Nature of β-1,3-Glucan-Exposing Features on Candida albicans Cell Wall and Their Modulation

• Published in: mBio Vol. 13; no. 6; p. e0260522
• Main Authors: de Assis, Leandro José, Bain, Judith M., Liddle, Corin, Leaves, Ian, Hacker, Christian, Peres da Silva, Roberta, Yuecel, Raif, Bebes, Attila, Stead, David, Childers, Delma S., Pradhan, Arnab, Mackenzie, Kevin, Lagree, Katherine, Larcombe, Daniel E., Ma, Qinxi, Avelar, Gabriela Mol, Netea, Mihai G., Erwig, Lars P., Mitchell, Aaron P., Brown, Gordon D., Gow, Neil A. R., Brown, Alistair J. P.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.12.2022
• Subjects: Antifungal Agents - pharmacology; beta-Glucans - metabolism; Candida albicans; cell wall; Cell Wall - metabolism; Cicatrix - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Glucans - metabolism; Lactates - metabolism; Mig1; Mig2; Mycology; Pathogen-Associated Molecular Pattern Molecules; protein kinase A; Research Article; β-1,3-glucan; Candida albicans; Eng1; Mig1; Mig2; Xog1; β-1,3-glucan; Sin3; cell wall; protein kinase A
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.02605-22

Microbes that coexist with humans have evolved ways of avoiding or evading our immunological defenses. These include the masking by these microbes of their “pathogen-associated molecular patterns” (PAMPs), which are recognized as “foreign” and used to activate protective immunity. Candida albicans exists as a commensal of mucosal surfaces and the gastrointestinal tract without causing pathology. However, this fungus is also a common cause of mucosal and systemic infections when antifungal immune defenses become compromised. The activation of antifungal host defenses depends on the recognition of fungal pathogen-associated molecular patterns (PAMPs), such as β-1,3-glucan. In C. albicans , most β-1,3-glucan is present in the inner cell wall, concealed by the outer mannan layer, but some β-1,3-glucan becomes exposed at the cell surface. In response to host signals, such as lactate, C. albicans induces the Xog1 exoglucanase, which shaves exposed β-1,3-glucan from the cell surface, thereby reducing phagocytic recognition. We show here that β-1,3-glucan is exposed at bud scars and punctate foci on the lateral wall of yeast cells, that this exposed β-1,3-glucan is targeted during phagocytic attack, and that lactate-induced masking reduces β-1,3-glucan exposure at bud scars and at punctate foci. β-1,3-Glucan masking depends upon protein kinase A (PKA) signaling. We reveal that inactivating PKA, or its conserved downstream effectors, Sin3 and Mig1/Mig2, affects the amounts of the Xog1 and Eng1 glucanases in the C. albicans secretome and modulates β-1,3-glucan exposure. Furthermore, perturbing PKA, Sin3, or Mig1/Mig2 attenuates the virulence of lactate-exposed C. albicans cells in Galleria. Taken together, the data are consistent with the idea that β-1,3-glucan masking contributes to Candida pathogenicity. IMPORTANCE Microbes that coexist with humans have evolved ways of avoiding or evading our immunological defenses. These include the masking by these microbes of their “pathogen-associated molecular patterns” (PAMPs), which are recognized as “foreign” and used to activate protective immunity. The commensal fungus Candida albicans masks the proinflammatory PAMP β-1,3-glucan, which is an essential component of its cell wall. Most of this β-1,3-glucan is hidden beneath an outer layer of the cell wall on these microbes, but some can become exposed at the fungal cell surface. Using high-resolution confocal microscopy, we examine the nature of the exposed β-1,3-glucan at C. albicans bud scars and at punctate foci on the lateral cell wall, and we show that these features are targeted by innate immune cells. We also reveal that downstream effectors of protein kinase A (Mig1/Mig2, Sin3) regulate the secretion of major glucanases, modulate the levels of β-1,3-glucan exposure, and influence the virulence of C. albicans in an invertebrate model of systemic infection. Our data support the view that β-1,3-glucan masking contributes to immune evasion and the virulence of a major fungal pathogen of humans.