Candida species are commensal fungal organisms as well as opportunistic pathogens of mucosal tissues. From the commensal relationship, most healthy individuals have demonstrable Candida-specific immunity. In immunocompromised persons, however, fungal infections caused primarily by C. albicans often occur. In HIV disease, up to 90% of HIV+ persons will have a symptomatic episode of oropharyngeal candidiasis (OPC) sometime during progression to AIDS, many of which become recurrent. In contrast, vulvovaginal candidiasis (VVC) and systemic Candida infections (candidaemia) are much less common during HIV disease, indicating the diversity and compartmentalization of the host response to Candida. Both innate resistance and acquired immunity play some role in maintaining C. albicans in the commensal state and protecting the systemic circulation. Polymorphonuclear leukocytes (PMNL) are critical for protection against systemic infections, whereas cell-mediated immunity (CMI) by Th1-type CD4+ T-cells is important for protection against mucosal infections. However, there is a discordant role for CMI at the vaginal versus oral mucosa, whereas little to no role for local or systemic CMI is evident at the vaginal mucosa. In contrast, there is a strong correlation between reduced blood CD4+ cells and the incidence of OPC, but it remains unclear whether systemic or local CMI is more important. Evaluation of systemic CMI in a cohort of HIV+ individuals with and without mucosal candidiasis revealed that Candida-specific CMI is not different between HIV+ persons with OPC or VVC and HIV- persons. Thus, the correlation of reduced CD4+ cell numbers to OPC may be explained by the requirement for a threshold number of systemic CD4+ cells to protect the oral mucosa together with the status of local immunity. Indeed, HIV+ persons with and without OPC had a Th2-type salivary cytokine profile suggestive of susceptibility to Candida infection compared with a protective Th0/Th1-type profile in HIV- persons. Candida-specific antibodies, although present, are controversial relative to a role in protection or eradication of infection. While studies of mucosal innate resistance are limited, we recently found that epithelial cells from saliva and vaginal lavages of healthy individuals inhibit the growth of Candida in vitro. This epithelial cell anti-Candida activity requires cell contact by viable cells with no role for soluble factors, including saliva. Interestingly, oral epithelial cells from HIV+ persons with OPC had significantly reduced activity, indicating some protective role for the epithelial cells. Taken together, these data suggest that immunity to Candida is site-specific, compartmentalized and involves innate and/or acquired mechanisms from systemic and/or local sources.
BACKGROUND EPIDEMIOLOGY AND RATIONALE .
Oral candidiasis is perhaps the commonest infection seen in HIV disease. The aim of this workshop was to provide a sketch of the multifarious aspects of the disease from a global perspective. To this end the panellists addressed issues such as the virulence of Candida, emergence of antifungal resistance, management of candidiasis and other exotic, oral mycotic diseases. An all-pervasive theme was the dramatic differences in the management of fungal infections consequential to the availability (or the lack) of anti-HIV drugs in the developed and the developing world. Further, the social stigmata associated with the HIV disease in many developing regions in Africa and Asia appears to modify the therapeutic strategies. Additionally, the lesser-known regional variations in the disease manifestations and therapeutic approaches were stark. Further work is direly needed to address these issues.
Oropharyngeal candidiasis (OPC), caused primarily by Candida albicans, is the most common oral infection in HIV(+) persons. Although Th1-type CD4(+) T cells are the predominant host defense mechanism against OPC, CD8(+) T cells and epithelial cells become important when blood CD4(+) T cells are reduced below a protective threshold during progression to AIDS. In an early cross-sectional study, OPC(+) tissue biopsied from HIV(+) persons had an accumulation of activated memory CD8(+) T cells at the oral epithelial-lamina propria interface, with reduced expression of the adhesion molecule E-cadherin, suggesting a protective role for CD8(+) T cells but a dysfunction in the mucosal migration of the cells. In a subsequent 1-year longitudinal study, OPC(-) patients with high oral Candida colonization (indicative of a preclinical OPC condition), had higher numbers of CD8(+) T cells distributed throughout the tissue, with normal E-cadherin expression. In OPC(+) patients, where lack of CD8(+) T cell migration was associated with reduced E-cadherin, subsequent evaluations following successful treatment of infection revealed normal E-cadherin expression and cellular distribution. Regarding epithelial cell responses, intact oral epithelial cells exhibit fungistatic activity via an acid-labile protein moiety. A proteomic analysis revealed that annexin A1 is a strong candidate for the effector moiety. The current hypothesis is that under reduced CD4(+) T cells, HIV(+) persons protected from OPC have CD8(+) T cells that migrate to the site of a preclinical infection under normal expression of E-cadherin, whereas those with OPC have a transient reduction in E-cadherin that prohibits CD8(+) T cells from migrating for effector function. Oral epithelial cells concomitantly function through annexin A1 to keep Candida in a commensal state but can easily be overwhelmed, thereby contributing to susceptibility to OPC.
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