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Candida albicans oral infection shapes innate immunity and recruitment of myeloid-derived suppressor cells

Award Number: R01DE032058
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Candida albicans is a fungal commensal organism that causes oropharyngeal candidiasis (OPC) and may disseminate systemically in immune compromised people. However, most healthy people have oral levels of C. albicans and it is a beneficial organism in the human gut microbiome. Mice infected with C. albicans also have low numbers of oral fungi but have much higher numbers of C. albicans in the gut so that they are a good model to study what factors permit fungal tolerance at human mucosal sites. C. albicans hyphae secrete the aspartyl protease Sap6 that mediates virulence in OPC, induces cytokine release from oral epithelial cells, and initiates neutrophil recruitment. Oral infection by C. albicans in mice caused recruitment of neutrophil “swarms” surrounding invading hyphae, as well as localized Arginase1 positive (Arg1+) granulocytic cells. These Arg1+ cells showed suppression of T cells thus identifying them as myeloid-derived suppressor cells (MDSC). MDSCs have a well-known immunosuppressive role in cancer causing tumor immune evasion, but also have a major role in host immune responses to bacterial and fungal infections by favoring pathogen persistence and chronic infection. We are the first to identify MDSC recruitment upon C. albicans oral infection but we do not know their role here. C. albicans infection resulted in changes the oral epithelium (Ep) including expression of kallikrein (KLK5) proteases accompanying increased Ep desquamation, and increased levels of tissue Arginase 1 (Arg1). The Aims of this project are to 1) Identify in what manner Arg1 and KLK5 expression in oral Ep alters C. albicans infection by examining the effect of Arg1 and KLK5 depletion; 2) Determine how C. albicans induces neutrophil swarming and recruitment of MDSCs in vitro by using live imaging of neutrophil swarming induced by C. albicans and Sap6 and to measure fungicidal activity of MDSCs; and 3) Ascertain the contribution of MDSCs in oral and gut Ca infection in vivo by comparing C. albicans infection in tongue and intestine following MDSC depletion or adoptive transfer of MDSCs. The goal of this proposal is to determine the function of MDSCs in mucosal immunity as well as how Arginase metabolites and KLK5 expression control the final outcome of fungal infection. It is proposed that MDSCs are a novel and unexplored arm of oral epithelial immunity that contribute to oral or gut tolerance of fungal pathogens. The long-range goal of this project is to understand host response to C. albicans and that will guide future strategies to reduce the immune escape of C. albicans and add to our understanding of host tolerance.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $344,138 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	3	4/22/2024	NON-COMPETING CONTINUATION	$344,138
														Subtotal = $344,138

Issue Date FY: 2023 ( Subtotal = $381,188 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	2	4/26/2023	NON-COMPETING CONTINUATION	$381,188
														Subtotal = $381,188

Issue Date FY: 2022 ( Subtotal = $380,000 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	1	7/14/2022	NEW	$380,000
														Subtotal = $380,000

Grand Total All Awards = $1,105,326

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Candida albicans oral infection shapes innate immunity and recruitment of myeloid-derived suppressor cells

Award Number: R01DE032058

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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