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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Brown, G. D. et al. Hidden killers: human fungal infections. Sci. Transl. Med. 4, 165rv13 (2012).
Armstrong-James, D., Meintjes, G. & Brown, G. D. A neglected epidemic: fungal infections in HIV/AIDS. Trends Microbiol. 22, 120–127 (2014).
Cheng, S. C., Joosten, L. A. B., Kullberg, B.-J. & Netea, M. G. Interplay between Candida albicans and the mammalian innate host defense. Infect. Immun. 80, 1304–1313 (2012).
Diamond, R. D. Interactions of phagocytic cells with Candida and other opportunistic fungi. Arch. Med. Res. 24, 361–369 (1993).
Martino, P. et al. Candida colonization and systemic infection in neutropenic patients. A retrospective study. Cancer. 64, 2030–2034 (1989).
Lehrer, R. I. & Cline, M. J. Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection. J. Clin. Invest. 48, 1478–1488 (1969).
Qian, Q., Jutila, M. A., Van Rooijen, N. & Cutler, J. E. Elimination of mouse splenic macrophages correlates with increased susceptibility to experimental disseminated candidiasis. J. Immunol. 152, 5000–5008 (1994).
Romani, L. et al. An immunoregulatory role for neutrophils in CD4+ T helper subset selection in mice with candidiasis. J. Immunol. 158, 2356–2362 (1997).
Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 1, 1–23 (2004).
Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 4, 275–288 (2011).
Cannon, G. J. & Swanson, J. A. The macrophage capacity for phagocytosis. J. Cell Sci. 101, 907–913 (1992).
Gow, N. A. R. & Gooday, G. W. Growth kinetics and morphology of colonies of the filamentous form of Candida albicans. J. Gen. Microbiol. 128, 2187–2194 (1982).
Lewis, L. E. et al. Stage specific assessment of Candida albicans phagocytosis by macrophages identifies cell wall composition and morphogenesis as key determinants. PLoS Pathog. 8, e1002578 (2012). This paper demonstrates how the various phases of the interaction between macrophages and C. albicans from the initial chemotactic response to binding, uptake and engulfment depended on the glycosylation status, cellular morphology and viability of the cell.
Ingham, C. J. & Schneeberger, P. M. Microcolony imaging of Aspergillus fumigatus treated with echinocandins reveals both fungistatic and fungicidal activities. PLoS ONE. 7, e35478 (2012).
Zaragoza, O. & Nielsen, K. Titan cells in Cryptococcus neoformans: cells with a giant impact. Curr. Opin. Microbiol. 16, 409–413 (2013).
Brown, A. J. P., Brown, G. D., Netea, M. G. & Gow, N. A. R. Metabolism impacts Candida immunogenicity and pathogenicity at multiple levels. Trends Microbiol. 22, 614–622 (2014).
Van der Graaf, C. A. A., Netea, M. G., Verschueren, I., van der Meer, J. W. M. & Kullberg, B. J. Differential cytokine production and Toll-like receptor signaling pathways by Candida albicans blastoconidia and hyphae. Infect. Immun. 73, 7458–7464 (2005).
Joly, S. et al. Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J. Immunol. 183, 3578–3581 (2009).
Klis, F. M. Sosinska, G. J. de Groot, P. W. J. & Brul, S. Covalently linked cell wall proteins of Candida albicans and their role in fitness and virulence. FEMS Yeast Res. 9, 1013–1028 (2009).
Rubin-Bejerano, I., Abeijon, C., Magnelli, P., Grisafi, P. & Fink, G. R. Phagocytosis by human neutrophils is stimulated by a unique fungal cell wall component. Cell Host Microbe 2, 55–67 (2007).
Gow, N. A. R., van de Veerdonk, F. L., Brown, A. J. & Netea, M. G. Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat. Rev. Microbiol. 10, 112–122 (2011).
Gantner, B. N., Simmons, R. M. & Underhill, D. M. Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J. 24, 1277–1286 (2005).
Wheeler, R. T., Kombe, D., Agarwala, S. D. & Fink, G. R. Dynamic, morphotype-specific Candida albicans β-glucan exposure during infection and drug treatment. PLoS Pathog. 4, e1000227 (2008).
Wagener, J. et al. Fungal chitin dampens inflammation through IL-10 induction mediated by NOD2 and TLR9 activation. PLoS Pathog. 10, e1004050 (2014). This report identifies for the first time the PRRs required for chitin mediated IL-10 secretion by myeloid cells and suggests that chitin has a role in attenuating inflammatory mediated damage.
