Interactions of fungal pathogens with phagocytes

Key Points

  • Several mechanisms exist by which fungi can delay or interfere with the processes used by phagocytic cells of the innate immune system to uptake and kill invading cells.

  • Certain fungal species escape immune capture by generating cell types, such as Titan cells, elongated tubular hyphae or sporulating structures, known as spherules, that are too large to be taken up by phagocytic cells and cannot be killed by phagocytosis.

  • Fungal cell wall layers are highly heterogeneous and include components such as hydrophobic proteins and α-glucan that do not activate immune receptors and hence cloak other wall components that would otherwise result in detection by the host immune system.

  • Fungal pathogens can rapidly alter the composition of their cell walls when growing in the host where they are exposed to different nutrients and environmental conditions, or when undergoing morphogenesis. This makes them a moving target for immune detection.

  • Many fungi are able to induce their own exocytosis after they have been taken up by macrophages.

  • The formation of hyphae by Candida albicans is induced within phagosomes and this activates a modified form of programmed cell death known as pyroptosis. This process, and the physical rupture of the phagocyte membrane by growing hyphae, can eliminate a proportion of innate immune cells that would otherwise confer protection to the host.

  • Some fungi interfere with the mechanism of phagosome maturation, preventing or delaying the fusion of vesicles which contain microbicidal compounds that are required for fungal killing.

Abstract

The surveillance and elimination of fungal pathogens rely heavily on the sentinel behaviour of phagocytic cells of the innate immune system, especially macrophages and neutrophils. The efficiency by which these cells recognize, uptake and kill fungal pathogens depends on the size, shape and composition of the fungal cells and the success or failure of various fungal mechanisms of immune evasion. In this Review, we describe how fungi, particularly Candida albicans, interact with phagocytic cells and discuss the many factors that contribute to fungal immune evasion and prevent host elimination of these pathogenic microorganisms.

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Figure 1: Macrophage–fungus interactions.
Figure 2: Fungal morphology and phagocytosis.
Figure 3: Fungal cell wall composition and recognition by phagocytes.
Figure 4: Fungal survival strategies.

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Acknowledgements

The authors acknowledge L. Wight and the microscopy facility at the University of Aberdeen. The authors also acknowledge the support of the Wellcome Trust (grants 080088. 075470 and 099215) and a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (grant 097377).

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Correspondence to Lars P. Erwig or Neil A. R. Gow.

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Glossary

Keratitis

An infection of the cornea that can often lead to blindness.

Neutropenia

A temporary or longer lasting reduction in the number of circulating neutrophils in the bloodstream that can render a person susceptible to some forms of fungal infection.

Neutrophils

Abundant, short lived and motile phagocytic cells of the innate immune system that are one of the first cell types to migrate to a site of inflammation.

Macrophages

White blood cells produced by the differentiation of monocytes in tissues. Monocytes and macrophages are phagocytes that are important for host defence against fungal infection.

Pathogen-associated molecular patterns

(PAMPs). Molecules that are part of microbial cells, and typically not found in human cells, that are recognized by pattern recognition receptors (PRRs) and trigger immune defence responses.

Pattern recognition receptors

(PRRs). Receptor proteins, that are found mostly, but not exclusively, on the surface of immune cells and epithelial cells, and bind to pathogen- associated molecular patterns (PAMPs) triggering host cell signals that lead to the secretion of cytokines and activation of the innate immune response.

RAB GTPases

ATP hydrolysing enzymes of the monomeric RAB G protein superfamily that are involved in the regulation of membrane transport and vesicle movement as well as the fusion of vesicles within the phagosome of immune cells.

Phagosome

A membranous compartment in a phagocytic cell, such as a macrophage or a neutrophil, which is formed around a microorganism when engulfed through the process of phagocytosis. The microorganism is killed in the phagolysosome, which is formed by the phagosome fusing with lysosomes during the phagosomal maturation process. The phagolysosome is acidic and contains toxic oxidants and digestive enzymes which kill the microorganism.

