P-D1 Differential pathogenesis of human metapneumovirus clinical isolates in C57BL/6 mice

Abstract

Introduction: Human metapneumovirus (HMPV) is a member of the Pneumoviridae, formerly a subfamily of Paramyxoviridae. HMPV is a leading cause of lower respiratory infection in infants, children, and adults. The disease outcome of HMPV infection ranges from mild upper respiratory infection to severe pneumonia. Despite the clinical and economic burden, mechanisms of HMPV pathogenesis are not fully understood. In addition, no licensed vaccines or anti-viral drugs are available. Results: Most published HMPV studies use a few laboratory-adapted strains of the A2 lineage. Here, we tested eight HMPV clinical isolates from different genetic lineages in comparison to a laboratory reference strain in an established C57BL/6 mouse model. The clinical isolates induced variable disease severity. While mice infected by laboratory strain TN/94-49 (A2) did not lose weight, mice infected by clinical strains showed significant weight loss and greater lung histopathology. Several clinical isolates caused lethal disease, which is unusual in mouse models of HMPV. Viral replication in lungs was variable, but peak lung viral titer did not correlate with disease outcome. Higher proinflammatory cytokine production in mouse lungs was associated with more severe disease and death. Virulent clinical isolates of HMPV exhibited diminished innate immune responses and decreased antigen-presenting cells, suggesting active inhibition of innate immunity. The findings were confirmed in BALB/c and DBA/2 inbred mice. Conclusion: Our results indicate that severe disease caused by HMPV clinical isolates was due to exuberant immune response and immunopathology. These data suggest that distinct HMPV strains may engage host immune mediators differently.