title: 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 neurologic deficits are common in patients that survive, but the mechanism leading to this pathology is poorly understood, impeding clinical advancements in treatment to reduce 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 anti-secretory factor peptide 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 d postinfection through a Toll/IL-1R domain-containing adapter inducing IFN-β-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 HSV encephalitic patients.
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors: Christopher D
authors: CD
authors: Conrady
authors: Min
authors: M
authors: Zheng
authors: Nico
authors: N
authors: van Rooijen
authors: Douglas A
authors: DA
authors: Drevets
authors: Derek
authors: D
authors: Royer
authors: Anthony
authors: A
authors: Alleman
authors: Daniel J J
authors: DJ
authors: Carr
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020803:Encephalitis, Herpes Simplex / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D020022:Genetic Predisposition to Disease; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D020547:Lateral Ventricles / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008969:Molecular Sequence Data; D011828:Radiation Chimera / Q000276:immunology; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit
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