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Defining intestinal epithelial cell cytokine signaling in pyogranulomas during Yersinia infection

Award Number: F30AI202842
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/11/2027
PERIOD OF PERFORMANCE END DATE: 02/10/2028

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Defining intestinal epithelial cell cytokine signaling in pyogranulomas during Yersinia infection - Project Summary: Granulomas are organized aggregates of immune cells that form in a wide range of infectious and inflammatory diseases. Improving our understanding of the mechanisms that govern granuloma formation and function will enable the development of new therapeutic strategies to enhance protective granulomas or disrupt those that drive tissue damage. Although most studies of granulomas focus on immune cells, my preliminary data suggest that non-immune cells previously considered bystanders play an essential role in restricting bacterial infections within granulomas. To investigate these mechanisms, I use Yersinia pseudotuberculosis, a gram-negative enteric pathogen that forms neutrophil-rich intestinal pyogranulomas during oral infections in mice. In prior work, we demonstrated that monocyte-derived interleukin-1 (IL-1) is required for neutrophil recruitment and activation within pyogranulomas; however, the downstream targets of IL-1 signaling remain undefined. Intriguingly, my analysis of CITE-seq and spatial transcriptomics datasets reveals a unique cluster of intestinal epithelial cells with an inflammatory gene signature near pyogranulomas. I have shown that this gene signature is regulated by IL-22, leading me to investigate the role of IL-22 in pyogranuloma formation and the restriction of Yersinia. My preliminary data indicate that in pyogranulomas, IL-1R signaling promotes IL-22 production, which ultimately promotes IL-18 production by epithelial cells. Additionally, Il22-/- mice lacking this circuit form fewer pyogranulomas, and mice deficient in IL-18 in intestinal epithelial cells succumb to Yersinia infection. Based on these preliminary data, I hypothesize that during Yersinia infection, IL-1 in pyogranulomas initiates an IL-22 to IL-18 signaling loop which (1) promotes neutrophil-recruiting chemokine production to support pyogranuloma formation and (2) promotes a protective inflammatory response that limits Yersinia systemic dissemination to promote survival. In Aim 1, I will define the cell types that participate in this signaling loop and identify chemokines regulated by this circuit that promote granuloma formation. In Aim 2, I will investigate the effects of IL-22 and IL- 18 on survival and bacterial dissemination as the infection progresses. Completion of these aims will expand our understanding of the role of epithelial cells in enteric infections and granuloma biology, unveiling new therapeutic targets for infectious and granulomatous diseases. Additionally, this project will provide a platform to achieve my training goals of enhancing my scientific training in microbiology and immunology and improving my scientific communication and professional development opportunities. Completing these training goals will advance my future career as a physician-scientist leading a research team that studies mucosal immunity.


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: 2026 ( Subtotal = $55,114 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	8/11/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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Defining intestinal epithelial cell cytokine signaling in pyogranulomas during Yersinia infection

Award Number: F30AI202842

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/11/2027

PERIOD OF PERFORMANCE END DATE: 02/10/2028

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