Pneumonia Virus of Mice (PVM): Exploring Novel Therapeutic Options In a Severe Respiratory Disease Model

Respiratory syncytial virus (RSV) is the most important respiratory pathogen among infants and toddlers, with infections prevalent and nearly universal in this age group. Severe infections are more common among premature infants, those with cardiac and pulmonary anomalies, and the immunosupressed. Effective prophylactic monoclonal antibody treatment is available for high-risk infants, but there is no effective vaccine. Mouse challenge models have been used for the study of the human RSV pathogen, but the most severe forms of RSV disease are not replicated by this approach. Pneumonia virus of mice (PVM; family Paramyxoviridae, genus Pneumovirus) is a mouse pathogen of the same family as human respiratory syncytial virus. PVM replicates efficiently in mouse-lung epithelial cells in vivo in response to a minimal virus inoculum, and replication is accompanied by local production of proinflammatory cytokines (MIP-1α, MIP-2, MCP-1, and IFN-γ) and granulocyte recruitment to the lung. PVM infection and the ensuing inflammatory response can lead to pulmonary edema and respiratory compromise. Our laboratories have pioneered the use of the PVM model for the study of human clinical disease, which has provided important insights into the role of the inflammatory response in the pathogenesis of severe respiratory virus infection. As part of this work, we have presented several immunomodulatory strategies that clearly reduce morbidity and mortality when administered to PVM infected, symptomatic mice, and thus hold promise as realistic therapeutic strategies for severe RSV infection in human subjects.