Title: Long-term persistence of infectious Zika virus: Inflammation and behavioral sequela in mice

Abstract

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10–15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80 , Il-1α , and Ifn-γ together with Cd3 , Cd8 and perforin ( PrfA) , suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although themore » infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age.« less

Authors:

Ireland, Derek D. C. ;

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• Search DOE PAGES for ORCID "0000-0001-5829-4206"
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Manangeeswaran, Mohanraj ;

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Lewkowicz, Aaron P. ;

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Engel, Kaliroi ;

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Clark, Sarah M. ;

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Laniyan, Adelle ;

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Sykes, Jacob ;

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Lee, Ha-Na; McWilliams, Ian L. ;

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Kelley-Baker, Logan ;

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Tonelli, Leonardo H.; Verthelyi, Daniela ;

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Lazear, ed., Helen M.

Publication Date:

2020-12-10

Research Org.:

Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Org.:

USDOE Office of Science (SC); US Food & Drug Administration

OSTI Identifier:

1734969

Alternate Identifier(s):

OSTI ID: 1904906

Grant/Contract Number:  

SC0014664; U01FD005946

Resource Type:

Published Article

Journal Name:

PLoS Pathogens

Additional Journal Information:

Journal Name: PLoS Pathogens Journal Volume: 16 Journal Issue: 12; Journal ID: ISSN 1553-7374

Publisher:

Public Library of Science (PLoS)

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; central nervous system; Zika virus; cerebellum; apoptosis; mice; microglial cells; inflammation; magnetic resonance imaging