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Pneumonia-induced microglial activation causes blood-brain barrier breakdown, astrocyte activation, and tau pathology

Award Number: F99NS141403
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Pneumonia-induced microglial activation causes blood-brain barrier breakdown, astrocyte activation, and tau pathology - PROJECT SUMMARY / ABSTRACT Many survivors of respiratory infections (i.e., pneumonia, and SARS-CoV-2) have subsequent incident dementia causing decreased quality of life and are at a higher risk of developing Alzheimer’s disease and related dementias. The cause of this association between pneumonia and dementia is unknown. It is also unknown how bacterial pneumonia causes neurovascular unit dysfunction. Pseudomonas aeruginosa is a pathogen capable of causing bacterial pneumonia and can elicit cytotoxic tau from the mouse lung and induce neuronal tau seeding, reduce dendritic spine density, and impair synaptic plasticity and cognition in mice. Additionally, I have shown that P. aeruginosa causes microglia and astrocyte activation, blood-brain barrier breakdown, and tau pathology in wild-type mice 24 hours post-infection. At lower doses of P. aeruginosa, I have seen microglia activation but no blood-brain barrier dysfunction. Microglia can influence blood-brain barrier breakdown and tau pathology as well as regulate neuroimmune pathways. Taken together, this has led to the hypothesis that pneumonia first causes microglia activation, leading to blood-brain barrier breakdown, and tau phosphorylation in the brain. Using a quadruple labeled mouse model (PrismPlus), I will image longitudinally from just 3 hours post-infection to elucidate the temporal resolution and mechanisms of neurovascular unit dysfunction in the brain. I will also assess neurovascular unit dysfunction in matched pneumonia vs. non-pneumonia post-mortem brain and lung tissue. This project will be the first step towards developing novel and effective therapies to protect neurovascular function in patients with severe lung infections, while allowing me to master the amazing technique of multiphoton imaging of mouse brain through a cranial window. Migraine disorders have a global prevalence of approximately 15% and are the third highest cause of disability-adjusted life years. However, much is still unknown about the pathology of migraines, particularly at the capillary level, and more effective treatments are needed. For the K00 phase, I will utilize my mastery of intravital imaging of the neurovascular unit at the capillary level, to investigate neurovascular and neuroimmune mechanisms in migraine mouse models.


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 = $0 )
2026	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	12/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$34,537
2026	2025	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BLVD	MOBILE	AL	36688	MOBILE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/3/2025	NON-COMPETING CONTINUATION	-$34,537
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $34,538 )
2025	2025	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BLVD	MOBILE	AL	36688	MOBILE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/22/2025	NON-COMPETING CONTINUATION	$34,538
														Subtotal = $34,538

Issue Date FY: 2024 ( Subtotal = $33,974 )
2024	2024	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/30/2024	NEW	$33,974
														Subtotal = $33,974

Grand Total All Awards = $68,512

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Pneumonia-induced microglial activation causes blood-brain barrier breakdown, astrocyte activation, and tau pathology

Award Number: F99NS141403

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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