A human cerebral organoid model of West Nile virus encephalitis shows innate immunocompetency

TL;DR

Researchers created a human brain model to study West Nile virus infection, finding it causes inflammation and affects neurons and astrocytes.

Contribution

A novel human cerebral organoid model for studying West Nile virus encephalitis is developed.

Findings

WNV infection in cerebral organoids shows heterogeneous viral replication kinetics with early and late peaks.

Viral foci are found in neuron- and astrocyte-rich areas without microglia involvement.

Infection leads to increased release of pro-inflammatory cytokines and biomarkers.

Abstract

West Nile virus (WNV), an arbovirus of emerging global interest, can cause neuroinvasive disease in humans. Currently, no protective vaccine or specific treatment is available for human WNV encephalitis. The virus induces neuronal cell death, while astrocytes and microglia cells are suspected to contribute to WNV pathology. Hence, understanding their role is crucial for future treatment approaches. In this study, we establish a WNV encephalitis model using human cerebral organoids, generated with male iPSCs. Infection results in heterogeneous kinetics with an early strong replication potentially leading to viral clearance, while a late peak was associated with more long-term infection. Viral foci are seen in cortical-like areas, rich in neurons and astrocytes, however void of microglia. Pro-inflammatory cytokines (IL-6, TNF-α, IL-18), chemokines (CXCL10, CCL17, CX3CL1, CCL2) and biomarkers (IL-1RA, sTREM-1, sRAGE, BDNF) are increasingly released. Conclusively, human cerebral organoids make suitable WNV encephalitis models with valuable properties to study acute and long-term infection.

West Nile virus (WNV) can cause neuroinvasive disease. Here the authors develop a human cerebral organoid model for WNV infection and find heterogeneous viral kinetics with viral foci in neuron- and astrocyte-rich areas devoid of microglia, as well as increased release of cytokines and other biomarkers.

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