Antiviral Cytokine Response in Neuroinvasive and Non-Neuroinvasive West Nile Virus Infection.

Snjezana Zidovec-Lepej,Vladimir Stevanovic,Tatjana Vilibic-Cavlek,Tanja Potocnik-Hunjadi,Dario Sabadi,Vladimir Savic,Tamara Butigan,Ivana Grgic,Giovanni Savini,Eddy Listes,Thomas Ferenc,Irena Tabain,Ljiljana Peric,Maja Bogdanic,Krunoslav Capak,Maja Ilic,Lana Gorenec,Elizabeta Dvorski,Ljubo Barbic

doi:10.3390/v13020342

Abstract

Data on the immune response to West Nile virus (WNV) are limited. We analyzed the antiviral cytokine response in serum and cerebrospinal fluid (CSF) samples of patients with WNV fever and WNV neuroinvasive disease using a multiplex bead-based assay for the simultaneous quantification of 13 human cytokines. The panel included cytokines associated with innate and early pro-inflammatory immune responses (TNF-α/IL-6), Th1 (IL-2/IFN-γ), Th2 (IL-4/IL-5/IL-9/IL-13), Th17 immune response (IL-17A/IL-17F/IL-21/IL-22) and the key anti-inflammatory cytokine IL-10. Elevated levels of IFN-γ were detected in 71.7% of CSF and 22.7% of serum samples (p = 0.003). Expression of IL-2/IL-4/TNF-α and Th1 17 cytokines (IL-17A/IL-17F/IL-21) was detected in the serum but not in the CSF (except one positive CSF sample for IL-17F/IL-4). While IL-6 levels were markedly higher in the CSF compared to serum (CSF median 2036.71, IQR 213.82–6190.50; serum median 24.48, IQR 11.93–49.81; p < 0.001), no difference in the IL-13/IL-9/IL-10/IFN-γ/IL-22 levels in serum/CSF was found. In conclusion, increased concentrations of the key cytokines associated with innate and early acute phase responses (IL-6) and Th1 type immune responses (IFN-γ) were found in the CNS of patients with WNV infection. In contrast, expression of the key T-cell growth factor IL-2, Th17 cytokines, a Th2 cytokine IL-4 and the proinflammatory cytokine TNF-α appear to be concentrated mainly in the periphery.

Highlights

West Nile virus (WNV) is an emerging widely distributed flavivirus
WNV diagnosis was confirmed according to the EU case definition for diagnosing and reporting WNV infection by detection of a) WNV RNA in cerebrospinal fluid (CSF); b) WNV IgM antibodies in CSF or c) WNV IgM in serum confirmed by a virus neutralization test (VNT) [28]
Infection in a cohort of patients with WNV fever and WNND presenting with meningitis or meningoencephalitis

Summary

Introduction

WNV is maintained in a cycle between mosquitoes (mainly of the Culex spp.) and animal hosts (birds), while humans represent incidental or ‘dead-end’ hosts [1]. Human WNV infections are mainly subclinical (~80%) or presented as a non-specific febrile disease Central nervous system (CNS) manifestations of WNV infection include meningitis, encephalitis and poliomyelitislike syndrome, some atypical presentations such as cerebellitis, spastic paralysis and cranial nerve palsy are described [3,4,5]. These manifestations are generally more prevalent in older and immunosuppressed persons [2]. While clinical manifestations and outcomes of WNV infection are well described [6], data on the immunopathogenesis of WNV infections, in the context of complex cytokine immune responses, are limited

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