Zika virus infects pericytes in the choroid plexus and enters the central nervous system through the blood-cerebrospinal fluid barrier

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Zika virus (ZIKV) can infect and cause microcephaly and Zika-associated neurological complications in the developing fetal and adult brains. In terms of pathogenesis, a critical question is how ZIKV overcomes the barriers separating the brain from the circulation and gains access to the central nervous system (CNS). Despite the importance of ZIKV pathogenesis, the route ZIKV utilizes to cross CNS barriers remains unclear.</jats:p><jats:p>Here we show that in mouse models, ZIKV-infected cells initially appeared in the periventricular regions of the brain, including the choroid plexus and the meninges, prior to infection of the cortex. The appearance of ZIKV in cerebrospinal fluid (CSF) preceded infection of the brain parenchyma. We show that ZIKV infects pericytes in the choroid plexus, and that ZIKV infection of pericytes is dependent on AXL receptor tyrosine kinase. Using an in vitro Transwell system, we highlight the possibility of ZIKV to move from the blood side to CSF side, across the choroid plexus epithelial layers, via a nondestructive pathway (e.g., transcytosis). Finally, we demonstrate that brain infection is significantly attenuated by neutralization of the virus in the CSF, indicating that ZIKV in the CSF at the early stage of infection might be responsible for establishing a lethal infection of the brain. Taken together, our results suggest that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.</jats:p><jats:sec><jats:title>AUTHOR SUMMARY</jats:title><jats:p>Zika virus invades the human brains and causes Zika-associated neurological complications; however, the mechanism(s) by which Zika virus accesses the central nerves system remain unclear. Understanding of the cellular and molecular mechanisms will shed light on development of novel therapeutic and prophylactic targets for Zika virus and other neurotropic viruses. Here we use in vivo and in vitro models to understand how Zika virus enters the brain. In mouse models, we found that Zika virus infects pericytes in the choroid plexus at very early stages of infection and neutralization of Zika virus in the cerebrospinal fluid significantly attenuate the brain infection. Further we show evidence that Zika virus can cross the epithelial cell layers in the choroid plexus from the blood side. Our research highlights that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.</jats:p></jats:sec>

Dissecting the localization of Tilapiatilapinevirus in the brain of the experimentally infected Nile tilapia, Oreochromisniloticus (L.)

“…In well‐studied organisms, these two barriers were counteracted by various infectious pathogens including viruses, bacteria, pathogenic fungi and parasites leading to CNS invasion. For example, invasion into the brain of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus (Pellegrini et al., 2020; Rhea et al., 2020), human immunodeficiency virus (HIV) (de Almeida et al., 2016; Osborne et al., 2020), Zika virus (Kim et al., 2020; Mustafa et al., 2019), influenza virus (Chaves et al., 2011, 2014; Yamada et al., 2012), Neisseria meningitidis bacteria (Miller et al., 2013), Trypanosoma brucei parasite (Masocha & Kristensson, 2012) and Cryptococcus neoformans fungi (Aaron et al., 2018) was evidenced to proceed across both barriers. In this study, the strong positive signals were dominantly observed in the periventricular regions including the choroid plexus and the ventricular ependymal cells, suggesting that the blood–CSF barrier plays a major role in TiLV spreading to broad regions of the brain.…”

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

“…Various neurotrophic viruses have recently come under investigation in relation to the CP. It has been found that the Zika virus enters the brain from the blood through epithelial cells in the CP without active replication [152]. Polyomavirus JC (JCV) may first reach CP cells through the bloodstream and then be released into the CSF.…”

Immune response and blood–brain barrier dysfunction during viral neuroinvasion

“…52 Interestingly, the latest research on a murine model of ZIKV infection suggests that the ZIKV may invade the CNS by crossing the blood-CSF barrier rather than the BBB by infecting pericytes in the choroid plexus. 53 This puts forward new opportunities for us to study the mechanism of flavivirus invasion of the CNS.…”