Microbial Ecology in States of Health and Disease Workshop Summary (2014) / Chapter Skim
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A9 Host defense and immunomodulation of mucosal candidiasis--Paul L. Fidel, Jr., and Mairi C. Noverr
A9 Host defense and immunomodulation of mucosal candidiasis--Paul L. Fidel, Jr., and Mairi C. Noverr
Pages 249-272
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Noverr33,‡ Introduction Candida albicans is a commensal organism of the oral cavity and gastro intestinal tract of most human adults as well as the genital tract of adult females. Point prevalence studies show asymptomatic colonization by C
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began to suggest that factors associated with susceptibility to oral and vaginal candidiasis were different. Following some additional studies in HIV-infected persons with OPC, immunological data too began to follow the physiological anatomical distinctions and revealed that host defenses against Candida at the oral and vaginal mucosa were unique, distinct, and independent
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. As a result, it is now considered that all mucosa are not equal for mucosal Candida infections and that host defenses at the various mucosal sites need to be studied independently and exclusively at the local level with respect to cells and soluble immune factors.
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. Hence, the CD8 T cells appear as normal activated memory cells recruited into the oral mucosa but are inhibited or challenged from migrating through the tissue otherwise.
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We hypothesize that these two conditions can and do occur depending on the location of the epithelial cells. If Candida gains access to basal epithelial cells that are metabolically active it will use E-cadherin to gain intracellular access through endocytosis.
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Our laboratory has studied the role of epithelial cells for a number of years. These studies show that oral epithelial cells can inhibit up to 80 percent of the Candida growth in vitro by a fungistatic mechanism via cell contact by intact, but not necessarily live epithelial cells, through an acid-labile protein receptor (Nomanbhoy et al., 2002; Steele et al., 1999, 2000, 2001; Yano et al., 2005)
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When the mechanisms surrounding E-cadherin degradation/restoration, CD8 + T cell activity, and annexin-A1 antifungal activity are fully understood, each could be exploited to reverse susceptibility and/or enhance resistance or protection against OPC. Host Defense Against Vulvovaginal Candidiasis For VVC/RVVC, studies from a mouse model of vaginal candidiasis and many clinical studies evaluating women with RVVC over two decades have revealed a general lack of protection by local or systemic adaptive immunity (reviewed in Fidel and Noverr, 2012)
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. The secondary defense consists of CD8+ T cells migrating to the outer epithelium under normal expression of E-cadherin and functional oral epithelial cell anti-Candida activity that together keep Candida in check and prevent symptomatic infection.
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. Finally, when tested in an in vitro PMN migration assay, vaginal lavage fluid from women with symptomatic infection showed increased PMN chemotactic activity compared to lavage fluid from those with asymptomatic colonization, suggesting a chemotactic factor or factors (e.g., cytokines, chemokines)
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. Clinical cross-sectional and the live challenge natural history study also supports the protective effects of epithelial cell annexin-A1; women with RVVC or who were susceptible to symptomatic VVC following inoculation had lower epithelial cell anti fungal activity compared to women without RVVC or who simply became asymptomatically colonized following inoculation (Barousse et al., 2001, 2005)
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were unsuccessful and therefore could not be used as correlates to the PMN infiltration, vaginal PMNs levels appear to be rigid criteria based on the association with the clinical symptomatology of VVC. Accordingly, when tested in an in vitro PMN migration assay, results showed, similar to clinical studies, that vaginal lavage fluids from mice with high PMNs (symptomatic)
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This observation was further supported by increased S100 expression in vaginal epithelial cells at the mRNA levels, confirming epithelial cells as a primary source of S100 proteins produced under the symptomatic condition. Finally, neutralization of S100A8, but not S100A9, reduced the PMN chemotactic activity of vaginal lavage fluid in an in vitro migration assay, suggesting a role for S100A8 in mediating PMN migration during vaginal infection.
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Current studies are focused on testing the immunopathogenesis/alarmin hypothesis in clinical VVC/RVVC to provide the necessary evidence to embark on these diagnostic and immunotherapeutic strategies. The Emerging Role of Mucosal Candida Biofilms and Host Immunity Recently there has been a tremendous interest in the role of biofilms in infectious diseases.
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, vaginal epithelial cells are extremely sensitive to Candida. These women are susceptible to symptomatic infection following exposure to even small numbers of Candida (low organism threshold)
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, vaginal epithelial cells are extremely sensitive to Candida and exert weak antifungal activity through annexin A1. Epithelial cells become activated upon recognition of Candida via unidentified PRRs.
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Unexpectedly, the presence or absence of mucosal Candida biofilm had no effect on the alarmin response. The animals, irrespective of the Candida isolate used to inoculate, had similar vaginal fungal burden, vaginal S100 alarmin concentrations, and vaginal PMNs (Lilly et al.
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Conclusions Several major points should be emphasized regarding host defense and immunomodulation against mucosal candidiasis: (1) Host defense against Candida is extremely different at different mucosal sites, including adaptive immunity by T cells playing a significant role at the oral mucosa, and innate immunity via PMNs and epithelial cells playing critical roles in the vagina mucosa.
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2005. Vaginal epithelial cell anti-candida albicans activity is associated with protection against symptomatic vaginal candidiasis.
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2003a. Candida albicans triggers interleukin-8 by oral epithelial cells.
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2003b. Granulocyte-macrophage colony-stimulating fac tor responses of oral epithelial cells to Candida albicans.
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2004. Requirement of interleukin-17a for sys temic anti-candida albicans host defense in mice.
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2010. Annexin-a1 identified as the oral epithelial cell anti candida effector moiety.
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2002. Interleukin-18 and gamma interferon produc tion by oral epithelial cells in response to exposure to Candida albicans or lipopolysaccharide stimulation.
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2002. Cytokine and chemokine production by human oral and vaginal epithelial cells in response to Candida albicans.
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