Thursday, November 21, 2024
11/21/2024
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.
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