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

宿主细胞因子在新生儿单纯疱疹病毒 (HSV) 脑炎中的作用

基本信息

批准号：
9890025
负责人：
Richard M Longnecker
金额：
$ 32.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890025
关键词：
Address Adult Age Antiviral Response Astrocytes Benign Biological Assay Birth Blood - brain barrier anatomy Brain Cell Separation Cells Cellular Tropism Central Nervous System Diseases Central Nervous System Viral Diseases Child Clustered Regularly Interspaced Short Palindromic Repeats Data Development Disease Encephalitis Exhibits Expression Profiling Flow Cytometry Fluorescein Gene Expression Genetic study Herpesvirus 1 IFNAR1 gene Immune response Immunofluorescence Immunologic In Vitro Incidence Infection Infiltration Innate Immune Response Integration Host Factors Interferon Type I Interferon-alpha Interferon-beta Interferons Knockout Mice Mediating Messenger RNA Microglia Microspheres Modeling Morbidity - disease rate Mucous Membrane Mus Mutation Neonatal Neonatal Mortality Neuraxis Neuroglia Neurologic Neurological outcome Neurons Neurotropism Newborn Infant Outcome Pathogenesis Pathway interactions Play Population Predisposition Primary Cell Cultures Production Proteins Role Seroprevalences Severities Severity of illness Signal Pathway Signal Transduction Simplexvirus Structure of choroid plexus Survivors Target Populations Tropism United States Viral Viral Encephalitis Viral Pathogenesis Virus Diseases Virus Replication Work age group age related base blood-brain barrier permeabilization cytokine experimental study high risk immunomodulatory therapies improved improved outcome innate immune mechanisms insight mortality mouse model neonatal immune system neonatal infection neonatal morbidity neurodevelopment neurotropic neurotropic virus pathogen prevent receptor recombinase-mediated cassette exchange response small hairpin RNA survival outcome virus tropism

项目摘要

PROJECT SUMMARY 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.

项目总结