An Intravaginal Live Candida Challenge in Humans Leads to New Hypotheses for the Immunopathogenesis of Vulvovaginal Candidiasis

Abstract

Acute and recurrent vulvovaginal candidiasis (VVC) remains a significant problem in women of childbearing age. While clinical studies of women with recurrent VVC (RVVC) and animal models have provided important data about a limited protective role of adaptive immunity, there remains a paucity of information on the protective mechanisms or factors associated with susceptibility to infection. In the present study, an intravaginal live Candida challenge in healthy adult women showed a differential susceptibility to symptomatic VVC, where 3 (15%) of 19 women with no history of VVC acquired a symptomatic infection compared to 6 (55%) of 11 women with an infrequent history of VVC. Furthermore, these studies revealed that protection against infection is noninflammatory while symptomatic infection correlates with a vaginal infiltration of polymorphonuclear neutrophils (PMNs) and a high vaginal fungal burden. Thus, the presence of symptomatic infection appears more dependent on host factors than on properties of the organism. Finally, vaginal lavage fluid from women with a symptomatic infection, but not those asymptomatically colonized, promoted the chemotaxis of PMNs. These results suggest that rather than RVVC/VVC being caused by an aberrant adaptive immune response, symptoms that define infection appear to be due to an aggressive innate response by PMNs.Vulvovaginal candidiasis (VVC), caused primarily by Candida albicans, remains a significant problem in women of childbearing age (28). C. albicans is a commensal organism of the gastrointestinal and reproductive tracts (8). Several exogenous factors predispose menarchal women to acute VVC, including hormonal modulations associated with pregnancy, the luteal phase of the menstrual cycle, high-dose oral estrogen contraception, and hormone replacement therapy, and nonhormonal factors such as antibiotic usage and uncontrolled diabetes mellitus (29). There is also a population of women (5 to 10%) who suffer from recurrent VVC (RVVC), which is defined as three or more episodes per annum (28). While most women with RVVC have no known predisposing factors, hormonal or otherwise (idiopathic, and termed primary RVVC), another group of women have RVVC as a result of being unable to avoid certain predisposing factors (secondary RVVC) (28). Historically, primary RVVC has been attributed to a putative local immune deficiency (reviewed in reference 11).Candida-specific cell-mediated immunity, acquired by exposure to Candida early in life, has been considered the predominant host defense mechanism against mucosal Candida infections. However, studies from a mouse model of vaginal candidiasis and many cross-sectional clinical studies evaluating women with primary RVVC over the past several decades have revealed a general lack of protection by local or systemic adaptive immunity (reviewed in reference 11). While data suggest that this may be the result of immunoregulatory mechanisms (31,33,34) and as such have provided important information, these studies provided few clues to the mechan...

Vaginal IL-8 levels are positively associated with Candida albicans and inversely with lactobacilli in HIV-infected women

“…Heat-killed Candida albicans or zymosan, a yeast extract, induced in vitro the expression of IL-8 by vaginal epithelial cells (Pivarcsi et al, 2005), although live organisms do not induce IL-8 (Steele and Fidel, 2002). Experimentally-induced vaginal yeast infections have been associated with increased levels of neutrophils in the vagina, though IL-8 levels were not assessed (Fidel et al, 2004).…”

Vulvovaginal Candida albicans infections: pathogenesis, immunity and vaccine prospects

“…26 In women, symptoms of vaginal candidiasis, particularly RVVC, have been associated with both a high and a low Candida burden, as well as with the presence of both high and low numbers of inflammatory cells. [1][2][3]24 Fidel and collaborators investigated human volunteers intravaginally challenged with live fungal cells 27 and found a correlation between fungal intravaginal burden and inflammation, as shown by leucocyte infiltration but, again, this protocol does not reflect the natural source of infection.…”

Lack of association between genotypes and virulence factors in C. albicans strains isolated from vaginal secretion

“…However, the factors responsible for this transformation and the mechanisms that result in the pathological effects of C. albicans are poorly understood (7).…”