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 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 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.

Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

“…Persistence of SARS-CoV-2 in some patients with PASC symptoms is not unexpected. The literature is replete with examples of single-stranded RNA virus persistence, spanning decades of research on samples obtained from living human patients, autopsy studies, and animal studies ( Viola et al, 1978 ; Riddell et al, 2007 ; Doi et al, 2016 ; Randall and Griffin, 2017 ; Ireland et al, 2020 ). Persistence of single-stranded RNA viruses in the central nervous system has been documented on multiple occasions.…”

Systemic inflammation, innate immunity and pathogenesis after Zika virus infection in cynomolgus macaques are modulated by strain-specificity within the Asian lineage

“…It is not surprising that longer duration of acute ZIKV infections can lead to greater inflammation and thereby, increased pathology. Studies in mouse models have shown that long-term persistance of ZIKV in the brain can lead to inflammation and increased risk of neuropathology [60].…”

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…Often, when entering the brain, these viruses cause acute encephalitis. Nevertheless, they can persist in the brain [ 151 , 152 , 153 , 154 ]. However, there is paucity of knowledge about chronic effects of persisting virus in the brain and corresponding neuroinflammation.…”

“…Measles virus: [ 135 , 202 , 203 ]. Japanese encephalitis virus (JEV): [ 100 , 151 , 153 , 155 ]. Zika virus (ZIKV): [ 143 , 146 , 148 ].…”