Hall, R. A. et al. The Mnn2 mannosyltransferase family modulates mannoprotein fibril length, immune recognition and virulence of Candida albicans. PLoS Pathog. 9, e1003276 (2013).
Hall, R. A. & Gow, N. A. R. Mannosylation in Candida albicans: role in cell wall function and immune recognition. Mol. Microbiol. 90, 1147–1161 (2013).
Netea, M. G. et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J. Clin. Invest. 6, 1642–1650 (2006).
Dennehy, K. M. et al. Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors. Eur. J. Immunol. 38, 500–506 (2008).
Carmona, E. M. et al. Glycosphingolipids mediate pneumocystis cell wall β-glucan activation of the IL-23/IL-17 axis in human dendritic cells. Am. J. Respir. Cell. Mol. Biol. 47, 50–59 (2012).
Rappleye, C. A., Groppe Eissenberg, L. & Goldman, W. E. Histoplasma capsulatum α-(1, 3)-glucan blocks innate immune recognition by the β-glucan receptor. Proc. Natl Acad. Sci. USA 104, 1366–1370 (2007) (2007).
Kozel, T. R. & Gotschlich, E. C. The capsule of Cryptococcus neoformans passively inhibits phagocytosis of the yeast by macrophages. J. Immunol. 129, 1675–1680 (1982).
Cross, C. E. & Bancroft, G. J. Ingestion of acapsular Cryptococcus neoformans occurs via mannose and β-glucan receptors, resulting in cytokine production and increased phagocytosis of the encapsulated form. Infect. Immun. 63, 2604–2611 (1995).
Monari, C. et al. Glucuronoxylomannan, a microbial compound, regulates expression of costimulatory molecules and production of cytokines in macrophages. J. Infect. Dis. 191, 127–137 (2005).
Luberto, C. et al. Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans. J. Clin. Invest. 112, 1080–1094 (2003).
Stano, P. et al. App1: an antiphagocytic protein that binds to complement receptors 3 and 2. J. Immunol. 182, 84–91 (2009).
van Wetter, M. A., Wösten, H. A., Sietsma, J. H. & Wessels, J. G. H. Hydrophobin gene expression affects hyphal wall composition in Schizophyllum commune. Fungal Genet. Biol. 31, 99–104 (2000).
Aimanianda, V. et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature. 460, 1117–1121 (2009). This report demonstrates how fungal asexual conidiospores fail to be detected by the host immune system until the immunologically inert outer hydrophobin rodlet layer is disrupted.
Dagenais, T. R. et al. Aspergillus fumigatus LaeA-mediated phagocytosis is associated with a decreased hydrophobin layer. Infect. Immun. 78, 823–829 (2010).
Gresnigt, M. S. et al. A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist. PLoS Pathog. 10, e1003936 (2014).
Nosanchuk, J. D. & Casadevall, A. Impact of melanin on microbial virulence and clinical resistance to antimicrobial compounds. Antimicrob. Agents Chemother. 50, 3519–3528 (2006).
Jahn, B. et al. Isolation and characterization of a pigmentless-conidium mutant of Aspergillus fumigatus with altered conidial surface and reduced virulence. Infect. Immun. 12, 5110–5117 (1997).
Pihet, M. et al. Melanin is an essential component for the integrity of the cell wall of Aspergillus fumigatus conidia. BMC Microbiol. 9, 177 (2009).
da Gloria Sousa, M. et al. Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin. Cell Host Microbe 9, 436–443 (2011). This study demonstrates that augmentation of the normal immune response to F. pedrosoi with TLR agonists can lead to cure of the chronic skin infection chromoblastomycosis.
Shibata, N., Suzuki, A., Kobayashi, H. & Okawa, Y. Chemical structure of the cell-wall mannan of Candida albicans serotype A and its difference in yeast and hyphal forms. Biochem. J. 404, 365–372 (2007).
Keppler-Ross, S., Douglas, L., Konopka, J. B. & Dean, N. Recognition of yeast by murine macrophages requires mannan but not glucan. Eukaryot. Cell 9, 1776–1787 (2010).
Moyes, D. L. et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8, 225–235 (2010). This report highlights the difference in the immune response of epithelial cells to the yeast and hyphae forms of C. albicans and shows how this is related to the activation of different signalling pathways by cell surface components.
Moyes, D. L. et al. Candida albicans yeast and hyphae are discriminated by MAPK signaling in vaginal epithelial cells. PLoS ONE 6, e26580 (2011).
