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Nature of 尾-1,3-Glucan-Exposing Features on Candida albicans Cell Wall and Their Modulation
10.1128/mbio.02605-22
Leandro Jos茅 de Assis
Judith M. Bain
Corin Liddle
Ian Leaves
Christian Hacker
Roberta Peres da Silva
Raif Yuecel
Attila Bebes
David Stead
Delma S. Childers
Arnab Pradhan
Kevin Mackenzie
Katherine Lagree
Daniel E. Larcombe
Qinxi Ma
Gabriela Mol Avelar
Mihai G. Netea
Lars P. Erwig
Aaron P. Mitchell
Gordon D. Brown
Neil A. R. Gow
Alistair J. P. Brown
Research Article
Research Article
Candida albicans
cell wall
尾-1,3-glucan
protein kinase A
Mig1
Mig2
Sin3
Xog1
Eng1
American Society for Microbiology
de Assis et al.
Copyright 漏 2022 de Assis et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
20221011
2022
ABSTRACT
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 尾-1,3-glucan. In C. albicans, most 尾-1,3-glucan is present in the inner cell wall, concealed by the outer mannan layer, but some 尾-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 尾-1,3-glucan from the cell surface, thereby reducing phagocytic recognition. We show here that 尾-1,3-glucan is exposed at bud scars and punctate foci on the lateral wall of yeast cells, that this exposed 尾-1,3-glucan is targeted during phagocytic attack, and that lactate-induced masking reduces 尾-1,3-glucan exposure at bud scars and at punctate foci. 尾-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 尾-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 尾-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 鈥減athogen-associated molecular patterns鈥 (PAMPs), which are recognized as 鈥渇oreign鈥 and used to activate protective immunity. The commensal fungus Candida albicans masks the proinflammatory PAMP 尾-1,3-glucan, which is an essential component of its cell wall. Most of this 尾-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 尾-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 尾-1,3-glucan exposure, and influence the virulence of C. albicans in an invertebrate model of systemic infection. Our data support the view that 尾-1,3-glucan masking contributes to immune evasion and the virulence of a major fungal pathogen of humans.
20220916
20220919
2150-7511
Adobe LiveCycle PDF Generator; modified using iText庐 5.5.13.2 漏2000-2020 iText Group NV (AGPL-version)2023-04-04T07:47:54-07:00
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