Microglia and a Functional Type I IFN Pathway Are Required To Counter HSV-1–Driven Brain Lateral Ventricle Enlargement and Encephalitis

Abstract

HSV-1 is the leading cause of sporadic viral encephalitis with mortality rates approaching 30% despite treatment with the antiviral drug of choice, acyclovir. Permanent neurological deficits are common in patients that survive but the mechanism leading to this pathology is poorly understood impeding clinical advancements in treatment to reduce central nervous system (CNS) morbidity. Using magnetic resonance imaging and type I IFN receptor deficient mouse chimeras, we demonstrate HSV-1 gains access to the murine brain stem and subsequently brain ependymal cells leading to enlargement of the cerebral lateral ventricle and infection of the brain parenchyma. A similar enlargement in the lateral ventricles is found in a subpopulation of herpes simplex encephalitic patients. Associated with encephalitis is an increase in CXCL1 and CXCL10 levels in the cerebral spinal fluid, TNF-α expression in the ependymal region and the influx of neutrophils of encephalitic mouse brains. Reduction in lateral ventricle enlargement using the anti-secretory factor peptide, AF-16, reduces mortality significantly in HSV-1 infected mice without any effect on expression of inflammatory mediators, infiltration of leukocytes, or changes in viral titer. Microglial cells but not infiltrating leukocytes or other resident glial cells or neurons are the principal source of resistance in the CNS during the first 5 days post infection through a TRIF-dependent, type I IFN pathway. Our results implicate lateral ventricle enlargement as a major cause of mortality in mice and speculate such an event transpires in a subpopulation of human herpes simplex virus encephalitic patients.

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

“…Because animals vaccinated with HSV-1 0⌬NLS displayed such characteristics of protection upon challenge without experiencing consequential ocular pathology, the adaptive immune responses were compared among all experimental groups to extrapolate the respective correlates of protection. 50 challenge inoculum. Statistical differences were determined by one-way ANOVA with Student-Newman-Keuls multiple comparison tests for panel C and E and as described in the legend of Fig.…”

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

“…However, it is important to note that NK cell function in neonatal mice is developmentally immature and cannot be compared to results from studies in adult mice (106). In contrast, activated microglia have been suggested to contribute immunopathological responses to chronic viral infections of the CNS, such as HIV, as well as to provide early antiviral responses during acute viral encephalitis associated with both flaviviruses and herpes simplex virus (107)(108)(109). However, similar to limitations in our study, the previous studies were often carried out in the presence of peripheral inflammatory responses, and thus, the precise role of microglia in the mechanisms of CNS disease cannot be rigorously assigned.…”

Effects of toll-like receptor 3 on herpes simplex virus type-1-infected mouse neural stem cells

“…Herpes simplex encephalitis is one of the most common viral infections affecting the central nervous system; this disease is caused by Herpes simplex virus type-1 (HSV-1, which belongs to Herpesviridae) (Rempel et al 2005;Chakraborty et al 2010;Veerhuis et al 2011;Conrady et al 2013;Saijo et al 2013). Since HSV-1 infects the brain, astrocytes (AS) express numerous cytokines involved in the innate immune response of the nervous system.…”