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Aggor, FEY (2020) MECHANISTIC INSIGHTS INTO THE ROLES OF IL-22/IL-22RA1 AXIS IN ORAL ANTIFUNGAL IMMUNITY. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Oropharyngeal candidiasis (OPC, oral thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. IL-17 and IL-22 are produced by Type 17 lymphocytes.Both cytokines mediate antifungal immunity yet activate quite distinct downstream signaling
pathways. While much is now understood about how IL-17 promotes immunity in OPC, the activities of IL-22 are far less well delineated. In this dissertation, I focused on identifying mechanisms by which IL-22 mediates oral antifungal immunity. In chapters 3 and 4, I identified
key differences between IL-22 and IL-17-dependent antifungal events during innate OPC response. We show that, despite having similar requirements for induction from Type 17 cells, IL-22 and IL-17 function non-redundantly during OPC. We find that the IL-22 and IL-17 receptors are required in anatomically distinct locations within the oral mucosa; loss of IL-22RA1 or STAT3 in the oral basal epithelial layer (BEL) causes susceptibility to OPC, whereas IL-17RA is needed in the suprabasal epithelial layer (SEL). Transcriptional profiling of the tongue linked IL22/STAT3 to oral epithelial cell proliferation and survival, but also, unexpectedly, to driving an IL-17-specific gene signature. We show that IL-22 mediates regenerative signals on the BEL that replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to
respond to IL-17 and thus to mediate antifungal events. Consequently, IL-22 signaling in BEL ‘licenses’ IL-17 signaling in the oral mucosa, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis. In chapter 5, I assessed the roles of IL-22 in T cell recall OPC settings. IL-22 is protective in the adaptive response against OPC although the contribution
of innate IL-22-mediated responses could not be ruled out. While IL-22 deficiency resulted in cervical lymph node (cLN) hypertrophy, there was no evidence of C. albicans translocation to the cLN or increased proliferative expansion of Th17 cells. Loss of IL-22 resulted in increased Th17(CD4+IL-17A+) but decreased Th1(CD4+IFN-+) frequency. Hence IL-22 may be acting on the cLN stroma to modulate T cell responses in recall OPC settings. Our findings have implications for antifungal vaccine design strategies and oral immunosurveillance mechanisms against oral
pathologies and extra-oral diseases.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Aggor, FEYfea18@pitt.edufea180000-0002-0327-0095
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGaffen, SLsarah.gaffen@pitt.edusarah.gaffen0000-0001-8511-2041
Committee ChairBinder, RJrjb42@pitt.edurjb420000-0003-0857-3949
Committee MemberKaplan, Ddankaplan@pitt.edudankaplan0000-0003-0598-0047
Committee MemberHand, TWhandt@pitt.eduhandt0000-0002-2684-9462
Committee MemberAlcorn, JFjfa9@pitt.edujfa9@pitt.edu0000-0001-5997-7711
Committee MemberWeathington, Nweathington@pitt.eduweathington0000-0002-2937-8432
Date: 21 September 2020
Date Type: Publication
Defense Date: 15 July 2020
Approval Date: 21 September 2020
Submission Date: 11 August 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 157
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Chronic mucocutaneous candidiasis, primary immunodeficiency syndromes, Interleukin 17, Interleukin 22, STAT3
Date Deposited: 21 Sep 2020 15:02
Last Modified: 21 Sep 2020 15:02

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