Estrogen promotes innate immune evasion of Candida albicans through inactivation of the alternative complement system.
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ABSTRACT:
SUBMITTER: Kumwenda P
PROVIDER: S-EPMC8755443 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Candida albicans is a commensal of the urogenital tract and the predominant cause of vulvovaginal candidiasis (VVC). Roughly, 70% of otherwise healthy women succumb to VVC at least once in their life time. Elevated oestrogen levels are associated with C. albicans colonisation of the vagina and symptomatic infection. However, little is known about how C. albicans adapts to oestrogen. Here, we investigate how adaptation of C. albicans to elevated concentrations of oestrogen on the C. albicans host-pathogen interaction. Growth of C. albicans in physiological relevant concentrations of oestrogen promoted fungal innate immune evasion through reduction of both macrophage and neutrophil phagocytosis. Oestrogen-induced innate immune evasion was mediated via inhibition of opsonophagocytosis through enhanced Gpd2 dependent acquisition of Factor H on the fungal cell surface. The zebrafish larval model of infection confirmed that in vivo oestrogen and Gpd2 promote pathogenicity. Understanding the impact of oestrogen on C. albicans host-pathogen interaction will help improve our knowledge on how oestrogen promotes VVC.
2022-01-04 | GSE145240 | GEO
Project description:Oestrogen promotes innate immune invasion of Candida albicans through inactivation of complement
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Project description:Candida albicans strains that are homozygous at the mating type locus can spontaneously and reversibly switch from the normal yeast morphology (white) to an elongated cell type (opaque), which is the mating-competent form of the fungus. White-opaque switching also influences the ability of C. albicans to colonize and proliferate in specific host niches and its susceptibility to host defense mechanisms. We used live imaging to observe the interaction of white and opaque cells with host phagocytic cells. For this purpose, we generated derivatives of the switching-competent strain WO-1 that express green fluorescent protein from a white-specific promoter and red fluorescent protein from an opaque-specific promoter or vice versa. When mixed populations of these differentially labeled white and opaque cells were incubated with human polymorphonuclear neutrophils (PMNs) on a glass slide, the neutrophils selectively phagocytosed and killed white cells, despite frequent physical interaction with opaque cells. White cells were attacked only after they started to form a germ tube, indicating that the suppression of filamentation in opaque cells saved them from recognition by the PMNs. In contrast to neutrophils, dendritic cells internalized white as well as opaque cells. However, when embedded in a collagen matrix, the PMNs also phagocytosed both white and opaque cells with similar efficiency. These results suggest that, depending on the environment, white-opaque switching enables C. albicans to escape from specific host defense mechanisms.
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Project description:Candida albicans binds and utilizes human complement inhibitors, such as C4b-binding protein (C4BP), Factor H, and FHL-1 for immune evasion. Here, we identify Candida pH-regulated antigen 1 (Pra1) as the first fungal C4BP-binding protein. Recombinant Pra1 binds C4BP, as shown by ELISA and isothermal titration calorimetry, and the Pra1-C4BP interaction is ionic in nature. The Pra1 binding domains within C4BP were localized to the complement control protein domain 4 (CCP4), CCP7, and CCP8. C4BP bound to Pra1 maintains complement-inhibitory activity. C4BP and Factor H bind simultaneously to Candida Pra1 and do not compete for binding at physiological levels. A Pra1-overexpressing C. albicans strain, which had about 2-fold Pra1 levels at the surface acquired also about 2-fold C4BP to the surface, compared with the wild type strain CAI4. A Pra1 knock-out strain showed ?22% reduced C4BP binding. C4BP captured by C. albicans from human serum inhibits C4b and C3b surface deposition and also maintains cofactor activity. In summary, Candida Pra1 represents the first fungal C4BP-binding surface protein. Pra1, via binding to C4BP, mediates human complement control, thereby favoring the immune and complement evasion of C. albicans.
