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

Eleanor M. Marshall, Marion P.G. Koopmans, Barry Rockx*

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

6 Citations (Scopus)
72 Downloads (Pure)


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.

Original languageEnglish
Article number2096
Issue number10
Publication statusPublished - 21 Sept 2022

Bibliographical note

Funding Information:
This publication is part of the project ‘Preparing for vector-borne virus outbreaks in a changing world: a One Health Approach’ (NWA.1160.1S.210) which is (partly) financed by the Dutch Research Council (NWO).

Publisher Copyright:
© 2022 by the authors.


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