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Identification of linear plasmid lp36-encoded virulence determinants in the Lyme disease spirochete Borrelia burgdorferi

Award Number: R03AI159391
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: 11/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Identification of linear plasmid lp36-encoded virulence determinants in the Lyme disease spirochete Borrelia burgdorferi - PROJECT SUMMARY/ABSTRACT Lyme disease, which is caused by infection with the tick-borne pathogen Borrelia burgdorferi, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems. As there are no vaccines or effective vector controls against the infection, Lyme disease is and will continue to be a significant public health concern. This proposal directly addresses the NIH Strategic Plan for Tickborne Disease Research, with specific applications towards understanding the fundamental biology of, and the host interactions with tickborne pathogens. The overall goal of these studies is to identify candidate B. burgdorferi targets for prophylactic and therapeutic treatments for Lyme disease. Isolates of B. burgdorferi display a high level of genetic heterogeneity, and certain genotypes correlate with increased pathogenesis in humans. High pathogenicity genotypes have been reported to induce a more robust Type I interferon response from host cells, and blocking Type I interferon abrogates pathology in laboratory mouse models of Lyme disease; underscoring the importance of Type I interferon in the pathogenesis of Lyme disease. Despite the importance of interferon signaling in the pathogenesis of Lyme disease, the bacterial factors involved in stimulating production of interferon are not well understood. Recently, the presence of the B. burgdorferi linear plasmid lp36 was shown to correlate with Type I and Type III interferon production from host cells ex vivo, however the specific genes involved and the consequences during mammalian infection have not been determined. We hypothesize that lp36 encodes unidentified virulence determinants required for stimulating production of interferon from host cells, as well as induction of disease pathology during mammalian infection. By selectively deleting different regions of lp36 in B. burgdorferi, we will address the following aims in our studies: (1) Define the lp36 genes required for innate immune cell responses; and (2) Determine the requirement of lp36 genes for bacterial colonization and induction of pathology during mammalian infection. Our innovative approach of linear plasmid truncation allows for screening large plasmid regions for the presence of novel virulence factors. Using systematic truncations of different sizes, we expect to identify the lp36 genes involved in stimulation of interferon production from host cells, and determine their roles in pathogen fitness and tissue pathology during infection. This work will move the field of Lyme disease research forward, as such factors are ideal candidate targets for novel prophylactic and therapeutic treatments for B. burgdorferi infection and associated immunopathologies.


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 = -$5,051 )
2025	2023	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR STOP 8371	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	2	4/16/2025	NON-COMPETING CONTINUATION	-$5,051
														Subtotal = -$5,051

Issue Date FY: 2023 ( Subtotal = $70,500 )
2023	2023	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	2	10/26/2022	NON-COMPETING CONTINUATION	$70,500
														Subtotal = $70,500

Issue Date FY: 2022 ( Subtotal = $70,500 )
2022	2022	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	1	10/25/2021	NEW	$70,500
														Subtotal = $70,500

Grand Total All Awards = $135,949

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Identification of linear plasmid lp36-encoded virulence determinants in the Lyme disease spirochete Borrelia burgdorferi

Award Number: R03AI159391

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: 11/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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