Long-Term Infection and Pathogenesis in a Novel Mouse Model of Human Respiratory Syncytial Virus

Intensive efforts have been made to develop models of hRSV infection or disease using various animals. However, the limitations such as semi-permissiveness and short duration of infection have impeded their applications in both the pathogenesis of hRSV and therapeutics development. Here, we present a mouse model based on a Rag2 gene knockout using CRISPR/Cas9 technology. Rag2(-/-) mice sustained high viral loads upon intranasal inoculation with hRSV. The average peak titer rapidly reached 1 x 10(9.8) copies/g and 1c10(6) TCID50 in nasal cavity, as well as 1 x 10(8) copies/g and 1 x 10(5) TCID50 in the lungs up to 5 weeks. Mild interstitial pneumonia, severe bronchopneumonia, elevated cytokines and NK cells were seen in Rag2(-/-) mice. A humanized monoclonal antibody showed strong antiviral activity in this animal model, implying that Rag2(-/-) mice that support long-term stable infection are a useful tool for studying the transmission and pathogenesis of human RSV, as well as evaluating therapeutics.