Abstract
The fetal brain is highly vulnerable to teratogens, including many infectious agents. As a consequence of prenatal infection, many children suffer severe and permanent brain injury and dysfunction. Because most animal models of congenital brain infection do not strongly mirror human disease, the models are highly limited in their abilities to shed light on the pathogenesis of these diseases. The animal model for congenital lymphocytic choriomeningitis virus (LCMV) infection, however, does not suffer from this limitation. LCMV is a well-known human pathogen. When the infection occurs during pregnancy, the virus can infect the fetus, and the developing brain is particularly vulnerable. Children with congenital LCMV infection often have substantial neurological deficits. The neonatal rat inoculated with LCMV is a superb model system of human congenital LCMV infection. Virtually all of the neuropathologic changes observed in humans congenitally infected with LCMV, including microencephaly, encephalomalacia, chorioretinitis, porencephalic cysts, neuronal migration disturbances, periventricular infection, and cerebellar hypoplasia, are reproduced in the rat model. Within the developing rat brain, LCMV selectively targets mitotically active neuronal precursors. Thus, the targets of infection and sites of pathology depend on host age at the time of infection. The rat model has further shown that the pathogenic changes induced by LCMV infection are both virus-mediated and immune-mediated. Furthermore, different brain regions simultaneously infected with LCMV can undergo widely different pathologic changes, reflecting different brain region–virus–immune system interactions. Because the neonatal rat inoculated with LCMV so faithfully reproduces the diverse neuropathology observed in the human counterpart, the rat model system is a highly valuable tool for the study of congenital LCMV infection and of all prenatal brain infections In addition, because LCMV induces delayed-onset neuronal loss after the virus has been cleared, the neonatal rat infected with LCMV may be an excellent model system to study neurodegenerative or psychiatric diseases whose etiologies are hypothesized to be virus-induced, such as autism, schizophrenia, and temporal lobe epilepsy.
Highlights
Multiple viruses, bacteria, and parasites can infect the developing human fetus, resulting in a range of outcomes that include fetal demise, developmental anomalies, and disease of the newborn [1]
Human infection with the rubella virus during the first 11 weeks of gestation results in teratogenic changes in most fetuses that survive the acute infection, with abnormalities commonly detected in the heart, eye, and central nervous system [2]
The neonatal rat model of congenital lymphocytic choriomeningitis virus (LCMV) infection was pioneered by Monjan and coworkers during the 1970s and early 1980s
Summary
Bacteria, and parasites can infect the developing human fetus, resulting in a range of outcomes that include fetal demise, developmental anomalies, and disease of the newborn [1]. Periventricular calcifications, gyral dysplasia, cerebellar hypoplasia, and focal cerebral destruction are common pathologic effects of congenital LCMV infection [11] These pathologic changes reflect both the viral tropism for replicating neuroblasts and disrupted brain development induced by loss or dysfunction of immature or replicating neurons [5,8,30,31]. The neonatal rat model of congenital LCMV infection was pioneered by Monjan and coworkers during the 1970s and early 1980s They discovered that LCMV induces a distinct pattern of infection in which certain neuronal populations are infected, while others are spared [31,32]. All of these neuropathologic changes observed among children with congenital LCMV infection can be recapitulated in the rat model by infecting the host at different ages (Table 1) This finding strongly suggests that the diversity in pathology and outcome among children with doi:10.1371/journal.ppat.0030149.g002. Whether glial cells are an important target of LCMV in the developing human brain is unknown
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