Role of NS1 and TLR3 in Pathogenesis and Immunity of WNV.

Sameera Patel,Florian Sparber,Mathias Ackermann,Matteo Fassan,Alessandro Sinigaglia,Luisa Barzon,Salome Leibundgut-Landmann

doi:10.3390/v11070603

Abstract

West Nile Virus (WNV) is a mosquito-transmitted flavivirus which causes encephalitis especially in elderly and immunocompromised individuals. Previous studies have suggested the protective role of the Toll-like receptor 3 (TLR3) pathway against WNV entry into the brain, while the WNV non-structural protein 1 (NS1) interferes with the TLR3 signaling pathway, besides being a component of viral genome replication machinery. In this study, we investigated whether immunization with NS1 could protect against WNV neuroinvasion in the context of TLR3 deficiency. We immunized mice with either an intact or deleted TLR3 system (TLR3KO) with WNV envelope glycoprotein (gE) protein, NS1, or a combination of gE and NS1. Immunization with gE or gE/NS1, but not with NS1 alone, induced WNV neutralizing antibodies and protected against WNV brain invasion and inflammation. The presence of intact TLR3 signaling had no apparent effect on WNV brain invasion. However, mock-immunized TLR3KO mice had higher inflammatory cell invasion upon WNV brain infection than NS1-immunized TLR3KO mice and wild type mice. Thus, immunization against NS1 may reduce brain inflammation in a context of TLR3 signaling deficiency.

Highlights

West Nile Virus (WNV) is a neurotropic flavivirus that naturally cycles between wild birds and Culex spp. mosquitoes which may incidentally transmit the virus to humans and other mammals [1].Importantly, the virus can cause a fatal neurological disease in humans and horses, only a minor percentage of infected individuals will show any disease symptoms
In comparison to non-immunized siblings, TLR3-knockout mice (TLR3KO) mice immunized against WNV non-structural protein 1 (NS1) showed reduced cell infiltration to the WNV-infected brain, which was comparable to the degree observed in wild type (WT) mice with or without previous vaccination against NS1
The degree of inflammation measured in the brain was affected by viral load, Toll-like receptor 3 (TLR3) signaling, and previous immunization again NS1

Summary

Introduction

West Nile Virus (WNV) is a neurotropic flavivirus that naturally cycles between wild birds and Culex spp. mosquitoes which may incidentally transmit the virus to humans and other mammals [1].Importantly, the virus can cause a fatal neurological disease in humans and horses, only a minor percentage of infected individuals will show any disease symptoms. A vaccine for humans has not yet been licensed, a variety of vaccine candidates have been proposed, including vaccines based on inactivated viruses, recombinant viruses, chimeric viruses, recombinant DNA, purified proteins, or combinations thereof [5,6,7,8,9,10,11,12,13,14] Such candidate vaccines have been extensively tested, mostly in mouse models and in Syrian hamsters [13,15,16,17,18,19,20,21,22,23,24,25] and nonhuman primates [26]

Methods

Results

Discussion

Conclusion