Microglia and a functional type I IFN pathway are required to counter HSV-1-driven brain lateral ventricle enlargement and encephalitis.
Microglia and a functional type I IFN pathway are required to counter HSV-1-driven brain lateral ventricle enlargement and encephalitis.
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DOI：
10.4049/jimmunol.1203265
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发表时间：
2013-03-15
期刊：
影响因子：
--
通讯作者：
Carr DJ
中科院分区：
文献类型：
--
作者：
Conrady CD;Zheng M;van Rooijen N;Drevets DA;Royer D;Alleman A;Carr DJ
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.
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