A Zika Virus Primary Isolate Induces Neuroinflammation, Compromises the Blood-Brain Barrier, and Upregulates CXCL12 in Adult Macaques

Abstract

Zika virus (ZIKV) is a neurotropic virus that can cause neuropathy in adults and fetal neurologic malformation following infection of pregnant women. We used a nonhuman primate model, the Indian-origin Rhesus macaque (IRM), to gain insight into virus-associated hallmarks of ZIKV-induced adult neuropathy. We find that the virus causes prevalent acute and chronic neuroinflammation and chronic disruption of the blood-brain barrier (BBB) in adult animals. Infection results in significant, targeted, and sustained upregulation of the chemokine, CXCL12, in the central nervous system (CNS). CXCL12 plays a key role both in regulating lymphocyte trafficking through the BBB to the CNS, and in mediating repair of damaged neural tissue including remyelination. Understanding how CXCL12 expression is controlled will likely be of central importance in the definition of ZIKV-associated neuropathy in adults. Author summaryZika virus (ZIKV) is a virus that can cause neurological problems in adults and damage to the fetal brain. Nonhuman primates (NHPs) are usually superior animal models for recapitulating human neurological disease because their brain, nervous system structure and immune response to virus infection are very similar to that of humans. We have studied the effect of ZIKV infection on the adult NHP brain and made several significant observations. Infection resulted in a high incidence of mild to moderate brain inflammation that persisted for a surprisingly long period of time. We also found that the virus disrupted the blood brain barrier, which is important for controlling transport of material from blood to the brain. It appears that the central nervous system expresses a specific substance in response to virus infection called a chemokine. This specific chemokine may be involved in virus-induced inflammation and/or in repair of virus-induced brain damage. Our data are significant since they help in understanding the mechanism of brain damage caused by ZIKV in adults.