Viral persistence and chronic immunopathology in the adult central nervous system following Coxsackievirus infection during the neonatal period.
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 ( approximately 10(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.
Feuer
Ralph
R
Department of Immunology and Microbial Science, La Jolla, California 92037, USA. rfeuer@sciences.sdsu.edu
Ruller
Chelsea M
CM
An
Naili
N
Tabor-Godwin
Jenna M
JM
Rhoades
Ross E
RE
Maciejewski
Sonia
S
Pagarigan
Robb R
RR
Cornell
Christopher T
CT
Crocker
Stephen J
SJ
Kiosses
William B
WB
Pham-Mitchell
Ngan
N
Campbell
Iain L
IL
Whitton
J Lindsay
JL
D000818:Animals; D000831:Animals, Newborn; D002490:Central Nervous System / Q000821:virology*; D002540:Cerebral Cortex / Q000473:pathology / Q000821:virology; D018925:Chemokines / Q000032:analysis; D002908:Chronic Disease; D003384:Coxsackievirus Infections / Q000276:immunology / Q000473:pathology*; D004770:Enterovirus / Q000235:genetics / Q000472:pathogenicity*; D029822:Enterovirus B, Human; D016679:Genome, Viral; D006624:Hippocampus / Q000473:pathology / Q000821:virology; D006801:Humans; D007249:Inflammation; D007370:Interferon Type I / Q000032:analysis; D051379:Mice; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors; D015854:Up-Regulation
D018925:Chemokines; D007370:Interferon Type I; D012367:RNA, Viral