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

Assis, Leandro José de; Bain, Judith M.; Liddle, Corin; Leaves, Ian; Hacker, Christian; Silva, Roberta Peres da; Bebes, Attila; Stead, David; Childers, Delma S.; Pradhan, Arnab; MacKenzie, K.; Lagree, Katherine; Larcombe, Daniel E.; Ma, Qinxi; Avelar, Gabriela Mól; Netea, Mihai G.; Erwig, Lars P.; Mitchell, Aaron P.; Brown, Gordon D.; Gow, Neil A. R.; Brown, Alistair J. P.

doi:10.1128/mbio.02605-22

Cited by 25 publications

(35 citation statements)

References 104 publications

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“…Immune evasion through epitope masking result in decreased recognition by host immune cells, such as macrophages which should result in increased survival of C. albicans when challenged with macrophages (13, 22). However, in our hands, deletion of GPR1 results in a significantly lower survival rate (p = 0,0001) compared to SC5314 in such a macrophage co-culture assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Differential sensing by theC. albicansGpr1 receptor results in morphogenesis, β-glucan masking and survival in macrophages

Genechten

Wijnants

Vreys

et al. 2022

Preprint

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The human fungal pathogen, Candida albicans, is very proficient at several classical virulence factors such as morphogenesis, adhesion, biofilm formation and immune evasion through β-glucan masking. The protein kinase A (PKA) pathway is involved in both morphogenesis and β-glucan masking. Several signals converge onto the PKA pathway, but it contains only a single upstream G-protein coupled receptor, Gpr1. We identified specific residues within the N-terminal tail of Gpr1 that are required for methionine-induced morphogenesis through Tpk2. Furthermore, we observe that Gpr1-Gpa2 has an active role in exposing glucans. Even though Gpr1 is required for survival when C. albicans is challenged with macrophages, specifically disrupting morphogenesis did not attenuate this survival. Additionally, constitutive The human fungal pathogen, Candida albicans, is very proficient at several classical virulence factors such as morphogenesis, adhesion, biofilm formation and immune evasion through β-glucan masking. The protein kinase A (PKA) pathway is involved in both morphogenesis and β-glucan masking. Several signals converge onto the PKA pathway, but it contains only a single upstream G-protein coupled receptor, Gpr1. We identified specific residues within the N-terminal tail of Gpr1 that are required for methionine-induced morphogenesis through Tpk2. Furthermore, we observe that Gpr1-Gpa2 has an active role in exposing glucans. Even though Gpr1 is required for survival when C. albicans is challenged with macrophages, specifically disrupting morphogenesis did not attenuate this survival. Additionally, constitutive β-glucan masking did not improve C. albicans survival rates in the macrophage assay. Taken together, this indicates that Gpr1 may regulate additional mechanisms, possibly through glutamine 461, which are crucial in a macrophage context. β-glucan masking did not improve C. albicans survival rates in the macrophage assay. Taken together, this indicates that Gpr1 may regulate additional mechanisms, possibly through glutamine 461, which are crucial in a macrophage context.

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Section: Resultsmentioning

confidence: 99%

“…This illustrates that this novel pathway utilizes components, Gpr1, Cag1 and Crz1, from different well-characterized pathways (12). Nevertheless, recent papers report a role of the PKA pathway in β-glucan masking through Sin3 and Mig1/Mig2 regulating exo- and endoglucanases (13).…”

Section: Introductionmentioning

confidence: 99%

Differential sensing by theC. albicansGpr1 receptor results in morphogenesis, β-glucan masking and survival in macrophages

Genechten

Wijnants

Vreys

et al. 2022

Preprint

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“…HAT1 regulated histone modifications and was the target of ACE2 ( Pinto et al., 2020 ). SIN3 increased the virulence of lactate-exposed Candida; TAF10 controlled the drug tolerance and virulence of C. albicans ( de Assis et al., 2022 ) . Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation as an eraser in vivo ( Kelly et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection

Zhang

Ma²,

Liu³

et al. 2023

Front. Cell. Infect. Microbiol.

