Oropharyngeal candidiasis (OPC) remains the most common oral manifestation of HIV infection. Although considerable progress has been made toward identifying the immunological events taking place at the oral mucosa that protects against, or contributes to, the development of clinical OPC, the underlying mechanisms or resistance and susceptibility to OPC remain poorly understood. Clinical and laboratory investigations suggest that Th1-type cell-mediated immunity by CD4+ T cells and related cytokines is the predominant host defense mechanism against oral C. albicans infection. Our data over the past 5 years supports this, but also adds considerable complexity. While OPC primarily occurs in those with reduced CD4 cell numbers, there is no evidence for a dysfunction in Candida-specific responsiveness by peripheral blood lymphocytes. Instead there appears to be a threshold number of CD4+ T cells required to protect the oral cavity against OPC, below which local mucosal mechanisms become increasingly critical. Accordingly, susceptibility to OPC during reduced CD4 cells correlates with a predominant Th2-type cytokine profile in saliva, an accumulation of CD8+ T cells that appear restricted from trafficking to the site of the superficial infection at the outer epithelium, and a reduced capacity for oral epithelial cells to inhibit the growth of C. albicans. Therefore, we hypothesize that CD8+ T cells and related cytokines/chemokines, together with epithelial cells, represent important oral host defense mechanisms when CD4+ T cells drop below protective levels and that dysfunctions in one or more of these defenses contribute to episodes of OPC. To test this hypothesis we w continue to focus on our large urban cohort of individuals with and without OPC in the HIV Outpatient Program at LSU Health Sciences Center and 1) evaluate the immune status of CD8+ T cells in oral tissue o HIV+ persons with and without OPC (longitudinal evaluation, adhesion molecules, activation/costimulation), 2) evaluate CD8+ T cell-associated cytokines/chemokines in oral tissues (protein and mRNA), and 3) identify the functional moiety and characterize the activity and mechanism of oral epithelial cell anti-Candida activity. The long-term goals of the project are to identify the specific immune factors associated with the susceptibility to OPC in HIV+ individuals, and to develop immunotherapeutic strategies to enhance resistance against OPC during periods of reduced CD4+ T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012178-08
Application #
7069682
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Nokta, Mostafa A
Project Start
1998-04-01
Project End
2008-11-30
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
8
Fiscal Year
2006
Total Cost
$345,222
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
Quimby, K; Lilly, E A; Zacharek, M et al. (2012) CD8 T cells and E-cadherin in host responses against oropharyngeal candidiasis. Oral Dis 18:153-61
Fidel Jr, P L (2011) Candida-host interactions in HIV disease: implications for oropharyngeal candidiasis. Adv Dent Res 23:45-9
Lilly, E A; Yano, J; Fidel Jr, P L (2010) Annexin-A1 identified as the oral epithelial cell anti-Candida effector moiety. Mol Oral Microbiol 25:293-304
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
Lilly, E A; Leigh, J E; McNulty, K M et al. (2006) Chemokine receptor expression in HIV-positive persons with oropharyngeal candidiasis. Oral Dis 12:493-9
Leigh, Janet E; McNulty, Kelly M; Fidel Jr, Paul L (2006) Characterization of the immune status of CD8+ T cells in oral lesions of human immunodeficiency virus-infected persons with oropharyngeal Candidiasis. Clin Vaccine Immunol 13:678-83
Mercante, Donald E; Leigh, Janet E; Lilly, Elizabeth A et al. (2006) Assessment of the association between HIV viral load and CD4 cell count on the occurrence of oropharyngeal candidiasis in HIV-infected patients. J Acquir Immune Defic Syndr 42:578-83
Coogan, M M; Fidel Jr, P L; Komesu, M C et al. (2006) (B1) Candida and mycotic infections. Adv Dent Res 19:130-8
Lilly, E A; Leigh, J E; Joseph, S H et al. (2006) Candida-induced oral epithelial cell responses. Mycopathologia 162:25-32
Fidel Jr, P L (2006) Candida-host interactions in HIV disease: relationships in oropharyngeal candidiasis. Adv Dent Res 19:80-4

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