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Project description:Candida albicans is well adapted to its host and is able to sense and respond to the nutrients available within. We have shown that C.?albicans avidly utilizes amino acids as a carbon source, which allows this opportunistic pathogen to neutralize acidic environments, including the macrophage phagosome. The transcription factor Stp2 is a key regulator of this phenomenon, and we sought to understand the mechanism of activation of Stp2, focusing on the SPS sensor system previously characterized for its role in nitrogen acquisition. We generated deletion mutants of the three components, SSY1, PTR3 and SSY5 and demonstrated that these strains utilize amino acids poorly as carbon source, cannot neutralize the medium in response to these nutrients, and have reduced ammonia release. Exogenous amino acids rapidly induce proteolytic processing of Stp2 and nuclear translocation in an SPS-dependent manner. A truncated version of Stp2, lacking the amino terminal nuclear exclusion domain, could suppress the growth and pH neutralization defects of the SPS mutants. We showed that the SPS system is required for normal resistance of C.?albicans to macrophages and that mutants defective in this system reside in more acidic phagosomes compared with wild type cells; however, a more equivocal contribution was observed in the murine model of disseminated candidiasis. Taken together, these results indicate that the SPS system is activated under carbon starvation conditions resembling host environments, regulating Stp2 functions necessary for amino acid catabolism and normal interactions with innate immune cells.
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Project description:Organisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen while minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonize hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humans Candida albicans includes changes in cell wall structure and reduced exposure, at the cell surface, of ?-glucan, a key pathogen-associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow-derived macrophages and decreased production of IL-10, RANTES, and TNF-? by peripheral blood mononuclear cells, suggesting that hypoxia-induced ?-glucan masking has a significant effect upon C. albicans-host interactions. We show that hypoxia-induced ?-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signaling. The decrease in ?-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1? and upc2?) or that decrease production of hydrogen peroxide in the inner membrane space (sod1?). Furthermore, ?-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1?). The ?-glucan masking defects displayed by goa1? and upc2? cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1?) or PKA (tpk1? tpk2?) block the masking phenotype. Our data suggest that C. albicans responds to hypoxic niches by inducing ?-glucan masking via a mitochondrial cAMP-PKA signaling pathway, thereby modulating local immune responses and promoting fungal colonization.IMPORTANCE Animal, plant, and fungal cells occupy environments that impose changes in oxygen tension. Consequently, many species have evolved mechanisms that permit robust adaptation to these changes. The fungal pathogen Candida albicans can colonize hypoxic (low oxygen) niches in its human host, such as the lower gastrointestinal tract and inflamed tissues, but to colonize its host, the fungus must also evade local immune defenses. We reveal, for the first time, a defined link between hypoxic adaptation and immune evasion in C. albicans As this pathogen adapts to hypoxia, it undergoes changes in cell wall structure that include masking of ?-glucan at its cell surface, and it becomes better able to evade phagocytosis by innate immune cells. We also define the signaling mechanisms that mediate hypoxia-induced ?-glucan masking, showing that they are dependent on mitochondrial signaling and the cAMP-protein kinase pathway. Therefore, hypoxia appears to trigger immune evasion in this fungal pathogen.
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Project description:Oropharyngeal candidiasis is an opportunistic infection considered to be a harbinger of AIDS. The etiologic agent Candida albicans is a fungal species commonly colonizing human mucosal surfaces. However, under conditions of immune dysfunction, colonizing C. albicans can become an opportunistic pathogen causing superficial or even life-threatening infections. The reasons behind this transition, however, are not clear. In the oral cavity, salivary antimicrobial peptides are considered to be an important part of the host innate defense system in the prevention of microbial colonization. Histatin-5 specifically has exhibited potent activity against C. albicans. Our previous studies have shown histatin-5 levels to be significantly reduced in the saliva of HIV+ individuals, indicating an important role for histatin-5 in keeping C. albicans in its commensal stage. The versatility in the pathogenic potential of C. albicans is the result of its ability to adapt through the regulation of virulence determinants, most notably of which are proteolytic enzymes (Saps), involved in tissue degradation. In this study, we show that C. albicans cells efficiently and rapidly degrade histatin-5, resulting in loss of its anti-candidal potency. In addition, we demonstrate that this cellular activity is due to proteolysis by a member of the secreted aspartic proteases (Sap) family involved in C. albicans pathogenesis. Specifically, the proteolysis was attributed to Sap9, in turn identifying histatin-5 as the first host-specific substrate for that isoenzyme. These findings demonstrate for the first time the ability of a specific C. albicans enzyme to degrade and deactivate a host antimicrobial peptide involved in the protection of the oral mucosa against C. albicans, thereby providing new insights into the factors directing the transition of C. albicans from commensal to pathogen, with important clinical implications for alternative therapy. This report characterizes the first defined mechanism behind the enhanced susceptibility of HIV+ individuals to oral candidiasis since the emergence of HIV.
