Host defenses at the vaginal mucosa are poorly understood. This includes those against C. albicans, the causative agent of >90 percent of cases of vulvovaginal candidiasis (VVC). Cell-mediated immunity (CMI) is important in host defense against C. albicans infections at several mucosal sites. Our laboratory has employed clinical studies and an estrogen-dependent murine model of vaginal candidiasis to understand the role of CMI as a host defense mechanism against vaginitis. To date, our data suggests that anti-Candida host defense mechanisms at the vaginal mucosa may be distinct from those protecting other mucosal tissues. To this end, studies show that systemic-derived Candida-specific CD4+ Th1-type cells associated with resistance against candidal infections does not provide protection against clinical or experimental vaginitis. Partial protection from experimental infection in the absence of Candida-specific systemic CMI suggested that protective mechanisms were localized to the vaginal mucosa consistent with clinical data. Analysis of local immunity showed that while phenotypically distinct T cells were present in the vagina, they did not significantly change during experimental vaginal infection and there was no evidence for infiltration of systemic T cells into the vaginal mucosa. In addition, polymorphonuclear leukocytes (PMNL) present at times during infection do not influence vaginal C. albicans burden. Together, these data suggest that some level of immunoregulation acts at the vaginal mucosa that limits the function of the local and possibly systemic immune responses. This is supported by the vaginal presence of down-regulatory cytokines. In light of limited activity by conventional immune cells at the vaginal mucosa, we discovered that vaginal epithelial cells have anti-Candida activity in vitro. Based on these findings, we hypothesize that immunoregulatory events at the vaginal mucosa significantly affect local cellular immune mechanisms (innate and/or acquired) important for protection against C. albicans vaginal infection, and that vaginal epithelial cells provide some level of innate resistance against C. albicans. To test this hypothesis, we will (i) further characterize vaginal CMI responses during C. albicans vaginal infection, (ii) elucidate immunoregulatory mechanisms potentially responsible for inefficient anti-Candida responses, and (iii) elucidate properties critical to the mechanism for the epithelial cell-mediated anti-Candida activity. The long term goal is to understand vaginal host defense mechanisms against C. albicans so that immunotherapeutic strategies can be developed to prevent or treat disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI032556-10S1
Application #
7286896
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Rothermel, Annette L
Project Start
1994-12-01
Project End
2009-05-31
Budget Start
2006-09-30
Budget End
2009-05-31
Support Year
10
Fiscal Year
2006
Total Cost
$213,000
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Yano, Junko; Noverr, Mairi C; Fidel Jr, Paul L (2017) Vaginal Heparan Sulfate Linked to Neutrophil Dysfunction in the Acute Inflammatory Response Associated with Experimental Vulvovaginal Candidiasis. MBio 8:
Yano, Junko; Palmer, Glen E; Eberle, Karen E et al. (2014) 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. Infect Immun 82:783-92
Yano, Junko; Noverr, Mairi C; Fidel Jr, Paul L (2012) Cytokines in the host response to Candida vaginitis: Identifying a role for non-classical immune mediators, S100 alarmins. Cytokine 58:118-28
Yano, Junko; Kolls, Jay K; Happel, Kyle I et al. (2012) The acute neutrophil response mediated by S100 alarmins during vaginal Candida infections is independent of the Th17-pathway. PLoS One 7:e46311
Yano, Junko; Fidel Jr, Paul L (2011) Protocols for vaginal inoculation and sample collection in the experimental mouse model of Candida vaginitis. J Vis Exp :
Yano, Junko; Lilly, Elizabeth; Barousse, Melissa et al. (2010) Epithelial cell-derived S100 calcium-binding proteins as key mediators in the hallmark acute neutrophil response during Candida vaginitis. Infect Immun 78:5126-37
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Pereira, H Anne; Tsyshevskaya-Hoover, Irina; Hinsley, Heather et al. (2010) Candidacidal activity of synthetic peptides based on the antimicrobial domain of the neutrophil-derived protein, CAP37. Med Mycol 48:263-72
Yano, J; Lilly, E A; Steele, C et al. (2005) Oral and vaginal epithelial cell anti-Candida activity is acid labile and does not require live epithelial cells. Oral Microbiol Immunol 20:199-205
Singleton, David R; Fidel Jr, Paul L; Wozniak, Karen L et al. (2005) Contribution of cell surface hydrophobicity protein 1 (Csh1p) to virulence of hydrophobic Candida albicans serotype A cells. FEMS Microbiol Lett 244:373-7