The oral cavity is a portal of entry for many infectious pathogens. However, despite advances in the field of mucosal immunity, mechanisms of immunity in the oral mucosa are surprisingly poorly understood. Whereas much of our understanding of mucosal immunity comes from studies of the gastrointestinal tract, immunity at other mucosal sites does not always parallel the gut. A good example of this dichotomy comes from studies of Candida albicans, a commensal dimorphic fungus that colonizes oral, esophageal and vaginal mucosal surfaces. In healthy individuals, C. albicans colonization is non-pathogenic. However, in conditions of immunodeficiency such as HIV/AIDS, Sj?gren's syndrome or congenital immunodeficiency, this microbe causes severe opportunistic infections of the oral cavity, known as "thrush" or oropharyngeal candidiasis (OPC). The high incidence of OPC in HIV/AIDS (>90%) implicates CD4+ T cells in immunity against C. albicans. Until recently, this was thought to be the province of Th1 cells and their signature cytokine, IFNg. In 2005, a new subset of T cell was discovered that produces IL-17, and hence is known as "Th17." IL-17-producing cells are highly enriched at mucosal surfaces, particularly the GI tract, and are selectively depleted in AIDS. In a gastrointestinal model of mucosal candidiasis, Th1 cells and IFNg appear to be host-protective, whereas IL-17 and the Th17-inductive cytokine IL-23 promote a deleterious immunopathology. In contrast, work from our group in mice and new studies in IL-17R-deficient humans indicate that IL-17 is an essential mediator of immunity against oral mucosal candidiasis. However, the specific mechanisms by which IL-17 drives host defense against Candida is not known, including the target cells within the oral mucosa or the downstream receptor signaling mechanisms mediated by the IL-17 receptor. The objective of this application is to fill this gap in our knowledge, by focusing specifically on the role of IL-1 and its receptor in mediating immune defense against Candida albicans in the oral cavity. To that end, we will use a series of gene-targeted mice to systematically define the important IL-17-responsive cell types in the context of OPC, and to delineate specific molecular signaling pathways used by the IL-17 receptor to mediate host defense.

Public Health Relevance

Oral candidiasis, also known as oral thrush, is an AIDS-defining fungal infection of the oral mucosa. This disease also afflicts individuals on chemotherapy, transplant patients taking immunosuppressive drugs, asthma patients using inhaled corticosteroid drugs or others with compromised immune function such as infants and the elderly. The objective of this project is to understand in detail how the immune system normally keeps oral candidiasis under control, with an emphasis on the role of a particular cytokine receptor, the IL-17R. The long-term goal of this research is to develop better therapies or vaccines for mucosal disease of the oral cavity, and to understand the consequences of therapies that suppress specific immune events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE022550-02S1
Application #
8705624
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-09-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$50,436
Indirect Cost
$15,986
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Gaffen, Sarah (2016) IL-17 receptor composition. Nat Rev Immunol 16:4
Huppler, Anna R; Gaffen, Sarah L (2016) Editorial: Fake it 'til you make it: mast cells acquire IL-17 exogenously. J Leukoc Biol 100:445-6
Whibley, Natasha; Tritto, Elaine; Traggiai, Elisabetta et al. (2016) Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis. J Leukoc Biol 99:1153-64
Chen, Kong; Eddens, Taylor; Trevejo-Nunez, Giraldina et al. (2016) IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K.√ā¬†pneumoniae. Cell Host Microbe 20:596-605
Monin, Leticia; Gudjonsson, Johann E; Childs, Erin E et al. (2016) MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation. J Immunol :
Conti, Heather R; Bruno, Vincent M; Childs, Erin E et al. (2016) IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis. Cell Host Microbe 20:606-617
Conti, Heather R; Whibley, Natasha; Coleman, Bianca M et al. (2015) Signaling through IL-17C/IL-17RE is dispensable for immunity to systemic, oral and cutaneous candidiasis. PLoS One 10:e0122807
Whibley, Natasha; Gaffen, Sarah L (2015) Beyond Candida albicans: Mechanisms of immunity to non-albicans Candida species. Cytokine 76:42-52
Huppler, Anna R; Verma, Akash H; Conti, Heather R et al. (2015) Neutrophils Do Not Express IL-17A in the Context of Acute Oropharyngeal Candidiasis. Pathogens 4:559-72
Conti, Heather R; Gaffen, Sarah L (2015) IL-17-Mediated Immunity to the Opportunistic Fungal Pathogen Candida albicans. J Immunol 195:780-8

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