Comparison of the Neuropathology Induced by Two West Nile Virus Strains

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.

Investigation of neuropathogenesis and control of an equine-pathogenic Australian West Nile virus isolate in an established CD1 Swiss white mouse and a novel rabbit model

“…Similar variability has also been observed in other studies using different mouse and WNV strains (e.g. [261,262]). Yet, variability in disease outcome has not been well recognised as a significant factor influencing the interpretation of results from time-point sacrifice experiments.…”

“…Given the observation of neuronophagia in earlier fatalities ( Figure 4-5F), it is possible that the late lethal end-points in our study captured a temporal snapshot after complete clearance of infected neurons. The cause of the severe symptoms/death in these late fatalities, therefore, may be due to drop out of essential neurons in vital areas of the CNS, such as the brainstem or spinal cord [245,262]. Complete characterisation of the distribution and degree of neuronal dropout is beyond the scope of the current study.…”

“…Other inbred mouse strains, such as C57BL6, also produce variable disease outcomes, such as brain viral load, in moribund or dead mice when infected with specific WNV strains at specific doses and routes [262]. This highlights that the "virulence phenotype" of a virus isolate and its associated disease spectrum are dependent on the model system used.…”

End-point disease investigation for virus strains of intermediate virulence as illustrated by flavivirus infections

“…4f), it is possible that the late lethal end-points in our study captured a temporal snapshot after complete clearance of infected neurons. The cause of the severe symptoms/death in these late fatalities, therefore, may be due to drop out of essential neurons in vital areas of the CNS, such as the brainstem or spinal cord (Donadieu et al, 2013;Fratkin et al, 2004). Complete characterization of the distribution and degree of neuronal dropout is beyond the scope of the current study.…”

“…Other inbred mouse strains, such as C57BL6, also produce variable disease outcomes, such as brain viral load, in moribund or dead mice when infected with specific WNV strains at specific doses and routes (Donadieu et al, 2013). This highlights that the 'virulence phenotype' of a virus isolate and its associated disease spectrum are dependent on the model system used.…”