Role of Host Cell Factors in Newborn Herpes Simplex Virus (HSV) Encephalitis

Project: Research project

Project Details

Description

The newborn brain is uniquely susceptible to a wide range of pathogens compared to the adult, and this is exemplified following infection with herpes simplex virus type-1 (HSV-1), the most common cause of viral encephalitis. The majority of newborns infected with HSV-1 will go on to have severe disease, including viral dissemination and encephalitis, whereas infection in the adult population typically results in asymptomatic acquisition or benign mucosal infection. HSV encephalitis in the adult remains rare despite a HSV-1 seroprevalence of 50-80% in this population. The significantly different outcomes between adults and newborns following HSV infection suggest an age-dependent difference in susceptibility to central nervous system (CNS) disease based on host factors. A relative immaturity of the neonatal immune system is commonly implicated in their overall increased susceptibility to HSV and other neurotropic viruses, however, the precise reasons underlying their increased susceptibility to viral encephalitis remain unknown. The incomplete understanding of pathogenesis in the neonatal population remains as a critical barrier to improving survival and neurologic outcomes following HSV encephalitis.
In this proposal, we plan to investigate the innate immune mechanisms in the brain responsible for differences in susceptibility and severity of HSV disease between the newborn and adult. We will build on our previously unfunded work to understand the role of the host response in determining viral tropism within the brain, the contribution of glial cells to HSV-1 infection, and modulation of the blood brain barrier (BBB) by type I interferon (IFN) signaling in the newborn during infection. HSV-1 and the host antiviral response has been frequently studied in the context of neuronal infection, however, there is an emerging role for astrocytes and microglia in the pathogenesis of viral encephalitis. Preliminary data from our lab demonstrates astrocytic infection in the newborn brain in addition to neurons, and significant differences in the type I IFN response between the two age groups. We hypothesize that the contribution of astrocytes and microglia to viral replication and survival following HSV encephalitis is age-dependent. Our proposed studies will demonstrate the contribution of type I IFN signaling specifically in astrocytes and microglia to HSV pathogenesis, and how this response changes through different developmental ages. HSV encephalitis often occurs in the context of disseminated disease in the newborn, and we also plan to investigate the role of type I IFN in modulating the BBB during infection and its contribution to HSV spread to the brain. Preliminary data from our lab suggests that type I IFN treatment improves survival and reduces HSV neuroinvasion during disseminated disease. In this proposal, we will pursue the innate immune mechanisms that underlie BBB modulation in the newborn brain, and elucidate the potential of immunomodulatory therapy to improve outcomes in this age group.
StatusActive
Effective start/end date1/1/193/31/24

Funding

  • National Institute of Neurological Disorders and Stroke (5R01NS110631-02)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.