Murciano, C. et al. Candida albicans cell wall glycosylation may be indirectly required for activation of epithelial cell pro-inflammatory responses. Infect. Immun. 12, 4902–4911 (2011).
Cheng, S.-C. et al. The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans. J. Leukoc. Biol. 90, 357–366 (2011).
Lowman, D. W. et al. Novel structural features in Candida albicans hyphal glucan provide a basis for differential innate immune recognition of hyphae versus yeast. J. Biol. Chem. 289, 3432–3443 (2012). This paper demonstrates a new structure of β -1,3-glucan in the hyphae of C. albicans that may have profound implications for differential immune recognition mechanisms.
Smeekens, S. P. et al. An anti-inflammatory property of Candida albicans β-glucan: induction of high levels of interleukin-1 receptor antagonist via a Dectin-1/CR3 independent mechanism. Cytokine. 71, 215–222 (2015).
Lohse, M. B. & Johnson, A. D. Differential phagocytosis of white versus opaque Candida albicans by Drosophila and mouse phagocytes. PLoS ONE 3, e1473 (2008).
Brown, A. J. P. et al. Stress adaptation in a pathogenic fungus. J. Exp. Biol. 217, 144–155 (2014).
Ene, I. V. et al. Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cell. Microbiol. 14, 1319–1335 (2012). Important observations are described in this study showing that different carbon sources used for growth in vivo radically affect cell wall properties and hence the immune response and virulence.
Ene, I. V. et al. Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans. Proteomics 12, 3164–3179 (2012).
Ene, I. V. Cheng, S.-C., Netea, M. G. & Brown, A. J. P. Growth of Candida albicans cells on the physiologically relevant carbon source, lactate, affects their recognition and phagocytosis by immune cells. Infect. Immun. 81, 238–248 (2013).
Synnott, J. M., Guida, A., Mulhern-Haughey, S., Higgins, D. G. & Butler, G. Regulation of the hypoxic response in Candida albicans. Eukaryot. Cell. 11, 1734–1746 (2010).
Hall, R. A. et al. CO2 acts as a signalling molecule in populations of the fungal pathogen Candida albicans. PLoS Pathog. 6, e1001193 (2010).
Latgé, J. P. The cell wall: a carbohydrate armour for the fungal cell. Mol. Microbiol. 66, 279–290 (2007).
Chen, J. & Seviour, R. Medicinal importance of fungal β-(1-3), (1-6)-glucans. Mycol. Res. 111, 635–652 (2007).
Goodridge, H. S. et al. Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'. Nature. 472, 471–475 (2011).
Da Silva, C. A. et al. Chitin is a size-dependent regulator of macrophage TNF and IL-10 production. J. Immunol. 182, 3573–3582 (2009).
Casadevall, A. & Pirofski, L. A. The damage-response framework of microbial pathogenesis. Nat. Rev. Microbiol. 1, 17–24 (2003).
Rudkin, F. M., Walls, J. M., Lewis, L. E., Gow, N. A. R. & Erwig, L. P. Altered dynamics of Candida albicans phagocytosis by macrophages and PMNs when both phagocyte subsets are present. mBio 4, e00810-13 (2013).
Ngo, L. Y. et al. Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis. J. Infect. Dis. 209, 109–119 (2014).
Lionakis, M. S. et al. CX3CR1- dependent renal macrophage survival promotes Candida control and host survival. J. Clin. Invest. 123, 5035–5051 (2013).
Uzun, O., Ascioglu, S., Anaissie, E. J. & Rex, J. H. Risk factors and predictors of outcome in patients with cancer and breakthrough candidemia. Clin. Infect. Dis. 32, 1713–1717 (2001).
Lionakis, M. S., Lim, J. K. & Murphy, P. M. Organ-specific innate immune responses in a mouse model of invasive candidiasis. J. Innate Immun. 3, 180–199 (2011).
Edens, H. A., Kiang, C. A., Jesuits, T. W., Cutler, J. E. & Miettinen, H. M. Non-serum-dependent chemotactic factors produced by Candida albicans stimulate chemotaxis by binding to the formyl peptide receptor on neutrophils and to an unknown receptor on macrophages. Infect. Immun. 67, 1063–1071 (1999).
Geiger, J., Wessels, D., Lockhart, S. R. & Soll, D. R. Release of a potent polymorphonuclear leukocyte chemoattractant is regulated by white-opaque switching in Candida albicans. Infect. Immun. 72, 667–677 (2004).
