Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by the commensal fungus Candida albicans (C. albicans). OPC is a serious clinical complication for the immunocompromised populations, including Sj?gren's Syndrome and other dry-mouth etiologies, HIV/AIDS patients, and those with rare genetic defects such as Hyper-IgE Syndrome. Th17 cells confer the majority of protection to oral and mucocutaneous C. albicans infection. We previously used a mouse model of OPC to show that the IL-17 receptor subunits IL- 17RA and IL-17RC are critical for immunity to oral infection with C. albicans, implicating the IL-17A/F signaling axis exclusively. IL-17 induces a neutrophil influx and production of antimicrobial proteins important in protection to C. albicans. We also demonstrated that mouse and human salivary components, defensins and histatins, are essential in limiting Candida carriage and infection. Saliva is an important immune component, as patients with salivary defects are susceptible to OPC. Protection to OPC involves components derived from oral epithelium and salivary gland, but the underlying mechanisms of IL-17 anti-Candida host defense are largely undefined. This application investigates IL-17R signaling components and gene targets in human salivary gland cells, and dissects the specific contribution of the salivary gland during OPC.
In Aim 1, we will assess responses of the human salivary gland cell line to IL-17, and the molecular components important downstream of the IL-17R. This is the first time these signaling pathways will be studied in human cells where IL-17 plays a physiologically relevant role during infection.
Aim 2 will define IL-17A/F-specific effects required for protection to OPC, by specifically deleting IL-17RC in the salivary gland. This will allow a better understanding of the importance of saliva and the salivary gland in host defense, and the development of more targeted therapeutics to treat Candida infections in a manner that avoids exacerbating the pathogenic inflammatory effect of IL-17.
Candida albicans causes the disease oral candidiasis in patients with immune system defects. Both the oral mucosal epithelium and salivary gland are involved in host protection to Candida albicans, but the exact mechanisms are not well understood. This application will study the mechanism of IL-17R signaling in the salivary gland, and how this contributes to protection against disease.
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|Conti, Heather R; Peterson, Alanna C; Brane, Lucas et al. (2014) Oral-resident natural Th17 cells and ?? T cells control opportunistic Candida albicans infections. J Exp Med 211:2075-84|
|Huppler, Anna R; Conti, Heather R; Hernández-Santos, Nydiaris et al. (2014) Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. J Immunol 192:1745-52|