The oral cavity is the portal of entry for many infectious pathogens. Despite advances in the field of mucosal immunity, mechanisms of immunity in the oral mucosa remain surprisingly poorly understood. Candida albicans is a commensal fungus that commonly colonizes mucosal surfaces including the mouth. In healthy individuals, Candida is non-pathogenic. However, in immunodeficient patients, such as those with HIV/AIDS, Sjgren's syndrome, congenital immunodeficiency or those receiving chemotherapy, this microbe causes severe opportunistic infections of the oral cavity, known as "thrush" or oropharyngeal candidiasis (OPC). We recently discovered that immunity to OPC is highly dependent on IL-23, IL-17, and ROR?t, overturning the long-held paradigm that immunity to Candida is mediated by Th1 cells and IFN?. Our findings have been validated in in patients with rare immunodeficiency diseases that impact the IL-23/IL-17 pathway and who suffer from OPC and other forms of chronic mucocutaneous candidiasis (CMC). For example, Hyper-IgE/Job's Syndrome (HIES) is caused by mutations in STAT3, a transcription factor downstream of IL-23 and other cytokines. HIES patients have low levels of Th17 cells but not Th1 cells, and usually suffer recurrent OPC/CMC. Similarly, rare IL-17R-deficient families present with OPC and CMC. In this proposal, we will address several unanswered questions regarding oral immunity to Candida, emphasizing the IL-23/STAT3/IL- 17 pathway. It is clear there is a powerful innate response to Candida, but the nature of this cell type is unknown. Using new reporter mice, in Aim 1 we will determine the nature of the key IL-17-producing innate cell type that provides the early response to this organism.
In Aim 2, we will evaluate mechanisms of immunity to OPC controlled by STAT3, particularly in oral epithelial cells.
In Aim 3, we will evaluate the mechanisms by which IL-23 and STAT3 signaling regulate the adaptive anti-Candida Th17 response. Together, these studies will define the roles of STAT3, IL-23 signaling and IL-17 in the maintenance of oral mucosal immunity.

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 the IL-23/STAT3 signaling pathway leading to production of IL-17. 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 #
1R01DE023815-01
Application #
8611195
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$383,125
Indirect Cost
$133,125
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Whibley, Natasha; Maccallum, Donna M; Vickers, Mark A et al. (2014) Expansion of Foxp3(+) T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge. Eur J Immunol 44:1069-83
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
Ferreira, Maria Carolina; Whibley, Natasha; Mamo, Anna J et al. (2014) Interleukin-17-induced protein lipocalin 2 is dispensable for immunity to oral candidiasis. Infect Immun 82:1030-5