Comparison of the Neuropathology Induced by Two West Nile Virus Strains

Jennifer Richardson,Stéphan Zientara,Muriel Coulpier,Eve Laloy,Norbert Nowotny,Jean-Luc Servely,Emilie Donadieu,Steeve Lowenski,Sylvie Lecollinet,Thomas Lilin

doi:10.1371/journal.pone.0084473

Abstract

Some strains of West Nile virus (WNV) are neuroinvasive and may induce fatal encephalitis/meningitis in a variety of animal species including humans. Whether, however, there is a strain-specific signature in the brain is as yet unknown. Here we investigated the neuropathogenesis induced by two phylogenetically distant WNV strains of lineage 1, WNVIS98 and WNVKUN35 911. While four-week old C57Bl/6J mice were susceptible to both strains and succumbed rapidly after intraperitoneal inoculation, differences were observed in virulence and clinical disease. WNVKUN35 911, the less virulent strain as judged by determination of LD50, induced typical signs of encephalitis. Such signs were not observed in WNVIS98-infected mice, although they died more rapidly. Histological examination of brain sections also revealed differences, as the level of apoptosis and inflammation was higher in WNVKUN35 911- than WNVIS98-infected mice. Moreover, staining for cleaved caspase 3 showed that the two WNV strains induced apoptotic death through different molecular mechanisms in one particular brain area. Finally, the two strains showed similar tropism in cortex, striatum, brainstem, and cerebellum but a different one in hippocampus. In summary, our data show that, upon peripheral administration, WNVIS98 and WNVKUN35 911 strains induce partially distinct lesions and tissue tropism in the brain. They suggest that the virulence of a WNV strain is not necessarily correlated with the severity of apoptotic and inflammatory lesions in the brain.

Highlights

West Nile virus (WNV) is a member of the Flaviviridae family and harbors a positive-sense single-stranded RNA genome of approximately 11 kb
The complete genomic sequence of our WNVIS98 strain was identical to that reported by Lucas et al, 2004 [24]
Partial sequencing of the NS5 gene of the WNVKUN35911 strain confirmed its classification in clade 1b (Figure S1A)

Summary

Introduction

West Nile virus (WNV) is a member of the Flaviviridae family and harbors a positive-sense single-stranded RNA (ssRNA) genome of approximately 11 kb. It is maintained in an enzootic cycle between mosquitoes and birds, but can infect and cause disease in other vertebrates including humans. First isolated in Uganda in 1937 [1], WNV is endemic in many parts of the world It was introduced into North America in 1999, and is the leading cause of mosquito-borne and epidemic encephalitis in the United States with more than 200 human fatalities annually (CDC, http://www.cdc.gov/ncidod/ dvbid/westnile/index.htm). In 20% of cases, patients develop a mild flu-like illness [5], while severe neuroinvasive disease such as encephalitis, meningitis or acute flaccid paralysis, all of which may be fatal or accompanied by long term neurological sequelae [6], occurs in less than 1% of cases [7]

Methods

Results

Conclusion