Klippel, N., Cui, S., Groebe, L. & Bilitewski, U. Deletion of the Candida albicans histidine kinase gene CHK1 improves recognition by phagocytes through an increased exposure of cell wall β-1,3-glucans. Microbiology 156, 3432–3444 (2010).
Erwig, L. P. et al. Differential regulation of phagosome maturation in macrophages and dendritic cells mediated by rho GTPases and ezrin-radixin-moesin (ERM) proteins. Proc. Natl Acad. Sci. USA 103, 12825–12830 (2006).
McKenzie, C. G. et al. Contribution of Candida albicans cell wall components to recognition by and escape from murine macrophages. Infect. Immun. 78, 1650–1658 (2010).
Jouault, T. et al. Early signal transduction induced by Candida albicans in macrophages through shedding of a glycolipid. J. Infect. Dis. 178, 792–802 (1998).
Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).
Tóth, R. et al. Kinetic studies of Candida parapsilosis phagocytosis by macrophages and detection of intracellular survival mechanisms. Front Microbiol. 5, 633 (2014).
Schäfer, K., Bain, J. M., Di Pietro, A., Gow, N. A. R. & Erwig, L. P. Hyphal growth of phagocytosed Fusarium oxysporum causes cell lysis and death of murine macrophages. PLoS ONE. 5, e101999 (2014).
Erwig, L. P. & Henson, P. M. Clearance of apoptotic cells by phagocytes. Cell Death Differ. 15, 243–250 (2008).
Knox, B. P. et al. Distinct innate immune phagocyte responses to Aspergillus fumigatus conidia and hyphae in zebrafish larvae. Eukaryot. Cell 10, 1266–1277 (2014).
Finkel-Jimenez, B., Wüthrich, M. & Klein, B. S. BAD1, an essential virulence factor of Blastomyces dermatitidis, suppresses host TNF-α production through TGF-β-dependent and –independent mechanisms. J. Immunol. 168, 5746–57755 (2002).
Rappleye, C. A. & Goldman, W. E. Fungal stealth technology. Trends Immunol. 29, 18–24 (2008).
Fairn, G. D. & Grinstein, S. How nascent phagosomes mature to become phagolysosomes. Trends Immunol. 33, 397–405 (2012).
Flannagan, R. S., Cosio, G. & Grinstein, S. Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nat. Rev. Microbiol. 7, 355–366 (2009).
Eissenberg, L. G., Goldman, W. E. & Schlesinger, P. H. Histoplasma capsulatum modulates the acidification of phagolysosomes. J. Exp. Med. 177, 1605–1611 (1993).
Seider, K. et al. The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation. J. Immunol. 187, 3072–3086 (2011).
Fernández-Arenas, E. et al. Candida albicans actively modulates intracellular membrane trafficking in mouse macrophage phagosomes. Cell. Microbiol. 11, 560–589 (2009).
Bain, J. M. et al. Candida albicans hypha formation and mannan masking of β-glucan inhibit macrophage phagosome maturation. mBio 5, e01874 (2014). This report gives a detailed temporal analysis of the mechanisms that underlie fungal cell interference of macrophage phagosome maturation.
Enjalbert, B. et al. Role of the Hog1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans. Mol. Biol. Cell. 17, 1018–1032 (2006).
da Silva Dantas, A. et al. Thioredoxin regulates multiple hydrogen peroxide-induced signaling pathways in Candida albicans. Mol. Cell. Biol. 30, 4550–4563 (2010).
Patterson, M. J. et al. Ybp1 and Gpx3 signaling in Candida albicans govern hydrogen peroxide-induced oxidation of the Cap1 transcription factor and macrophage escape. Antioxid. Redox Signal. 19, 2244–2260 (2013).
Brothers, K. M. et al. NADPH oxidase-driven phagocyte recruitment controls Candida albicans filamentous growth and prevents mortality. PLoS Pathog. 9, e1003634 (2013).
Tillman, A. et al. Contribution of Fdh3 and Glr1 to glutathione redox state, stress adaptation and virulence in Candida albicans. PLoS ONE. 10, e0126940 (2015).
Káposzta, R., Maródi, L., Hollinshead, M., Gordon, S. & da Silva, R. P. Rapid recruitment of late endosomes and lysosomes in mouse macrophages ingesting Candida albicans. J. Cell Sci. 112, 3237–3248 (1999).
Vylkova, S. & Lorenz, M. C. Modulation of phagosomal pH by Candida albicans promotes hyphal morphogenesis and requires Stp2p, a regulator of amino acid transport. PLoS Pathog. 10, e1003995 (2014).
