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Generation of CD8+ Tissue-Resident Memory T cell response during Yersinia pseudotuberculosis foodborne infection

Award Number: R21AI173788
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract The tissue resident memory T (TRM) cells that reside at barrier tissues respond immediately following pathogen encounter. Eliciting TRM cells has become a priority in vaccine development to combat infectious diseases and in cancer immunotherapy. Live attenuated Gram-negative bacterial pathogen Yersinia pseudotuberculosis (Yptb) will be evaluated here as a new vaccine vector to produce antigen-specific intestinal CD8+ TRM cells. As a rare pathogen, Yptb causes mostly self-limited mesenteric lymphadenitis in immune competent humans and is treatable with antibiotics. Sub-lethal infection with Yptb in C57BL/6 mice elicits a large H-2Kb-restricted CD8+ T cell response specific to bacterial epitope YopE69-77. Following foodborne infection, two different subsets of Yptb- specific CD8+ TRM cells were identified in intestinal tissues: the scattered CD103+ and the clustered CD103neg cells. The CD103+ cells depend on transforming growth factor-b (TGFb) and the CD103neg cells require interferon-b (IFNb) and interleukin-12 (IL-12), inflammatory cytokines mostly generated from CCR2-dependent cells. Several unique characteristics of Yptb suggest that this previously overlooked pathogen is at an advantageous position to be transformed into a vaccine vector. Yptb utilizes a type 3 secretion system (T3SS) to inject a set of 6-7 toxic effector proteins, collectively called Yops, from the bacterium directly into the cytosol of eukaryotic cells during infection. Injection of these Yop effectors through the Yptb T3SS is contact dependent and following mouse infection, a high percentage of phagocytes are among the targets. Therefore, the Yptb-based vaccine vector introduces antigenic proteins directly into the cytosol of phagocytic antigen-presenting cells without the need to manipulate the genome or transcriptome of eukaryotic cells. Studies are proposed here to initiate investigation to understand the bacterial and cellular determinants of the two types of TRM generation. In addition, because the Yop effectors interfere with host immune responses, efforts will be made to attenuate the Yptb- based vaccine vector and increase its immunogenicity through inactivation of the relevant Yop effectors. Moreover, because cytotoxic CD8+ T cell response is required to control Yptb even in the presence of protective antibody response, the possibility that the attenuated Yptb vaccine vector can be introduced repeatedly to elicit TRM cells with additional antigenic specificity will be evaluated. Accomplishing the studies proposed here will set the foundation to develop a new type of live attenuated vaccine that is urgently needed for gut TRM cell generation.


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 = $199,375 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	5/6/2024	NON-COMPETING CONTINUATION	$199,375
														Subtotal = $199,375

Issue Date FY: 2023 ( Subtotal = $239,250 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	7/3/2023	NEW	$0
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	6/26/2023	NEW	$239,250
														Subtotal = $239,250

Grand Total All Awards = $438,625

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Generation of CD8+ Tissue-Resident Memory T cell response during Yersinia pseudotuberculosis foodborne infection

Award Number: R21AI173788

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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