Vaginal Epithelial Cell-Derived S100 Alarmins Induced by Candida albicans via Pattern Recognition Receptor Interactions Are Sufficient but Not Necessary for the Acute Neutrophil Response during Experimental Vaginal Candidiasis

Yano, Junko; Palmer, Glen E.; Eberle, Karen E.; Peters, Brian M.; Vogl, Thomas J.; McKenzie, Andrew N. J.; Fidel, Paul L.

doi:10.1128/iai.00861-13

Cited by 58 publications

(70 citation statements)

References 56 publications

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“…Although CP can be toxic to C. albicans in vitro, its efficacy as an antifungal agent in vivo may vary depending on the host niche. For example, CP Ϫ/Ϫ mice are substantially more susceptible to C. albicans infection of the lung (26), but not to vaginal candidiasis, in spite of abundant neutrophil recruitment to the vaginal tissue (78). If anything, the opposite was observed: the fungal burden was decreased in vaginal tissues of CP Ϫ/Ϫ mice (78), and we observed that the same is true during fungal invasion of the kidney.…”

Section: Discussionsupporting

confidence: 57%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the hostpathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.

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Section: Discussionsupporting

confidence: 57%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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“…Expression of the gene coding for S100A8 (S100a8), a calciumbinding protein with important functions in antifungal defense and danger responses and strongly induced during C. albicans infection, was almost completely absent during infection with Candidalysin deletion strains (Fig. 5J) (21,22). Similarly, the gene encoding serum amyloid A3 (Saa3), an inducible acute-phase apolipoprotein capable of recruiting immune cells to inflammatory sites, was similarly increased in a Candidalysin-dependent fashion (Fig.…”

Section: Figmentioning

confidence: 82%

Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa

et al. 2018

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Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen Candida albicans, is a disease of immunocompetent and otherwise healthy women. Despite its prevalence, the fungal factors responsible for initiating symptomatic infection remain poorly understood. One of the hallmarks of vaginal candidiasis is the robust recruitment of neutrophils to the site of infection, which seemingly do not clear the fungus, but rather exacerbate disease symptomatology. Candidalysin, a newly discovered peptide toxin secreted by C. albicans hyphae during invasion, drives epithelial damage, immune activation, and phagocyte attraction. Therefore, we hypothesized that Candidalysin is crucial for vulvovaginal candidiasis immunopathology. Anti-Candida immune responses are anatomical-site specific, as effective gastrointestinal, oral, and vaginal immunities are uniquely compartmentalized. Thus, we aimed to identify the immunopathologic role of Candidalysin and downstream signaling events at the vaginal mucosa. Microarray analysis of C. albicans-infected human vaginal epithelium in vitro revealed signaling pathways involved in epithelial damage responses, barrier repair, and leukocyte activation. Moreover, treatment of A431 vaginal epithelial cells with Candidalysin induced dose-dependent proinflammatory cytokine responses (including interleukin 1␣ [IL-1␣], IL-1␤, and IL-8), damage, and activation of c-Fos and mitogen-activated protein kinase (MAPK) signaling, consistent with fungal challenge. Mice intravaginally challenged with C. albicans strains deficient in Candidalysin exhibited no differences in colonization compared to isogenic controls. However, significant decreases in neutrophil recruitment, damage, and proinflammatory cytokine expression were observed with these strains. Our findings demonstrate that Candidalysin is a key hypha-associated virulence determinant responsible for the immunopathogenesis of C. albicans vaginitis.

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“…86 Recently it was shown that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during experimental vaginal candidiasis. 87 …”

Section: Prrs Of Epithelial Cellsmentioning

confidence: 99%