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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DE023293-02
Application #
8594174
Study Section
Special Emphasis Panel (ZDE1-MH (22))
Program Officer
Frieden, Leslie A
Project Start
2012-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$54,742
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Conti, Heather R; Huppler, Anna R; Whibley, Natasha et al. (2014) Animal models for candidiasis. Curr Protoc Immunol 105:19.6.1-19.6.17
Bishu, Shrinivas; Hernández-Santos, Nydiaris; Simpson-Abelson, Michelle R et al. (2014) The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections. Infect Immun 82:1173-80
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