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Project description:Commensal and pathogenic bacteria hydrolyze host lipid substrates with secreted lipases and phospholipases for nutrient acquisition, colonization, and infection. Bacterial lipase activity on mammalian lipids and phospholipids can promote release of free fatty acids from lipid stores, detoxify antimicrobial lipids, and facilitate membrane dissolution. The gram-positive bacterium Staphylococcus aureus secretes at least two lipases, Sal1 and glycerol ester hydrolase (Geh), with specificities for short- and long-chain fatty acids, respectively, each with roles in the hydrolysis of environmental lipids. In a recent study from our group, we made the unexpected observation that Geh released by S. aureus inhibits activation of innate immune cells. Herein, we investigated the possibility that S. aureus lipases interface with the host immune system to blunt innate immune recognition of the microbe. We found that the Geh lipase, but not other S. aureus lipases, prevents activation of innate cells in culture. Mutation of geh leads to enhancement of proinflammatory cytokine production during infection, increased innate immune activity, and improved clearance of the bacterium in infected tissue. These in vitro and in vivo effects on innate immunity were not due to direct functions of the lipase on mammalian cells, but rather a result of inactivation of S. aureus lipoproteins, a major pathogen-associated molecular pattern (PAMP) of extracellular gram-positive bacteria, via ester hydrolysis. Altogether, these studies provide insight into an adaptive trait that masks microbial recognition by innate immune cells through targeted inactivation of a broadly conserved PAMP.
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Project description:Candida albicans is the most common etiological agent of vaginal candidiasis. Elevated host estrogen levels and the incidence of vaginal candidiasis are positively associated. Elevated estrogen levels may affect host and/or fungal cells. This study investigates the effect of 17-beta-estradiol, 17-alpha-estradiol, ethynyl estradiol, and estriol on several C. albicans strains at concentrations ranging from 10(-5) to 10(-10) M. The addition of 17-beta-estradiol or ethynyl estradiol to C. albicans cells caused an increase in the number of cells forming germ tubes and an increase in germ tube length in a dose- and strain-dependent manner. The addition of 17-alpha-estradiol or estriol did not have a significant effect on germ tube formation by the cultured cells. Exposure to exogenous estrogens did not significantly change the biomass of any C. albicans culture tested. The transcriptional profile of estrogen-treated C. albicans cells showed increased expression of CDR1 and CDR2 across several strain-estrogen concentration-time point combinations, suggesting that these genes are the most responsive to estrogen exposure. Analysis of strain DSY654, which lacks the CDR1 and CDR2 coding sequences, showed a significantly decreased number of germ tube-forming cells in the presence of 17-beta-estradiol. PDR16 was the most highly up-regulated gene in strain DSY654 under these growth conditions. The cell biology and gene expression data from this study led to a model that proposes how components of the phospholipid and sterol metabolic pathways may interact to affect C. albicans germ tube formation and length.
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Project description:Mammalian innate immune cells produce reactive oxygen species (ROS) in the oxidative burst reaction to destroy invading microbial pathogens. Using quantitative real-time ROS assays, we show here that both yeast and filamentous forms of the opportunistic human fungal pathogen Candida albicans trigger ROS production in primary innate immune cells such as macrophages and dendritic cells. Through a reverse genetic approach, we demonstrate that coculture of macrophages or myeloid dendritic cells with C. albicans cells lacking the superoxide dismutase (SOD) Sod5 leads to massive extracellular ROS accumulation in vitro. ROS accumulation was further increased in coculture with fungal cells devoid of both Sod4 and Sod5. Survival experiments show that C. albicans mutants lacking Sod5 and Sod4 exhibit a severe loss of viability in the presence of macrophages in vitro. The reduced viability of sod5Delta/Delta and sod4Delta/Deltasod5Delta/Delta mutants relative to wild type is not evident with macrophages from gp91phox(-/-) mice defective in the oxidative burst activity, demonstrating a ROS-dependent killing activity of macrophages targeting fungal pathogens. These data show a physiological role for cell surface SODs in detoxifying ROS, and suggest a mechanism whereby C. albicans, and perhaps many other microbial pathogens, can evade host immune surveillance in vivo.
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