[R01] The contribution of HSV-2 ICP34.5 variation to neurovirulence during neonatal infection
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2030-06-30
Importo max: 604.164 EUR
Paese: US
Descrizione
PROJECT SUMMARY / ABSTRACT
Herpes simplex virus (HSV)-2 infection of the neonatal brain causes severe meningoencephalitis and
permanent neurologic deficits. However, infants infected with HSV-2 at the time of birth follow different clinical
courses. Some infants develop only external infection of the skin, eyes, or mouth (SEM disease), while others
develop invasive infection of the central nervous system resulting in encephalitis (CNS disease). The factors that
promote HSV-2 infection of the neonatal brain are not well understood. While adults can be predisposed to HSV
encephalitis by an innate immune defect, no such host susceptibility has been identified in neonates. Recent
work has shown that variation in neurovirulence potential exists between clinical HSV-2 strains isolated from
neonates. These data suggest an opportunity to use naturally-occurring viral variation to elucidate key viral
virulence factors, and critical features of a successful host immune defense, in the neonatal brain. However, the
specific variations driving clinically meaningful differences in neurovirulence and the molecular mechanisms
responsible remain unknown. This knowledge gap prevents the development of neuroprotective anti-viral
therapies. An unbiased analysis of HSV-2 whole genome sequences revealed variations in the neurovirulence
gene g34.5, which were unique to isolates producing the most severe neurologic disease in both human neonates
and mouse models of encephalitis. This proposal will determine the impact of g34.5 expression on HSV-2
infection of the neonatal brain. The central hypothesis is that viral genomic variation in HSV-2 g34.5 contributes
to neurovirulence by promoting evasion of effective innate and adaptive immunity.
Aim 1 will determine the effect of naturally-occurring g34.5 genomic variations on key protein characteristics.
This Aim will utilize infection with clinical isolates, and transfection of isolate-specific expression plasmids, to
determine how variations in g34.5 alter RNA splicing and stability, protein localization, and ultimately host protein
binding partners. Aim 2 will determine the impact of g34.5 genomic variations on HSV disease within the brain.
Single-nucleus RNA-sequencing of murine brain at early timepoints following infection with clinical or mutant
viruses will be used to determine the response of CNS-resident cells to neurovirulent g34.5 variations.
Additionally, we will evaluate how neurovirulent g34.5 variations alter the influx of adaptive immune cells into the
brain at late timepoints following murine infection. Successful completion of these Aims will harness naturally-
occurring viral variation to determine the impact of HSV-2 g34.5 on neurovirulence, and identify critical aspects
of the innate and adaptive neuroimmune response which determine the outcome of neurologic infection, to inform
development of new neuroprotective therapies that drive clearance of virus from the brain in all children.
Istituzione: LURIE CHILDREN'S HOSPITAL OF CHICAGO
PI: Lisa Nowoslawski Akhtar
Progetto: 5R01NS136691-02
Settori: National Institute of Neurological Disorders and Stroke
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