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Microglial activation and inflammatory cytokine secretion as mechanisms driving CNS consequences of intermittent exposure to pathogens

Award Number: R01NS146649
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Microglial activation and inflammatory cytokine secretion as mechanisms driving CNS consequences of intermittent exposure to pathogens - Increased appreciation for chronic manifestations of infection exposure, and the host inflammatory response to infection, has revealed novel factors that could drive neurological disease such as dementia and exciting opportunities for prevention of these devastating conditions. Indeed, a robust literature has documented central nervous system (CNS) manifestations with exposure to a pathogen both during acute sickness and in the long- term recovery period. For instance, we have preliminary data that intermittent virus exposure impairs cognition, alters brain microvessel energy metabolism, induces neuroinflammation, increases hippocampal blood-brain barrier permeability, and results in distinct transcriptional and epigenetic profiles relative to age-matched. While accumulating evidence supports chronic neuroinflammation (via activated microglia and a proinflammatory cytokine milieu) as a mechanism by which infection experience perturbs brain function, the extent to which neuroinflammation represents a convergence point through which diverse pathogen subtypes potential induce their effects remains unknown. For this research program, in exploring the interaction between infection history, neurological disease vulnerability, and both systemic and neuroinflammation, we will contribute fundamental and critically needed knowledge regarding the chronic brain and behavior impacts of exposure to distinct pathogen subtypes. In this proposal, we will 1) investigate viral infection contributions to long-term brain and behavior function in normal and neurodegenerative disease mouse models, 2) characterize transcriptional and epigenetic profiles of distinct populations of pathogen-exposed cells in the brain, 3) interrogate microglia and inflammatory cytokines as mechanisms driving these neurological consequences, 4) discern the extent to neurotropism and pathogen subtype is required for these effects. Our approach is innovative as our recurrent infection exposure regimen represents a departure from the scientific status quo and more translationally mimics human systemic infection experience during adulthood. Further, it leverages cutting-edge spatial transcriptomics to comprehensively examine pathogen-induced transcriptomic profile shits at a sub-cellular level in brain and reveal new targets. Finally, our use of both neurotropic and peripherally-restricted infections will enable us to discern the extent to which different pathogens converge on similar targets to induce CNS effects. Our accomplished interdisciplinary research team of experts in neuroscience, infectious disease, immunology, and neurological diseases is well-poised to carry out the proposed studies. More broadly, a key component of this program is in pairing our impactful research with efforts to engage key stakeholders in the community through our robust and established neuroscience outreach initiatives. These activities represent a priority for the NINDS as well as the millions of patients, caregivers, and clinicians shouldering the burden of infection-induced chronic disease. disease.


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 = $625,392 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/31/2026	NEW	$625,392
														Subtotal = $625,392

Grand Total All Awards = $625,392

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Microglial activation and inflammatory cytokine secretion as mechanisms driving CNS consequences of intermittent exposure to pathogens

Award Number: R01NS146649

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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