Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected

Abstract

The recent global outbreak of Zika virus (ZIKV) infection has been linked to severe neurological disorders affecting the peripheral and central nervous systems (PNS and CNS, respectively). The pathobiology underlying these diverse clinical phenotypes are the subject of intense research; however, even the principal neural cell types vulnerable to productive Zika infection remain poorly characterised. Here we used CNS and PNS myelinating cultures from wild type and Ifnar1 knockout mice to examine neuronal and glial tropism and short-term consequences of direct infection with a Brazilian variant of ZIKV. Cell cultures were infected pre- or post-myelination for various intervals, then stained with cell-type and ZIKV-specific antibodies. In bypassing systemic immunity using ex vivo culture, and the type I interferon response in Ifnar1 deficient cells, we were able to evaluate the intrinsic infectivity of neural cells. Through systematic quantification of ZIKV infected cells in myelinating cultures, we found that ZIKV infection is enhanced in the absence of the type I interferon responses and that CNS cells are considerably more susceptible to infection than PNS cells. In particular, we demonstrate that CNS axons and myelinating oligodendrocytes are especially vulnerable to injury. These results have implications for understanding the pathobiology of neurological symptoms associated with ZIKV infection. Furthermore, we provide a quantifiable ex vivo infection model that can be used for fundamental and therapeutic studies on viral neuroinvasion and its consequences.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0450-8) contains supplementary material, which is available to authorized users.

Basic insights into Zika virus infection of neuroglial and brain endothelial cells

“…ZIKV infection and replication has previously been shown for neuroglia within the CNS radial glia [34], myelinating oligodendrocytes [35] and astrocytes [36], but never for OECs, the neuroglia of the primary olfactory nervous system. OECs surround and support the axons of olfactory sensory neurons as they extend from the olfactory mucosa into the olfactory bulb in the brain, forming the olfactory nerve.…”

Guillain–Barré syndrome, transverse myelitis and infectious diseases

“…Rather, myelin changes probably represent a combination of the arrest of myelination and the degradation of previously established sheaths. 185 Following reports linking ZIKV infection to GBS, it has been analyzed the peptide sharing between the virus and human proteins potentially related to GBS related proteins. 186 The immunological potential of the peptide sharing was described, which appeared to favor an autoimmune cross-reactive connection between ZIKV and GBS.…”

Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System

“…Based on these associations, a key question was whether the PNS was a direct target of infection or if the pathology was indirectly due to inflammatory responses, as was suggested by case reports of sensory neuropathy that developed weeks after the initial infection (Martinez et al 2017). In CNS and PNS myelinating cultures from Ifnar1 KO mice, all CNS cells were vulnerable to ZIKV infection, especially oligodendrocytes, but infection rates of PNS cells were much lower (Cumberworth et al 2017). A study using both hiPSCs and mouse models showed that ZIKV could directly infect PNS cell populations, especially neurons in vivo and in vitro (Oh et al 2017).…”