Abstract
ABSTRACTDespite acute inflammation by polymorphonuclear neutrophils (PMNs) during vulvovaginal candidiasis (VVC), clearance of Candida fails to occur. The purpose of this study was to uncover the mechanism of vaginal PMN dysfunction. Designs included assessing PMN migration, proinflammatory mediators, and tissue damage (by analysis of the activity of lactate dehydrogenase [LDH]) in mice susceptible (C3H/HeN-C57BL/6) or resistant (CD-1) to chronic VVC (CVVC-S or CVVC-R) and testing morphology-specific Candida albicans strains under conditions of preinduced PMN migration (CVVC-S mice) or PMN depletion (CVVC-R mice). In vitro designs included evaluation of C. albicans killing by elicited vaginal or peritoneal PMNs in standard or vaginal conditioned medium (VCM). Results showed that despite significant migration of PMNs and high levels of vaginal beta interleukin-1 (IL-1β) and alarmin S100A8, CVVC-S mice failed to reduce vaginal fungal burden irrespective of morphology or whether PMNs were present pre- or postinoculation, and had high LDH levels. In contrast, CVVC-R mice had reduced fungal burden and low LDH levels following PMN recruitment and IL-1β/S100A8 production, but maintained colonization in the absence of PMNs. Elicited vaginal and peritoneal PMNs showed substantial killing activity in standard media or VCM from CVVC-R mice but not in VCM from CVVC-S mice. The inhibitory effect of VCM from CVVC-S mice was unaffected by endogenous or exogenous estrogen and was ablated following depletion/neutralization of Mac-1 ligands using Mac-1+/+ PMNs or recombinant Mac-1. Heparan sulfate (HS) was identified as the putative inhibitor as evidenced by the rescue of PMN killing following heparanase treatment of VCM, as well as by inhibition of killing by purified HS. These results suggest that vaginal HS is linked to PMN dysfunction in CVVC-S mice as a competitive ligand for Mac-1.
Highlights
IMPORTANCE Vaginal candidiasis, caused by Candida albicans, affects a significant number of women worldwide
Vaginal fungal burden in chronic VVC-resistant condition (CVVC-R) CD-1 mice progressively declined throughout the observation period (P Ͻ 0.05 compared to levels in C3H/HeN mice at each time point), with 40% of CD-1 mice showing clearance by 4 days postinoculation (Fig. 1A)
We have confirmed that CVVC-R CD-1 mice are able to clear C. albicans infection following vaginal polymorphonuclear neutrophils (PMNs) recruitment, which was associated with close physical interaction of PMNs with Candida and reduced fungal burden compared to chronic VVC-susceptible conditions (CVVC-S) C3H/HeN mice
Summary
IMPORTANCE Vaginal candidiasis, caused by Candida albicans, affects a significant number of women worldwide. Results revealed that heparan sulfate present in the vagina of mice susceptible to chronic vaginitis served as a competitive ligand for the receptor (Mac-1) necessary for fungal recognition and neutrophil-mediated killing This inhibitory function of heparan sulfate, confirmed through several approaches, provides the first evidence to explain the lack of antifungal immune reactivity during vaginal candidiasis. The lack of fungal clearance by PMNs confines the vaginal mucosa in a chronic inflammatory state This has been shown for a variety of mouse strains [16, 19, 20] that can collectively be described as representative of chronic VVC-susceptible conditions (CVVC-S). This Mac-1-mediated PMN activation has been shown to promote fungal killing by
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