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Molecular mechanisms of Helicobacter pylori trans-kingdom DNA conjugation

Award Number: R21AI180274
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Molecular mechanisms of Helicobacter pylori trans-kingdom DNA conjugation - PROJECT SUMMARY Of the recognized infection-associated malignancies, the most significant carcinogenic microbe is the gastric bacterium Helicobacter pylori, which chronically colonizes the stomach of over half of the global population and contributes to the development of more than one million new cases of cancer per year. Despite many decades of research, we do not fully understand how H. pylori balances interactions with the human host to stimulate the development of gastric disease. The cancer-associated H. pylori cag type IV secretion system (cag T4SS) has emerged as a paradigm for understanding how a single molecular device transports diverse immunostimulatory cargo into target eukaryotic cells. Whereas some T4SSs have the capacity to secrete multiple protein effectors, the ability to translocate a pro-inflammatory bacterial oncoprotein and a repertoire of DNA and polysaccharide substrates distinguishes the cag T4SS from other nanomachines. In exciting new studies, we discovered that cag T4SS-dependent trans-kingdom DNA conjugation stimulates cytosolic nucleic acid reconnaissance systems to provoke the production of multifarious interferons and inflammatory cytokines that orchestrate diverse immune responses. Our long-term objective is to mechanistically characterize how the dynamic cag T4SS transports carcinogenic molecular cargo into gastric cells. Towards our objective, we aim to define the kinetics and biogeography of cag T4SS-dependent DNA translocation in vivo and delineate the mechanism by which chromosomal DNA cargo is excised and coupled to the cag T4SS apparatus. Our studies will employ rodent infection models, high-resolution microscopy, biochemical approaches, and immunological assays to address longstanding knowledge gaps in gastric cancer biology and uncover microbial mechanisms that are involved in the development of pre-malignant lesions. Collectively, these investigations will advance our understanding of important host-pathogen conflicts that engage nucleic acid surveillance pathways to regulate host immunity and trigger microbial carcinogenesis. Furthermore, our studies will provide the foundational framework for developing new treatment and intervention strategies to reduce the incidence and severity of malignancies that arise as a consequence of infection-induced chronic inflammation.


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: 2025 ( Subtotal = $172,539 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	001	2	9/26/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	2	11/27/2024	NON-COMPETING CONTINUATION	$172,539
														Subtotal = $172,539

Issue Date FY: 2024 ( Subtotal = $214,238 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	1	11/22/2023	NEW	$192,814
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$21,424
														Subtotal = $214,238

Grand Total All Awards = $386,777

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Molecular mechanisms of Helicobacter pylori trans-kingdom DNA conjugation

Award Number: R21AI180274

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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