Lethal model for respiratory syncytial virus infection using C57BL/6 mice

Abstract

Respiratory syncytial virus (RSV) infection is a major infectious disease affecting public health. Infants and elderly infected with RSV can develop severe respiratory symptoms. A mouse model mimicking human RSV infection could be useful in elucidating the pathogenesis of RSV. However, previous mouse models did not adequately mimic the pathophysiology of human patients. We attempted to establish a new mouse-adapted RSV strain via serial passaging of mice. We rescued the MP11 virus (which had one non-synonymous substitution in each of the F, G, and L genes) through serial passaging in mice. The MP11 virus was inoculated into mice to evaluate whether it had adapted to the mouse. Viral RNA levels in the lungs of 25-week-old mice infected with MP11 virus were higher than those in the lungs of mice infected with A2 virus. There was a high infiltration of inflammatory cells and high expression of several inflammatory cytokines (IFN-γ, CCL2, TNF-α, and IL-6) in the MP11 virus-infected lungs. Furthermore, the MP11 virus can also cause lethal pneumonia in mice via high-concentration inoculation. These results indicated that the MP11 virus is a more mouse-adapted strain than the A2 virus. We generated a recombinant MP11 virus (rMP11) using reverse genetics. The rMP11 virus could grow in the lungs of mice, similar to the parent MP11 virus. In conclusion, we successfully established a new mouse-adapted strain, MP11, and reverse genetics for this strain. These MP11 and rMP11 viruses could contribute to mouse experiments aimed at elucidating RSV pathogenesis. IMPORTANCE A mouse model of respiratory syncytial virus (RSV) infection is useful for fundamental research aimed at developing antiviral drugs. Previous mouse models of RSV infection were unable to adequately mimic the pathophysiology of human patients due to the low amplification efficiency of this virus in the mouse lung. Furthermore, mice other than BALB/C mice are difficult to use for the RSV infectious model. We established a new mouse-adapted RSV strain, MP11. The MP11 virus can cause severe pneumonia in C57BL/6 mice and efficiently replicate and induce inflammation in the lung. Therefore, C57BL/6 mice can be used for RSV infection experiments using MP11 virus. We established a reverse genetics system for the MP11 virus using our mouse model. This system enables detailed analyses of the MP11 virus, such as functional analysis of each viral protein. Our study provides techniques that can advance fundamental research in elucidating the pathogenesis of RSV infections.