Viral Persistence and Chronic Immunopathology in the Adult Central Nervous System following Coxsackievirus Infection during the Neonatal Period

Abstract

Coxsackieviruses are significant human pathogens, and the neonatal central nervous system (CNS) is a major target for infection. Despite the extreme susceptibility of newborn infants to coxsackievirus infection and viral tropism for the CNS, few studies have been aimed at determining the long-term consequences of infection on the developing CNS. We previously described a neonatal mouse model of coxsackievirus B3 (CVB3) infection and determined that proliferating stem cells in the CNS were preferentially targeted. Here, we describe later stages of infection, the ensuing inflammatory response, and subsequent lesions which remain in the adult CNS of surviving animals. High levels of type I interferons and chemokines (in particular MCP-5, IP10, and RANTES) were upregulated following infection and remained at high levels up to day 10 postinfection (p.i). Chronic inflammation and lesions were observed in the hippocampus and cortex of surviving mice for up to 9 months p.i. CVB3 RNA was detected in the CNS up to 3 months p.i at high abundance (ϳ10 6 genomes/mouse brain), and viral genomic material remained detectable in culture after two rounds of in vitro passage. These data suggest that CVB3 may persist in the CNS as a low-level, noncytolytic infection, causing ongoing inflammatory lesions. Thus, the effects of a relatively common infection during the neonatal period may be long lasting, and the prognosis for newborn infants recovering from acute infection should be reexplored.

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

“…Also, the restriction in antigen presentation and inhibition of the type I IFN response following CVB3 infection may ultimately contribute to the establishment of persistent infection in the CNS. 30 Although Figure 5c revealed a reduction in CVB3 protein expression in the choroid plexus and SVZ at 48 h PI, these results more likely reflect the restricted tropism for CVB3 and the migration of CVB3-infected progenitor cells away from the SVZ and into the olfactory bulb, hippocampus, and retrosplenial cortex (shown in Figure 1k). 20 Low amounts of MHC class I protein expression was also observed in mock-infected mice, most likely reflecting limited levels of protein expression or, alternatively, a low-level inflammatory response following the ic inoculation procedure.…”

“…32 Nonetheless, 3-day-old pups survive acute infection and establish a persistent infection characterized by chronic immunopathology and CNS developmental defects. 30,32,46 In addition, early GFP-CVB3 infection induced the recruitment of a novel population of infected myeloid cells expressing nestin into the neonatal CNS. 14 The induction of a family of chemokines that included CCL12 was observed as early as 12 h PI.…”

“…We previously established a neonatal mouse model to study both CVB3 and LCMV infection of the CNS, 14 and persistent CVB3 infection. 30 We utilized a recombinant CVB3 expressing GFP (GFP-CVB3) to track virus spread in the neonatal CNS and compared these results with that of LCMV (Armstrong strain). GFP-CVB3 can infect NPSCs and is highly pathogenic in the neonatal CNS of 1-day-old pups.…”

“…14 Alternatively, 3-dayold pups were infected intracranially with 10 7 pfu eGFP-CVB3 to examine CNS pathology in surviving mice at 30, 75, and 90 days PI. 30 The amount of inoculum utilized in the study was chosen to closely equate viral replication kinetics and viral protein expression in the neonatal CNS for each virus. The procedure for intracranial (ic) inoculation of 1-day-old pups has been described previously.…”

Virus Infections as Potential Targets of Preventive Treatments for Type 1 Diabetes

“…Chronic cardiomyopathy represents such condition in man [12]. In mouse models, persistent EV infection causes inflammatory myopathies, cardiac injury, and central nervous system damage [13,14]. Immunocompromised patients, especially those with humoral immunodeficiency, also suffer from chronic EV infections.…”