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Dissecting GBP1-Mediated Immune Responses: From Pathogen Sensing and Defense to Organelle Dynamics

Award Number: R01AI201547
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: 08/11/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Dissecting GBP1-Mediated Immune Responses: From Pathogen Sensing and Defense to Organelle Dynamics - Project Abstract Intracellular bacterial pathogens cause significant morbidity and mortality worldwide, with antibiotic resistance necessitating alternative therapeutic approaches. The interferon- induced GTPase GBP1 serves as a critical mediator of cell-autonomous immunity by forming antimicrobial coats on diverse pathogens including Salmonella, Mycobacterium, and Toxoplasma. Despite two decades since the first GBP1 X-ray structure was solved, it lacks physiological relevance, leaving GBP1-mediated immune defense mechanisms unknown. How does prenylation switch GBP1 function? How does GBP1 recognize diverse pathogens? How does it discriminate pathogen from host membranes? Our preliminary data show farnesylation is essential for coat formation, Kdo2-lipid A is the minimal LPS recognition unit, and GBP1 forms ring-like polymers as intermediates. We hypothesize prenylation switches GBP1 to function as a pattern recognition receptor employing conserved conformations to recognize diverse pathogen surfaces while discriminating self-membranes. Aim 1 will define how prenylation drives antimicrobial activity by comparing farnesylation versus geranylgeranylation and determining cryo-EM structures of GBP1-LPS complexes. Aim 2 will capture 3D structures of GBP1 on non-LPS pathogens (M. smegmatis, T. gondii) and characterize polymerization intermediates using ex situ cryo-ET. Aim 3 will visualize GBP1 at host organelles in situ and develop protein tagging strategies for small protein visualization using in situ cryo-ET. We will integrate in vitro reconstitution, cryo-electron tomography, and high-throughput in situ imaging to achieve molecular-resolution insights. Our studies will establish GBP1 as a pattern recognition receptor, reveal coat assembly principles, and define membrane discrimination mechanisms. This work addresses NIAID priorities, will inform host- directed therapy design, and provide generalizable technologies for studying immune proteins in native cellular contexts.


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 = $428,203 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	8/11/2026	NEW	$428,203
														Subtotal = $428,203

Grand Total All Awards = $428,203

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Dissecting GBP1-Mediated Immune Responses: From Pathogen Sensing and Defense to Organelle Dynamics

Award Number: R01AI201547

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: 08/11/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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