Perturbations in host defenses can result in overgrowth of pathogens such as Candida albicans, resulting in a painful and debilitating condition, oropharyngeal candidiasis (OPC). Inadequate immune responses, through aging, chemotherapy or immune deficiency, are associated with increased risk of OPC. These disorders are reemerging due to the prevalence of AIDS, both in the underdeveloped world where HAART is not available, and in cases where drug resistance develops. The proinflammatory cytokine, interleukin-1 is critical in host defense against both disseminated and mucosal Candida infections yet the mechanisms that underlie the production of IL-1 or of IL-1-mediated protection in OPC are unknown. We have developed a mouse model of OPC that will be utilized to determine the innate immune mechanisms regulating IL-1 (3 production in vivo and will develop in vitro systems to define these mechanisms in molecular detail. Acute inflammatory responses are generated via germ-line encoded pattern-recognition receptors (PRRs) that recognize specific molecular structures on pathogens known as pathogen associated molecular patterns (PAMPs). Toll-like receptors (TLRs) constitute a class of membrane bound PRRs expressed on host cells, including human oral epithelial cells (HOECs). In addition to TLRs, a large family of cytoplasmic PRRs known as the NACHT-LRRs (NLRs) or inflammasome have been implicated in innate responses, particularly in the processing of the immature form of IL-1 (pro-IL-1). The central hypothesis to be tested is that interactions of fungal pathogens with TLRs (with or without the TLR2 co-receptor, dectin-1) or NLRs at the oral mucosa are critical for controlling Candida infections in the oral cavity and that induction of IL-1P is critical for protection. We propose the following specific aims: 1) To identify critical PRRs involved in the pathogenesis of localized and disseminated infection in OPC, 2) To define the potential role of the NLR family in the induction, processing and release of IL-1P in Candida infections. The ontogeny of expression and function of these innate PRRs will be defined. The long term goals of this project are to determine the innate immune receptors and pathways involved in host defense against the oral pathogen Candida albicans and develop novel approaches to host immunomodulation and anti-fungal therapeutic modalities.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-YL (20))
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Rodriguez-Chavez, Isaac R
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Martin, Bradley N; Wang, Chenhui; Zhang, Cun-jin et al. (2016) T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis. Nat Immunol 17:583-92
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
Tomalka, Jeffrey; Azodi, Elaheh; Narra, Hema P et al. (2015) ?-Defensin 1 plays a role in acute mucosal defense against Candida albicans. J Immunol 194:1788-95
Tomalka, Jeffrey; Hise, Amy G (2015) Inflammasomes in aspergillosis--it takes two to tango. Cell Host Microbe 17:290-2
Drummond, Rebecca A; Gaffen, Sarah L; Hise, Amy G et al. (2014) Innate Defense against Fungal Pathogens. Cold Spring Harb Perspect Med 5:
Tarabishy, Ahmad Bakir; Hise, Amy G; Traboulsi, Elias I (2012) Ocular manifestations of the autoinflammatory syndromes. Ophthalmic Genet 33:179-86
Tomalka, Jeffrey; Ganesan, Sandhya; Azodi, Elaheh et al. (2011) A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog 7:e1002379
Hise, Amy G; Tomalka, Jeffrey; Ganesan, Sandhya et al. (2009) An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe 5:487-97