Pathways Exploited by Flaviviruses to Counteract the Blood-Brain Barrier and Invade the Central Nervous System

Abstract

Human infection by different flaviviruses may cause severe neurologic syndromes, through pathogenic mechanisms that are still largely unknown. Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), yellow fever virus (YFV), dengue virus (DENV), and tick-borne encephalitis virus (TBEV) are believed to reach the central nervous system by a hematogenous route, upon crossing the blood-brain barrier. Although the disruption of BBB during flavivirus infection has been largely evidenced in experimental models, the relevance of BBB breakdown for virus entering the brain was not completely elucidated. In vitro models of BBB had demonstrated that these viruses replicated in brain microvascular endothelial cells (BMECs), which induced downregulation of tight junction proteins and increased the permeability of the barrier. Other reports demonstrated that infection of BMECs allowed the basolateral release of infectious particles, without a remarkable cytopathic effect, what might be sufficient for virus invasion. Virus replication and activation of other cells associated to the BBB, mostly astrocytes and microglia, were also reported to affect the endothelial barrier permeability. This event might occur simultaneously or after BMECs infection, being a secondary effect leading to BBB disruption. Importantly, activation of BMECs, astrocytes, and microglia by flaviviruses was associated to the expression and secretion of inflammatory mediators, which are believed to recruit leukocytes to the CNS. The leukocyte infiltrate could further mediate viral invasion through a Trojan horse mechanism and might contribute to BBB breakdown and to neurological alterations. This review discussed the previous studies regarding in vitro and in vivo models of JEV, WNV, ZIKV, YFV, DENV, and TBEV infection and addressed the pathways for BBB overcome and invasion of the CNS described for each virus infection, aiming to increment the knowledge and stimulate further discussion about the role of BBB in the neuropathogenesis of flavivirus infection.

Comparative analysis of neuroinvasion by Japanese encephalitis virulent and vaccine strains in anin cellulomodel of human blood-brain barrier

“…It has been suggested that JEV infects brain tissue cells as a consequence of a preceding inflammatory process which leads to the BBB disruption and viral neuroinvasion [31, 32]. However, the very early events of JEV BBB crossing are still poorly understood.…”

“…4). This finding is very relevant because it suggests that JEV could be able to get access to the CNS and establish a primary infection there without the preceding need of inflammatory cytokines that could lead to BBB disruption prior CNS cells viral infection as it is currently thought [31, 32].…”

“…Several lines of research in either in vivo and in vitro systems have suggested that JEV infects brain tissue cells as a consequence of a preceding inflammatory process which would lead to the BBB disruption and viral neuroinvasion [31, 32]. While in vivo approaches are useful to understand the systemic viral disease, in vitro models are also useful because they allow studying the molecular mechanisms that govern viral pathogenesis.…”

A Soluble Version of Nipah Virus Glycoprotein G Delivered by Vaccinia Virus MVA Activates Specific CD8 and CD4 T Cells in Mice

“…Another hypothesis is that NiV-specific T cells could be involved in potential immunopathologies. In this context, data from infections with other neurotropic viruses, for example, West Nile virus, demonstrated that antigen-specific T cells can open the blood brain barrier and contribute to virus infections of the brain [69][70][71][72][73]. Thus, to allow for more detailed studies characterizing T cells in NiV-associated immunity or pathogenesis, it is essential to identify NiV-G peptide epitopes allowing for the specific MHC-restricted antigen presentation and the activation of NiV-specific T cells.…”

Zika virus replicates in skeletal muscle contributing to peripheral viral amplification prior to reach neural tissue

“…It has been hypothesized that viral replication in peripheral tissues could contribute to amplification of viral loads early during ZIKV infection and before the virus invades the CNS (13). ZIKV has been shown to replicate and cross the endothelial barrier without significantly affect its permeability (14, 15). Additionally, it was demonstrated that ZIKV replicates in human peripheral neurons in vitro (16).…”