cell morphology affects host cell interactions and pathogenicity

    PLoS Pathog.

    (2010)
  • O. Zaragoza

    Fungal cell gigantism during mammalian infection

    PLoS Pathog.

    (2010)
  • E.P. Orner

    Cell wall-associated virulence factors contribute to increased resilience of old Cryptococcus neoformans cells

    Front. Microbiol.

    (2019)
  • J.P. Woods

    Revisiting old friends: developments in understanding Histoplasma capsulatum pathogenesis

    J. Microbiol.

    (2016)
  • G.S. Deepe

    Outbreaks of histoplasmosis: the spores set sail

    PLoS Pathog.

    (2018)
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