A Journey to the Central Nervous System: Routes of Flaviviral Neuroinvasion in Human Disease

Abstract

Many arboviruses, including viruses of the Flavivirus genera, are known to cause severe neurological disease in humans, often with long-lasting, debilitating sequalae in surviving patients. These emerging pathogens impact millions of people worldwide, yet still relatively little is known about the exact mechanisms by which they gain access to the human central nervous system. This review focusses on potential haematogenous and transneural routes of neuroinvasion employed by flaviviruses and identifies numerous gaps in knowledge, especially regarding lesser-studied interfaces of possible invasion such as the blood–cerebrospinal fluid barrier, and novel routes such as the gut–brain axis. The complex balance of pro-inflammatory and antiviral immune responses to viral neuroinvasion and pathology is also discussed, especially in the context of the hypothesised Trojan horse mechanism of neuroinvasion. A greater understanding of the routes and mechanisms of arboviral neuroinvasion, and how they differ between viruses, will aid in predictive assessments of the neuroinvasive potential of new and emerging arboviruses, and may provide opportunity for attenuation, development of novel intervention strategies and rational vaccine design for highly neurovirulent arboviruses.

Usutu virus and West Nile virus use a transcellular route of neuroinvasion across anin vitromodel of the human blood-brain barrier

“…Additionally, we primarily focused on the early-phase of invasion across the BBB, between 0 and 72hpi, not later stage effects of viral replication, up to 10dpi as previously studied 8 . Our in vitro data is in line with previously published in vivo data, describing an initial entry of WNV into the brain in absence of BBB disruption 9 followed by a later disruption due to infection of neural cells, leading to infiltration of immune cells that contribute to barrier disruption via release of chemotactic and inflammatory factors 4,10,11 .…”

“…WNV is thought to employ both transcellular and paracellular modes of invasion across the physical barriers that separate the blood from the CNS, such as the BBB. The BBB acts as a key entry-point for neuroinvasion, however the ability of USUV to invade the CNS across this barrier is not well understood 4 . Here we show that all three cell types of the human BBB are susceptible to infection with USUV and WNV.…”

“…This barrier is considered an important interface for invasion of viruses into the CNS from the blood. Such invasion can occur via a transcellular route in which the virus must infect or be transported across the cells of the barrier, or via a paracellular route in which virus is able to enter between the cells of a disrupted barrier, either as free virions or within infected immune cells in a so-called Trojan horse mechanism of invasion 4 .…”

“…WNV and USUV therefore appear to differ in their ability to cause severe disease in humans, which could stem from many factors, including the ability of the virus to gain access to the CNS via one or more routes of neuroinvasion. WNV is thought to use multiple routes of neuroinvasion, including both transcellular and paracellular invasion across the blood-brain barrier (BBB) 4 . The potential for use of these haematogenous routes of neuroinvasion by USUV is not well understood.…”

Mechanisms of Neuroinvasion and Neuropathogenesis by Pathologic Flaviviruses

“…Additionally, reports have shown a possible invasion route through an olfactory and a gut–brain neural circuit. However, more research is needed to confirm these routes of invasion and to determine their relative contribution to neuroinvasion [ 142 ].…”