Epitope Shaving Promotes Fungal Immune Evasion

Abstract

<jats:title>ABSTRACT</jats:title> <jats:p>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 <jats:named-content content-type="genus-species">Candida albicans</jats:named-content> masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which <jats:named-content content-type="genus-species">C. albicans</jats:named-content> 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 <jats:italic>XOG1</jats:italic> blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, <jats:italic>XOG1</jats:italic> 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.</jats:p> <jats:p><jats:bold>IMPORTANCE</jats:bold> 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 <jats:named-content content-type="genus-species">Candida albicans</jats:named-content> 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 <jats:italic>XOG1</jats:italic>-mediated “shaving” of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates <jats:named-content content-type="genus-species">C. albicans</jats:named-content> 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.</jats:p>

Clinical Candida albicans Vaginal Isolates and a Laboratory Strain Show Divergent Behaviors during Macrophage Interactions

“…In VSM, there also appeared to be group-specific effects for asymptomatic strains (less chitin) and acute strains (more β-glucan) compared to SC5314 and the other tested strains. Since β-glucan masking in lactate containing media such as VSM has been reported to reduce immune visibility ( 19 ), our results imply specifically that the acute strains might be more immunoreactive. This would fit to the common view that clinical symptoms during acute vaginal infections are mostly accounted for host-driven hyperinflammatory response toward Candida colonization ( 7 ).…”

“…It is known that fungal β-glucan is highly immuno-reactive ( 16 ) and β-glucan masking by mannan can inhibit fungal recognition and killing by macrophages ( 17 , 18 ). Nutritional factors, such as lactate, can induce β-glucan masking mediated by the exoglucanase Xog1 presumably as a strategy to reduce the visibility of the commensal fungus to the immune system ( 19 ). Here, we compared surface exposure of the cell wall components of the vaginal isolates when grown either in commonly used laboratory rich medium (YPD) or in niche-specific vaginal simulating medium (VSM).…”

The impact of the Fungus-Host-Microbiota interplay uponCandida albicansinfections: current knowledge and new perspectives

“…Our deeper comprehension of fungal immune evasion strategies affords the potential to block these phenotypes and thereby enhance the efficacy of natural antifungal immunity mechanisms (Childers et al . 2020 ). Significantly, the dramatic expansion in genomic and phenotypic datasets for clinical isolates of C. albicans is providing a much clearer picture of the nature of fungal variability and in-patient evolution (Selmecki, Forche and Berman 2006 ; Ford et al .…”

Anticipatory Stress Responses and Immune Evasion in Fungal Pathogens

“…This β-glucan masking reduces phagocytic recognition and attenuates immune responses against the fungus [91,93,94,96]. β-Glucan 'masking' is mediated by the exoglucanase, Xog1, which 'shaves' exposed β-glucan from the cell surface [97]. Some other, but not all, pathogenic Candida species display hypoxia-induced β-glucan masking, but there is no obvious relationship between phylogeny and phenotype [93].…”

“…virulence [97]. Therefore, drugs that block fungal immune evasion [97], or that promote exposure of proinflammatory PAMPs by modulating cell wall remodeling pathways [105], might prove useful for antifungal therapy.…”