Danhof, H. A. & Lorenz, M. C. The Candida albicans ATO gene family promotes neutralization of the macrophage phagolysosome. Infect. Immun. 83, 4416–4426 (2015).
Alvarez-Dominguez, C. et al. Characterization of a Listeria monocytogenes protein interfering with Rab5a. Traffic. 9, 325–337 (2008).
Gutierrez, M. G. Functional role(s) of phagosomal Rab GTPases. Small GTPases 4, 148–158 (2013).
Garin, J. et al. The phagosome proteome: insight into phagosome functions. J. Cell Biol. 152, 165–180 (2001).
Bakowski, M. A. et al. The phosphoinositide phosphatase SopB manipulates membrane surface charge and trafficking of the Salmonella-containing vacuole. Cell Host Microbe 7, 453–462 (2010).
Okai, B., Lyall, N., Gow, N. A., Bain, J. M. & Erwig, L. P. Rab14 regulates maturation of macrophage phagosomes containing the fungal pathogen Candida albicans and outcome of the host–pathogen interaction. Infect. Immun. 83, 1523–1535 (2015).
Mansour, M. K. et al. Dectin-1 activation controls maturation of β-1,3-glucan-containing phagosomes. J. Biol. Chem. 288, 16043–16054 (2013).
Strijbis, K. et al. Bruton's Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages. PLoS Pathog. 9, e1003446 (2013).
Artavanis-Tsakonas, K., Love, J. C., Ploegh, H. L. & Vyas, J. M. Recruitment of CD63 to Cryptococcus neoformans phagosomes requires acidification. Proc. Natl Acad. Sci. USA 103, 15945–15950 (2006).
Levitz, S. M. et al. Cryptococcus neoformans resides in an acidic phagolysosome of human macrophages. Infect. Immun. 67, 885–890 (1999).
Smith, L. M., Dixon, E. F. & May, R. C. The fungal pathogen Cryptococcus neoformans manipulates macrophage phagosome maturation. Cell. Microbiol. 17, 702–713 (2015).
Kasper, L. et al. Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages. PLoS ONE. 9, e96015 (2014).
Krysan, D. J., Sutterwala F. S. & Wellington M. Catching fire: Candida albicans, macrophages, and pyroptosis. PLoS Pathog. 10, e1004139 (2014).
Wellington, M., Koselny, K., Sutterwala, F. S. & Krysan, D. J. Candida albicans triggers NLRP3-mediated pyroptosis in macrophages. Eukaryot. Cell. 13, 329–340 (2014). First paper to suggest that fungal pathogens may escape host macrophages by pyroptosis rather than the hyphal mediated piercing of the cell membrane.
Wellington, M., Koselny, K. & Krysan, D. J. Candida albicans morphogenesis is not required for macrophage interleukin 1β production. mBio 4, e00433 (2012).
O'Meara, T. R. et al. Global analysis of fungal morphology exposes mechanisms of host cell escape. Nat. Commun. 6, 6741 (2015).
Uwanahoro, N. et al. The pathogen Candida albicans hijacks pyroptosis for escape from macrophages. mBio 5, e00003-14 (2014).
Ma, H., Croudace, J. E., Lammas, D. A. & May, R. C. Expulsion of live pathogenic yeast by macrophages. Curr. Biol. 16, 2156–2160 (2006).
Alvarez, M. & Casadevall, A. Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages. Curr. Biol. 16, 2161–2165 (2006).
Bain, J. M. et al. Non-lytic expulsion/exocytosis of Candida albicans from macrophages. Fungal Genet. Biol. 49, 677–678 (2012).
García-Rodas, R., Gonzalez-Camancho, F., Rodriguez-Tudela, J. L., Cuenca-Estrella, M. & Zaragoza, O. The interaction between Candida krusei and murine macrophages results in multiple outcomes, including intracellular survival and escape from killing. Infect. Immun. 79, 2136–2144 (2011).
Nicola, A. M., Robertson, E. J., Albuquerque, P., da Silveira Derengowski, L. & Casadevall, A. Nonlytic exocytosis of Cryptococcus neoformans from macrophages occurs in vivo and is influenced by phagosomal pH. mBio 2, e00167-11 (2011).
Johnston, S. A. & May, R. C. The human fungal pathogen Cryptococcus neoformans escapes macrophages by a phagosome emptying mechanism that is inhibited by Arp2/3 complex-mediated actin polymerisation. PLoS Pathog. 6, e1001041 (2010).