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Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most commonly encountered bacteria found in healthcare clinics and has been ranked a priority 2 pathogen. Research is urgently needed to develop new therapeutic approaches to combat the pathogen. Variations in the pattern of protein posttranslational modifications (PTMs) of host cells affect physiological and pathological events, as well as therapeutic effectiveness. However, the role of crotonylation in MRSA-infected THP1 cells remains unknown. In this study, we found that crotonylation profiles of THP1 cells were altered after MRSA infection. It was then confirmed that lysine crotonylation profiles of THP1 cells and bacteria were different; MRSA infection inhibited global lysine crotonylation (Kcro) modification but partially elevated Kcro of host proteins. We obtained a proteome-wide crotonylation profile of THP1 cells infected by MRSA further treated by vancomycin, leading to the identification of 899 proteins, 1384 sites of which were down-regulated, and 160 proteins with 193 sites up-regulated. The crotonylated down-regulated proteins were mainly located in cytoplasm and were enriched in spliceosome, RNA degradation, protein posttranslational modification, and metabolism. However, the crotonylated up-regulated proteins were mainly located in nucleus and significantly involved in nuclear body, chromosome, ribonucleoprotein complex, and RNA processing. The domains of these proteins were significantly enriched on RNA recognition motif, and linker histone H1 and H5 families. Some proteins related to protecting against bacterial infection were also found to be targets of crotonylation. The present findings point to a comprehensive understanding of the biological functions of lysine crotonylation in human macrophages, thereby providing a certain research basis for the mechanism and targeted therapy on the immune response of host cells against MRSA infection.

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“…The polymer, β‐(1,3)‐glucan, is an essential component of the cell walls of many fungi 27 . In C. albicans , most β‐(1,3)‐glucan is present in the inner cell wall, buried beneath the outer layer of mannan fibrils, 28 but some β‐(1,3)‐glucan becomes exposed at septal junctions between mother‐daughter cells, at bud scars and at punctate foci on the cell surface 29 . Also, β‐(1,3)‐glucan on the lateral cell wall can become exposed in vivo through stripping of the mannan outer layer by neutrophil attack 30 .…”

Section: Underlying Similarities In Immune Evasion Between Evolutiona...mentioning

confidence: 99%

“… 27 In C. albicans , most β‐(1,3)‐glucan is present in the inner cell wall, buried beneath the outer layer of mannan fibrils, 28 but some β‐(1,3)‐glucan becomes exposed at septal junctions between mother‐daughter cells, at bud scars and at punctate foci on the cell surface. 29 Also, β‐(1,3)‐glucan on the lateral cell wall can become exposed in vivo through stripping of the mannan outer layer by neutrophil attack. 30 To promote concealment, C. albicans secretes an exoglucanase (Xog1) and an endoglucanase (Eng1) that shave exposed β‐(1,3)‐glucan from the cell surface.…”

Section: Underlying Similarities In Immune Evasion Between Evolutiona...mentioning

confidence: 99%

Fungal resilience and host–pathogen interactions: Future perspectives and opportunities

Brown

2022

Parasite Immunology

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We are constantly exposed to the threat of fungal infection. The outcome—clearance, commensalism or infection—depends largely on the ability of our innate immune defences to clear infecting fungal cells versus the success of the fungus in mounting compensatory adaptive responses. As each seeks to gain advantage during these skirmishes, the interactions between host and fungal pathogen are complex and dynamic. Nevertheless, simply compromising the physiological robustness of fungal pathogens reduces their ability to evade antifungal immunity, their virulence, and their tolerance against antifungal therapy. In this article I argue that this physiological robustness is based on a ‘Resilience Network’ which mechanistically links and controls fungal growth, metabolism, stress resistance and drug tolerance. The elasticity of this network probably underlies the phenotypic variability of fungal isolates and the heterogeneity of individual cells within clonal populations. Consequently, I suggest that the definition of the fungal Resilience Network represents an important goal for the future which offers the clear potential to reveal drug targets that compromise drug tolerance and synergise with current antifungal therapies.

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

Abstract: 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.

Cited by 25 publications

References 104 publications

Differential sensing by theC. albicansGpr1 receptor results in morphogenesis, β-glucan masking and survival in macrophages

Differential sensing by theC. albicansGpr1 receptor results in morphogenesis, β-glucan masking and survival in macrophages

Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection

Fungal resilience and host–pathogen interactions: Future perspectives and opportunities

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