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Linking defects in DNA polymerase beta to mitochondrial dysfunction and cytosolic nucleic acid sensor in Helicobacter pylori associated inflammation

Award Number: R01AI179899
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 Targeting mitochondria has emerged as a key strategy for bacteria to hijack host cell physiology and promote infection. Mitochondrial dysfunction shapes innate immune response and promotes inflammatory responses. Several studies have shown that defective oxidative DNA damage repair pathways are associated with mitochondrial dysfunction and chronic inflammatory diseases. Base excision repair (BER) is the predominant pathway that corrects small base lesions caused by reactive oxygen and nitrogen species (RONS). BER is the major pathway for the repair of oxidative DNA lesions and is present in both nucleus and mitochondria by similar mechanisms that share many of the core BER enzymes. DNA polymerase beta (POLB) and gamma (POLG) are involved in maintenance of mitochondrial DNA (mtDNA) integrity. The 5’- deoxyribophosphodiesterase (5’-dRP lyase) functions of POLB is more active than POLG 5’-dRP lyase function to remove the 5’-dexyribose phosphate group (5’-dRP). In addition, we characterized 5’-dRP lyase deficient POLB (L22P point mutation)] that results in loss of 5’-dRP lyase function as a model to examine whether absence of 5’-dRP lyase impairs mitochondrial function and contributes to aberrant inflammatory response. Our preliminary data show that BER deficient cells significantly accumulate mitochondrial DNA (mtDNA) damage. Moreover, we found that Helicobacter pylori (H. pylori) infection exacerbates DNA damage and inflammatory response in 5’-dRP lyase deficient mice. However, there are no data to explain how the BER defect ( 5’-dRP lyase deficient POLB) influences mitochondrial DNA mediated innate immune response and its potential impact on induction of inflammation associated human diseases. In this application, we will examine how defective BER associated mitochondrial dysfunction contributes to cytosolic nucleic acid sensor mediated innate immune inflammatory response. Based on our highly significant and encouraging preliminary findings, we will test the hypothesis that defective BER promotes mitochondrial dysfunction and provokes cytosolic nucleic acid mediated signaling in H. pylori associated inflammation. In this study, we propose three specific aims as follows: i) Determine whether BER deficient cells release mtDNA in the cytoplasm; ii) Determine whether aberrant repair of mtDNA modulates innate immune signaling in vitro and in vivo; and iii) Define how the effects of aberrant BER (5’-dRP lyase deficient POLB) with H. pylori infection contribute to cytosolic nucleic acid sensor mediated innate immune signaling and inflammatory response. Completion of the proposed studies will provide novel mechanistic insight into how impaired mtBER and extracellular bacterial infection contribute to mitochondrial dysfunction related inflammation. Further, unlocking cytosolic surveillance and signaling upon extracellular bacterial infection may reveal new opportunities for future immune based therapeutic strategy.


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 = $385,402 )
2024	2024	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	1	12/8/2023	NEW	$385,402
														Subtotal = $385,402

Grand Total All Awards = $385,402

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Linking defects in DNA polymerase beta to mitochondrial dysfunction and cytosolic nucleic acid sensor in Helicobacter pylori associated inflammation

Award Number: R01AI179899

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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