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Infection driven inflammation as a novel driver of neurodegeneration in mitochondrial disease

Award Number: R21NS149367
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: 05/06/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Infection driven inflammation as a novel driver of neurodegeneration in mitochondrial disease - Project Summary Primary mitochondrial diseases (PMDs) are the most common inborn errors of metabolism, affecting ~1 in 5,000 births with devastating neurologic manifestations. A hallmark clinical feature of PMD is infection-triggered permanent neurologic deterioration, where intercurrent infections precipitate acute worsening of neurologic function without return to baseline after infection resolution. This distinctive pattern provides a compelling model to investigate fundamental mechanisms underlying post-infectious neurologic sequelae applicable to other infection-associated chronic neurologic illnesses and post-viral fatigue syndromes. Emerging preclinical and patient data support a central role for the immune system in the progression of PMD. Based on these emerging data, we propose that infections causally accelerate neurodegeneration in PMD through immune cell intrinsic mitochondrial dysfunction that results in dysfunctional immunity, and that different genetic causes of PMD lead to distinct patterns of immune alterations that actively contribute to the severity and phenotype of post-infectious neurologic deterioration. We aim to define the spectrum of immune dysfunction across diverse genetic forms of human PMD through comprehensive immunophenotyping and functional assessment using single-cell RNA sequencing and cytokine profiling of patient peripheral blood mononuclear cells at baseline and post-stimulation. Further, moving beyond correlation, we will determine if mitochondrial dysfunction in immune cells causally accelerates neurodegeneration using the NDUFS4 knockout mouse model of PMD. Specifically by investigating whether influenza infection drives neurologic decline and leveraging genetic restoration of mitochondrial function specifically in immune cells to establish causality. This work will integrate translational pipelines including single- cell sequencing with novel animal models to causally define the mechanisms linking mitochondrial dysfunction, immune dysregulation, and post-infectious neurologic deterioration. Importantly, This research directly addresses NINDS priorities by investigating mechanisms of mitochondrial dysfunction contributing to nervous system dysfunction in infection-associated chronic illnesses, providing insights into shared pathways across multiple post-infectious neurologic conditions and identifying potential therapeutic targets for these disorders.


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 = $214,329 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/11/2026	NEW	$214,329
														Subtotal = $214,329

Grand Total All Awards = $214,329

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Infection driven inflammation as a novel driver of neurodegeneration in mitochondrial disease

Award Number: R21NS149367

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: 05/06/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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