T helper cell

(TH cell). A type of T cell that helps or stimulates the function of other immune cells of the adaptive immune system by releasing specific cytokines. When mature TH cells express a CD4 protein on their cell surface they are known as CD4+ TH cells.

Regulatory T cell

(Treg cell). A class of T cell that regulates the immune system by downregulating the functions of other T cells and mitigates inflammatory damage.

Opsonization

The enhancement of microbial cell uptake through the coating of the cell surface of the microorganisms with opsonizing antibodies or complement proteins. This process enables the microbial cells to be recognized by opsonic receptors, such as the Fc receptor and complement receptor 1 (CR1), on phagocytes.

Conidia

A type of asexual spore formed by many types of the filamentous ascomycete group of fungi, including Aspergillus species.

Pseudohypae

Conjoined elongated yeast cells typical of most pathogenic Candida species.

Spherules

Characteristic spore forming structures formed by Coccidioides spp. within human tissues. Spherules are derived from inhaled arthroconidia, which swell and then become segmented through several septation events that result in the formation of endospores. Ruptured spherules release the endospores into the atmosphere where they can be inhaled and cause further infections.

Titan cells

Specialized greatly expanded yeast cells of the fungal pathogen Cryptococcus that can grow to 100 μm in diameter, approximately 20 times the size of a normal yeast cell. These Titan cells are so large that they are difficult or impossible to phagocytose and hence are resistant to the protective role of macrophages.

Complement

A set of proteins in the blood that can be activated by proteolysis enabling them to bind to, and opsonize, microbial cells resulting in markedly enhanced phagocytosis.

Echinocandins

A class of antifungal drug that targets the synthesis of β-1,3-glucan in the fungal cell wall.

TH17

(T helper 17). A subset of T helper cells (TH cells) that produce interleukin-17 (IL-17), IL-21 and IL-22. These are developmentally distinct from TH1 cells and TH2 cells and are thought to have a protective role in fungal infection.

Dimorphic pathogen

Fungal pathogens of humans that are capable of growth in two forms — as a budding yeast or branching hypha-forming mould. For Candida albicans, hyphae penetrate host tissues, whereas for all other dimorphic pathogens it is the yeast form that is found in the human body.

IL-1β

(Interleukin-1β). A pro-inflammatory polypeptide that is produced after infection, injury or antigenic challenge. IL-1β is primarily produced by macrophages through a pathway that is tightly regulated by the inflammasome.

Inflammasome

An oligomeric group of proteins found in myeloid cells, which includes caspase 1 or caspase 5 and other proteins, that is involved in innate immunity and triggers the maturation of inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, resulting in the induction of pyroptosis or other forms of programmed cell death.

Pyroptosis

A form of programmed cell death in which immune cells, such as macrophages, swell, burst and die on recognition of certain microbial cell components within themselves. This results in the release of cytokine signals that attract other immune cells to fight the infection. Pyroptosis can occur in response to the phagocytosis of fungal cells.

Ergosterol

A fungal membrane sterol equivalent to cholesterol found in mammals.

Non-lytic expulsion

An actin-dependent mechanism used by microorganisms to escape from within a macrophage. Both the macrophage and the microorganism are viable after expulsion takes place. Non-lytic expulsion is also known as vomocytosis.

ARP2/3 complex

A seven-subunit protein complex involved in the regulation of the actin cytoskeleton that is bound to and activated by Wiskott–Aldrich syndrome protein (WASP).

Amoeba

A common unicellular protozoan found in soils that moves and phagocytoses bacteria and other microorganisms in a fashion similar to that of phagocytes of the immune system.

Commensal

A fungus or other organism that lives in close association with another organism and receives a benefit from that organism without inflicting damage to it.

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Erwig, L., Gow, N. Interactions of fungal pathogens with phagocytes. Nat Rev Microbiol 14, 163–176 (2016). https://doi.org/10.1038/nrmicro.2015.21

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