Altered Central Nervous System Gene Expression Caused by Congenitally Acquired Persistent Infection with Lymphocytic Choriomeningitis Virus

Abstract

Neonatal infection of most mouse strains with lymphocytic choriomeningitis virus (LCMV) leads to a life-long persistent infection characterized by high virus loads in the central nervous system (CNS) inInfection of the central nervous system (CNS) in humans by various DNA and RNA viruses can represent a severe health problem. Acute viral infections of the CNS frequently result in the destruction of specific neural cell populations as a direct consequence of virus multiplication or as a result of the host's antiviral immune response (23, 26). Many viruses, however, adopt a noncytolytic strategy of multiplication and can escape from the host immune surveillance by use of a plethora of mechanisms that may result in long-term persistent infections of the CNS. Despite the absence of overt signs of pathology such as cell lysis and inflammation, these infections can lead to severe alterations in neuronal function (45, 46) manifested by cognitive and behavioral impairment (20,30,39,60). This, in turn, has led to the hypothesis that viruses may contribute to a variety of CNS disorders whose etiologies remain unknown (40,44).The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) provides an important model system for the investigation of the mechanisms and consequences of viral persistence in the CNS (8,16,18,42,43). Furthermore, increasing evidence indicates that LCMV might be a neglected human pathogen of clinical significance (3,4,64). LCMV has a noncytolytic strategy of multiplication, which enables the virus to persist both in vivo and in cultured cells. Neonatal infection of mice with LCMV leads to the establishment of a life-long persistent infection (LCMV-Pi). Brains of LCMV-Pi mice contain high virus load primarily in neurons in the neocortex, limbic system, and certain hypothalamic regions (19,53). Neither inflammation nor cytolysis occurs within the brain parenchyma of LCMV-Pi mice. However, as adults LCMV-Pi mice exhibit an impaired learning ability and a reduced tendency to explore a novel environment (20,25). Since cognitive defects occur in the absence of overt signs of pathology, we hypothesized that chronic virus infection might contribute to neuronal dysfunction by altering the host's gene expression profile. Accordingly, previous studies have shown altered levels of acetylcholine enzymes (46) as well as neurotransmitter mRNAs (31) in LCMV-infected mice. Moreover, we have documented that LCMV persistence causes a specific reduction in expression of the growth-associated protein 43 (GAP-43), a well-established marker of neuroplasticity (5) in hippocampus (15). LCMV persistent infection reduced GAP-43 mRNA levels by affecting both the rate of GAP-43 transcription and the posttranscriptional stabilization of GAP-43 mRNA (10).In the present study, we aimed at the identification of additional host genes whose expression is changed in the CNS of mice persistently infected with LCMV. To recreate the natural route of congenital viral CNS infection (2), we established a

Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses

“…Mice develop diffuse viral infection both systemically as well as in the CNS, including productive and widespread neuronal infection (Rodriguez et al, 1983). The infection is not cytopathic, but mice nevertheless develop deficits in behavior and learning ability (Hotchin and Seegal, 1977;Kunz et al, 2006). Infection of the thymus results in the development of T-cell tolerance to LCMV and inability to clear the virus (Pircher , 1989).…”

Lymphocytic choriomeningitis infection of the central nervous system

“…Expression of viral antigen is found in neurons localized in numerous regions of the brain including the neocortex, limbic system, hypothalamus, brain stem, thalamus, basal ganglia and the hippocampus -a region that is implicated in the development of memory and learning (104,106). Recently, it was shown that persistent viral infection is associated with alterations in the host gene profile of the brain (132). Most of the genetic perturbations were downstream of type 1 interferon (132) -a cytokine known to be systemically elevated in LCMV carrier mice (133,134).…”

“…Specifically, persistently infected mice show reductions in spatial-temporal learning, assessed in a Y maze discriminated avoidance learning task, and decreases in explorative behavior in the context of novel environments (130)(131)(132). Expression of viral antigen is found in neurons localized in numerous regions of the brain including the neocortex, limbic system, hypothalamus, brain stem, thalamus, basal ganglia and the hippocampus -a region that is implicated in the development of memory and learning (104,106).…”

“…Although carrier mice do not display signs of neuronal loss during infection, they do exhibit signs of neuronal dysfunction manifested as abnormalities in behavior and learning (130)(131)(132). Specifically, persistently infected mice show reductions in spatial-temporal learning, assessed in a Y maze discriminated avoidance learning task, and decreases in explorative behavior in the context of novel environments (130-132).…”

Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system

“…15 Similarly, while the cellular targets of infection and the subsequent immune response have been extensively studied for LCMV, the virus remains a significant prenatal and postnatal threat and few effective treatments exist. 16,25,28,29 We hypothesize that a direct comparison of these two viruses during early infection of the neonatal CNS may help determine previously unidentified targets of infection, illuminate the neonatal host immune response following early infection, and clarify the mechanism of viral pathogenesis. The brains of 1-day-old CVB3 and LCMVinfected mice were analyzed for gene expression changes at 12,24, and 48 h post infection (PI) utilizing Illumina BeadArray Technology (MouseWG-6 v2 Expression Beadchips) in order to reveal the global neonatal host response for both neurotropic viral infections.…”