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Regulatory Pathways in Borrelial Pathogenesis

Award Number: R01AI170940
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: 08/05/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Regulatory Pathways in Borrelial Pathogenesis - PROJECT SUMMARY The etiologic agent of Lyme Disease, Borrelia burgdorferi (Bb), is the leading arthropod-borne infection in the United States with over 470,000 cases diagnosed annually. Given that Lyme Disease is a significant public health concern, studies addressing how Bb establishes and maintains infection are vital to evaluating its pathogenic potential and developing prevention or therapeutic strategies. It is well known that Bb modifies its transcriptional profile throughout its pathogenic lifecycle, particularly during transmission from the arthropod vector into mammals. BosR is an important transcriptional regulator that functions as a global metalloregulatory protein and alters the expression of genes needed for mammalian colonization. Specifically, BosR is required for experimental infection in mice and is needed for the activation of the RpoS/RpoN/Rrp2 cascade that drives the expression of genetically unlinked genes, including virulence determinants required for Bb infection. While there is no doubt that the BosR-dependent regulation of rpoS is important to borrelial infectivity, there are additional genes that BosR regulates either directly or indirectly that may factor into Bb infection. How BosR is linked to this complex regulatory network has not been thoroughly addressed. Here, several novel BosR regulatory functions are described, heretofore unknown, including the recognition of RNA by BosR. The Preliminary Data shows that BosR binds to small non-coding RNA and exhibits chaperone activity suggesting that BosR forms a complex with sRNAs that binds to Bb transcripts and targets them for degradation or enhanced translation. This form of post-transcriptional regulation by BosR represents a new and innovative regulatory scheme that adds to its known DNA binding activity. In Aim 1, a subset of sRNAs that BosR binds will be evaluated, the transcripts recognized by the BosR::sRNA complex identified, and a link with the BosR-associated sRNAs to borrelial pathogenesis established. In Aim 2, recent ChIP-seq data will be mined to assess novel BosR DNA binding. Preliminary binding studies confirmed the ChIP-seq data for two targets and suggested that the redox status and metal coordination of BosR may alter DNA binding. BosR DNA binding will be analyzed to determine how the redox and metal binding status of BosR changes the target sequences recognized. Unique BosR binding motifs will be tracked, and a consensus sequence ascertained. Finally, experiments will be conducted to determine the phenotype of a bosR mutant that ectopically produces RpoS to query the direct role of BosR in Bb infection. Taken together, this proposal will provide new appreciation into how BosR-mediated transcriptional and post-transcriptional regulation ensues and novel insight into how BosR integrates the redox status of Bb to affect nucleic acid binding and borrelial pathogenesis.


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 = $663,145 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	4	8/6/2025	NON-COMPETING CONTINUATION	$663,145
														Subtotal = $663,145

Issue Date FY: 2024 ( Subtotal = $663,145 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	3	7/16/2024	NON-COMPETING CONTINUATION	$663,145
														Subtotal = $663,145

Issue Date FY: 2023 ( Subtotal = $663,145 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	7/7/2023	NON-COMPETING CONTINUATION	$663,145
														Subtotal = $663,145

Issue Date FY: 2022 ( Subtotal = $704,805 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	8/5/2022	NEW	$704,805
														Subtotal = $704,805

Grand Total All Awards = $2,694,240

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Regulatory Pathways in Borrelial Pathogenesis

Award Number: R01AI170940

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: 08/05/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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