Non-canonical signalling mediates changes in fungal cell wall PAMPs that drive immune evasion.
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ABSTRACT:
SUBMITTER: Pradhan A
PROVIDER: S-EPMC6876565 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As they proliferate, fungi expose antigens at their cell surface that are potent stimulators of the innate immune response, and yet the commensal fungus Candida albicans is able to colonize immuno competent individuals. We show that C. albicans may evade immune detection by presenting a moving immunological target. We report that the exposure of β-glucan, a key pathogen-associated molecular pattern (PAMP) located at the cell surface of C. albicans and other pathogenic Candida species, is modulated in response to changes in the carbon source. Exposure to lactate induces β-glucan masking in C. albicans via a signalling pathway that has recruited an evolutionarily conserved receptor (Gpr1) and transcriptional factor (Crz1) from other well-characterized pathways. In response to lactate, these regulators control the expression of cell-wall-related genes that contribute to β-glucan masking. This represents the first description of active PAMP masking by a Candida species, a process that reduces the visibility of the fungus to the immune system.
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Project description:The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armour is critical for fungal cell homeostasis and survival. Yet essential cell wall moieties, such as β-1,3-glucan, are recognised as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen, Candida albicans, masks β-1,3-glucan following exposure to lactate, hypoxia or iron depletion. However, the precise mechanism(s) by which C. albicans masks β-1,3-glucan have remained obscure. Here, we performed proteomic analysis of cell walls from C. albicans cells grown in hypoxia or lactate compared to glucose-grown controls to identify mechanisms driving β-1,3-glucan masking.
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Project description:Experiment Description RNA sequencing was performed on Candida albicans wild type cells (SC5314) grown to exponential phase on YNB Lactate, YNB Glucose, or YNB Glucose plus Lactate, and compared to exponential Candida albicans crz1 cells grown on YNB Glucose or YNB Glucose plus Lactate. Three independent experiments were performed.
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Project description: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 Candida albicans masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans 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 XOG1 blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 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.IMPORTANCE 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 Candida albicans 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 XOG1-mediated "shaving" of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans 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.
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Project description:Candida albicans is a commensal yeast of the human gut, which is tolerated by the immune system, but has the potential to become an opportunistic pathogen. One way in which C. albicans achieves this duality is through the concealing, or exposure of cell wall associated pathogen-associated molecular patterns (PAMPs) in response to host derived environment cues (pH, hypoxia, lactate). This cell wall remodelling allows C. albicans to evade or hyperactivate the host’s innate immune responses leading to disease. Previously we identified that adaptation of C. albicans to acidic environments, conditions encountered during colonisation of the female reproductive tract, induce significant cell wall remodelling resulting in the exposure of two key fungal PAMPs (glucan and chitin). Here we report that this pH-dependent cell wall remodelling is a highly dynamic process, requiring periods of both cell wall unmasking, with peak PAMP exposure occurring between 2-4 hrs, followed by subsequent PAMP remasking. b-glucan remasking was mediated via the cell density dependent fungal quorum sensing molecule farnesol, while chitin remasking was mediated via a small, heat-stable, non-proteinaceous secreted molecule(s). Transcript profiling identified a core set of 42 genes significantly regulated by pH over time, and linked the transcription factor Efg1p to being the main regulator of chitin exposure through regulation of CHT2. This dynamic cell wall remodelling, influenced innate immune recognition of C. albicans, suggesting that during infection C. albicans can manipulate the host innate immune responses.
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