VLDLR mediates Semliki Forest virus neuroinvasion through the blood-cerebrospinal fluid barrier

Miika Martikainen (), Roberta Lugano, Ilkka Pietilä, Sofie Brosch, Camille Cabrolier, Aishwarya Sivaramakrishnan, Mohanraj Ramachandran, Di Yu, Anna Dimberg and Magnus Essand
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Miika Martikainen: Uppsala University
Roberta Lugano: Uppsala University
Ilkka Pietilä: Uppsala University
Sofie Brosch: Uppsala University
Camille Cabrolier: Uppsala University
Aishwarya Sivaramakrishnan: Uppsala University
Mohanraj Ramachandran: Uppsala University
Di Yu: Uppsala University
Anna Dimberg: Uppsala University
Magnus Essand: Uppsala University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Semliki Forest virus (SFV) is a neuropathogenic alphavirus which is of interest both as a model neurotropic alphavirus and as an oncolytic virus with proven potency in preclinical cancer models. In laboratory mice, peripherally administered SFV infiltrates the central nervous system (CNS) and causes encephalitis of varying severity. The route of SFV CNS entrance is poorly understood but has been considered to occur through the blood-brain barrier. Here we show that neuroinvasion of intravenously administered SFV is strictly dependent on very-low-density-lipoprotein receptor (VLDLR) which acts as an entry receptor for SFV. Moreover, SFV primarily enters the CNS through the blood-cerebrospinal fluid (B-CSF) barrier via infecting choroid plexus epithelial cells which show distinctly high expression of VLDLR. This is the first indication of neurotropic alphavirus utilizing choroid plexus for CNS entry, and VLDLR playing a specific and crucial role for mediating SFV entry through this pathway.

Date: 2024
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DOI: 10.1038/s41467-024-55493-3

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