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Mechanisms of central nervous system invasion by the Lyme disease spirochete, Borrelia burgdorferi

Award Number: R21AI190212
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: 04/08/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Mechanisms of central nervous system invasion by 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. Neurologic disease, referred to as Lyme neuroborreliosis, can include meningitis, cranial and peripheral neuritis/neuropathy, and encephalopathy. 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. The overall goal of these studies is to identify key mechanisms of B. burgdorferi central nervous system invasion and associated host responses. A critical gap in our understanding of Lyme disease pathology has been the lack of a reproducible small animal model of neuroborreliosis. Laboratory mice have been instrumental in identifying the mechanisms of Lyme arthritis and carditis pathology, however the mechanisms of central nervous system invasion and pathology remain poorly understood as the prevailing view has been that mice do not develop central nervous system manifestations. Our recent work challenges this paradigm by demonstrating for the first time that B. burgdorferi colonizes the meninges and cerebrospinal fluid during murine infection, which is accompanied by an influx of leukocytes and increased inflammatory proteins. Furthermore, the extent of cerebrospinal fluid involvement is mouse strain dependent and correlates with strain-specific susceptibility to peripheral Lyme immunopathologies, suggesting a role for host genetics in central nervous system invasion. Expanding on our recent findings, we hypothesize that the inflammatory response to B. burgdorferi infection leads to blood-cerebrospinal fluid barrier breakdown, facilitating central nervous system invasion by both bacteria and immune cells. Using the murine model of B. burgdorferi infection, we will address the following aims in our studies: (1) Determine the role of the blood-cerebrospinal fluid barrier as a site for B. burgdorferi and immune cell entry into the central nervous system; and (2) Identify host immune responses associated with increased central nervous system invasion, with a focus on pathways previously associated with murine Lyme arthritis severity and/or blood-cerebrospinal fluid barrier permeability. The tractability of our novel murine model provides a unique opportunity to experimentally investigate the mechanisms of central nervous system manifestations during B. burgdorferi infection. By performing the proposed experiments in mouse strains with altered immune responses to B. burgdorferi infection, we expect to gain insight into host factors important for bacterial invasion into the central nervous system. This work will provide the foundation for a long-term research program focused on mechanisms of Lyme neuroborreliosis pathogenesis, with the overall goal of identifying new targets for prophylactic and therapeutic treatments.


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: 2026 ( Subtotal = $192,500 )
2026	2026	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BLVD	MOBILE	AL	36688	MOBILE	USA	Allergy and Infectious Diseases Research	000	2	4/1/2026	NON-COMPETING CONTINUATION	$192,500
														Subtotal = $192,500

Issue Date FY: 2025 ( Subtotal = $192,500 )
2025	2025	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Allergy and Infectious Diseases Research	000	1	4/8/2025	NEW	$192,500
														Subtotal = $192,500

Grand Total All Awards = $385,000

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Mechanisms of central nervous system invasion by the Lyme disease spirochete, Borrelia burgdorferi

Award Number: R21AI190212

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: 04/08/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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