Mouse models of Tembusu virus infection for differentiating between cluster 2.1 and 2.2 isolates

Abstract

Tembusu virus (TMUV) cluster 2.1 and 2.2 strains are known to produce lethal neurological disease in mice inoculated by intracerebral (ic) route. Here, we report the comparative clinicopathological findings following experimental infections of 3-week-old BALB/c and Kunming mice with cluster 2.1 isolate H and cluster 2.2 isolate Y. When infected by the subcutaneous (sc) route, both isolates failed to induce disease in mice. When infected by the ic route, both isolates caused lethal neurological disease in mice, with isolate H presenting markedly higher neurovirulence than isolate Y. Further studies with the Kunming mouse model showed that following sc inoculation, both H and Y isolates failed to replicate in brain and spleen, and that following ic inoculation, isolate H replicated to higher levels in brain and spleen than isolate Y. The findings may help to explain non-neuroinvasive property of clusters 2.1 and 2.2 and suggest that enhanced neurovirulence of cluster 2.1 relative to cluster 2.2 is associated with more efficient replication in the central nervous system and in the periphery. Moreover, isolate H induced significantly higher levels of IFN-β, IL-1β, IL-6, TNF-α, Ifit1, and Ifit2 expression relative to isolate Y, indicating a positive correlation between TMUV neurovirulence and magnitude of antiviral innate immune response. The present work demonstrates that the mouse models allow to differentiate between cluster 2.1 and 2.2 isolates and provides mechanistic insights into TMUV-induced disease.