Lymphocytic choriomeningitis virus infection of the developing brain: critical role of host age

Abstract

Lymphocytic choriomeningitis virus (LCMV) is a common human pathogen that causes substantial injury to the developing brain when the infection occurs during pregnancy. However, among children with congenital LCMV infection, there is considerable variability in the site, nature, and severity of neuropathology and in the clinical outcome. We hypothesize that the variability in neuropathology and outcome is due to differences in the gestational timing of LCMV infection. We utilized an animal model of human congenital LCMV infection, in which developing rat pups were inoculated with LCMV at a series of postnatal ages, including postnatal days 1, 4, 6, 10, 21, 30, and 60. Cellular targets of infection were determined immunohistochemically, viral titers were determined by plaque assay, and pathology was determined by histological analysis, neuronal quantification, and immunostaining for lymphocytic subclasses. Host age at the time of infection profoundly affected the cellular targets of infection, maximal viral titers, immune response to the viral infection, and the severity, nature, and location of the neuropathology. All of the pathological changes observed in children with congenital LCMV infection were reproduced in the rat model by infecting the rat pups at different ages. The effect of LCMV infection on the developing brain strongly depends on host age at the time of infection. Much of the variability in neuropathology and outcome among children with congenital LCMV infection probably depends on the gestational age at which the infection occurs.