Heinsbroek, S. E. M. et al. Actin and phosphoinositide recruitment of fully formed Candida albicans phagosomes in mouse macrophages. Innate Immunol. 1, 244–253 (2009).
Robbins, J. R. et al.Listeria monocytogenes exploits normal host cell processes to spread from cell to cell. J. Cell Biol. 146, 1333–1350 (1999).
Casadevall, A. Cryptococci at the brain gate: break and enter or use a Trojan horse? J. Clin. Invest. 120, 1389–1392 (2010).
Lewis, L. E., Bain, J. M., Lowe, C., Gow, N. A. R. & Erwig, L.-P. Candida albicans infection inhibits macrophage cell division and proliferation. Fungal Genet. Biol. 49, 679–680 (2012).
Ma, H., Croudace, J. E., Lammas, D. A. & May, R. C. Direct cell-to-cell spread of a pathogenic yeast. BMC Immunol. 8, 8–15 (2007).
Chrisman, C. J., Albuquerque, P., Guimaraes, A. J., Nieves, E. & Casadevall, A. Phospholipids trigger Cryptococcus neoformans capsular enlargement during interactions with amoebae and macrophages. PLoS Pathog. 7, e1002047 (2011).
Gow, N. A. R. & Hube, B. Importance of the Candida albicans cell wall during commensalism and infection. Curr. Opin. Microbiol. 4, 406–412 (2012).
Brown, G. D. Innate antifungal immunity: the key role of phagocytes. Annu. Rev. Immunol. 29, 1–21 (2011).
Hardison, S. E. & Brown, G. D. C-type lectin receptors orchestrate antifungal immunity. Nat. Immunol. 9, 817–822 (2012).
Netea, M. G., Brown, G. D., Kullberg, B. J. & Gow, N. A. R. An integrated model of the recognition of Candida albicans by the innate immune system. Nat. Rev. Microbiol. 1, 67–78 (2008).
Winterbourn, C. C., Hampton, M. B., Livesey, J. H. & Kettle, A. J. Modelling the reactions of superoxide and myeloperoxidase in the neutrophil phagosome: implications for microbial killing. J. Biol. Chem. 281, 39860–39869 (2006).
Brown, A. J. P., Haynes, K., Gow, N. A. R. & Quinn, J. in Candida and Candidiasis. (eds Calderone, R. A. & Clancy, C. J.) 225–242 (ASM Press, 2012).
Kaloriti, D. et al. Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes. mBio 5, e01334-14 (2014).
Arnett, E., Lehrer, R. I., Pratikhya, P., Lu, W. & Seveau, S. Defensins enable macrophages to inhibit intracellular proliferation of Listeria monocytogenes. Cell. Microbiol. 13, 635–651 (2011).
Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell. Biol. 10, 513–525 (2009).
de Barsy, M. et al. Identification of a Brucella spp. secreted effector specifically interacting with human small GTPase Rab2. Cell. Microbiol. 13, 1044–1058 (2011).
Kuijl, C. et al. Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1. Nature 450, 725–730 (2007).
Ninio, S. & Roy, C. R. Effector proteins translocated by Legionella pneumophila: strength in numbers. Trends Microbiol. 15, 372–380 (2007).
Ma, et al. Mechanisms of adaptation to life exclusively in mammalian hosts by Pneumocystis. Nat. Commun. (in press) (2015).
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).
The authors declare no competing financial interests.
An infection of the cornea that can often lead to blindness.
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.
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.
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.
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.
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.
A type of asexual spore formed by many types of the filamentous ascomycete group of fungi, including Aspergillus species.
Conjoined elongated yeast cells typical of most pathogenic Candida species.
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.
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.
A class of antifungal drug that targets the synthesis of β-1,3-glucan in the fungal cell wall.
(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.
(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.
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.
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.
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).
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.
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.
About this article
Cite this article
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
Differences in fungal immune recognition by monocytes and macrophages: N-mannan can be a shield or activator of immune recognition
The Cell Surface (2020)
Frontiers in Microbiology (2020)
Toll/IL-1 receptor-containing proteins STIR-1, STIR-2 and STIR-3 synergistically assist Yersinia ruckeri SC09 immune escape
Fish & Shellfish Immunology (2020)
Distinct Roles for Dectin-1 and Dectin-2 in Skin Wound Healing and Neutrophilic Inflammatory Responses
Journal of Investigative Dermatology (2020)
Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence
Cellular Microbiology (2020)