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HSV-1 preferentially induces neuroinflammation and senescence in female mice.

Award Number: R21AI178282
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: 02/02/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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HSV-1 preferentially induces neuroinflammation and senescence in female mice. - Project Summary Human alphaherpesvirus 1 (HSV-1) continues to be an important human pathogen because it infects two-thirds of the adults in the world. Following acute infection, HSV-1 establishes and maintains life-long latency in neurons within trigeminal ganglia (TG), and other neurons within the central nervous system, including brainstem. External stressful stimuli periodically induce reactivation from latency, which triggers virus transmission. HSV-1 reactivation from latency is essential for virus transmission and recurrent disease: including ocular disease, encephalitis, and congenital infections. The principal sensory nucleus of the spinal trigeminal tract (Pr5) and locus coeruleus (LC) regions of the brainstem receive afferent inputs (directly or indirectly) from TG. Consequently, brainstem is a biologically relevant site for viral replication and reactivation from latency. Our recent published study revealed wild-type (wt) HSV-1 and a latency associated transcript (LAT) mutant, referred to as dLAT2903, preferentially induce expression of neuroinflammatory and senescence markers in Pr5 of latently infected female, but not male mice. Strikingly, dLAT2903, but not wild-type HSV-1, preferentially induces expression of senescence and neuroinflammatory markers in LC of females, but not male mice. Pr5 contains many motor neurons whereas LC primarily contains medium-sized neurons. LC is also the principal site for norepinephrine synthesis in the brain. New studies suggest LAT expression impairs neuroinflammation in latently infected TG neurons or productively infected human astrocytes derived from brainstem. Based on these female dimorphic responses to HSV-1 infection, we hypothesize that Pr5, LC, and TG of female mice are predisposed to senescence, neuroinflammation, and potentially neurodegeneration during latency. To test our hypothesis, two Specific Aims are proposed. Specific Aim 1 studies will identify cellular genes that regulate neuroinflammation in TG, Pr5, and LC during latency and localize LAT coding sequences that impair neuroinflammation. Specific Aim 2 studies will identify senescent cells in brainstem and test whether LAT impairs senescence and inflammation in cultured human brainstem astrocytes. Completing these studies will provide insight into the mechanism by which HSV-1 causes neuroinflammation, including how LAT mediates this process.


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: 2025 ( Subtotal = $181,390 )
2025	2025	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Allergy and Infectious Diseases Research	000	2	12/4/2024	NON-COMPETING CONTINUATION	$181,390
														Subtotal = $181,390

Issue Date FY: 2024 ( Subtotal = $224,400 )
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Allergy and Infectious Diseases Research	000	1	2/2/2024	NEW	$201,960
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$22,440
														Subtotal = $224,400

Grand Total All Awards = $405,790

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HSV-1 preferentially induces neuroinflammation and senescence in female mice.

Award Number: R21AI178282

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: 02/02/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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