Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis

Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV. In this study, we isolated and characterized a panel of low passage HMPV clinical isolates representing all four genetic subgroups. The clinical isolates exhibited lower levels of in vitro replication compared to a lab-adapted strain. We compared disease phenotypes using a well-established mouse model. Several virulent isolates caused severe weight loss, lung pathology, airway dysfunction, and fatal disease in mice, which was confirmed in three inbred mouse strains. Disease severity did not correlate with lung viral titer, as virulent strains exhibited restricted replication in the lower airway. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production and neutrophil influx; however, depletion of neutrophils or genetic ablation of inflammasome components did not reverse disease. Virulent clinical isolates induced markedly increased type I and type III IFN (IFN) secretion in vitro and in vivo. STAT1/2-deficient mice lacking both type I and type III IFN signaling showed reduced disease severity and increased lung viral replication. Inhibition of type I IFN signaling using a blocking antibody or genetic ablation of the type I IFN receptor reduced pathology with minimal effect on viral replication. Conversely, blockade of type III IFN signaling with a neutralizing antibody or genetic ablation of the IFN-lambda receptor had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV pathogenesis and immunity. Human metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection in children and adults worldwide. However, little is known about mechanisms of pathogenesis and most published studies use a few laboratory-adapted strains of HMPV. In this study, we isolated and characterized disease phenotypes of a panel of HMPV isolates. We identified several virulent isolates capable of causing severe and fatal disease in mice. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production as well as increased type I and type III IFN (IFN) secretion in vitro and in vivo. Inhibition of type I IFN signaling reduced pathology with minimal effect on viral replication. Conversely, blockade or genetic ablation of type III IFN signaling had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV defense and disease.