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

Journal Article · 10 December 2020 · PLoS Pathogens

DOI: https://doi.org/10.1371/journal.ppat.1008689 · OSTI ID:1734969

Ireland, Derek C.  ^[1]; Manangeeswaran, Mohanraj  ^[1]; Lewkowicz, Aaron P.  ^[1]; Engel, Kaliroi  ^[1]; Clark, Sarah M.  ^[2]; Laniyan, Adelle  ^[2]; Sykes, Jacob  ^[1]; Lee, Ha-Na ^[1]; McWilliams, Ian L.  ^[1]; Kelley-Baker, Logan  ^[1]; Tonelli, Leonardo H. ^[2]; Verthelyi, Daniela  ^[1]

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1. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States)
2. University of Maryland, College Park, MD (United States)

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 the 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 longterm 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.

• Research Organization: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
• Sponsoring Organization: USDOE Office of Science (SC); US Food & Drug Administration; USDOE
• Grant/Contract Number: SC0014664; U01FD005946
• OSTI ID: 1734969
• Alternate ID(s): OSTI ID: 1904906
• Journal Information: PLoS Pathogens, Vol. 16, Issue 12; ISSN 1553-7374
• Publisher: Public Library of ScienceCopyright Statement
• Country of Publication: United States
• Language: English