Epitope Shaving Promotes Fungal Immune Evasion

• Published in: mBio Vol. 11; no. 4
• Main Authors: Childers, Delma S, Avelar, Gabriela Mol, Bain, Judith M, Pradhan, Arnab, Larcombe, Daniel E, Netea, Mihai G, Erwig, Lars P, Gow, Neil A R, Brown, Alistair J P
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 07-07-2020
• Subjects: Anaerobiosis; Animals; Candida albicans; Candida albicans - drug effects; Candida albicans - enzymology; Candida albicans - immunology; castanospermine; cell wall; Cellulose 1,4-beta-Cellobiosidase - antagonists & inhibitors; Cellulose 1,4-beta-Cellobiosidase - metabolism; Epitopes - immunology; Host-Microbe Biology; Immune Evasion; Lactic Acid - pharmacology; Larva - microbiology; Macrophages - microbiology; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Moths - microbiology; Xog1 exoglucanase; β-glucan shaving; Candida albicans; β-glucan shaving; castanospermine; immune evasion; virulence; Xog1 exoglucanase; cell wall
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.00984-20

The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen
masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which
masks β-1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced β-glucan "masking" pathway to promote β-1,3-glucan "shaving." Inactivation of
blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless,
deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines β-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes.
The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen
exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of β-glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating
-mediated "shaving" of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates
virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion.