The Upper Respiratory Tract Exhibits Reduced Interferon Response That Contributes to Limited CD8+T Cell Recruitment and Delayed Clearance of Human Metapneumovirus

Human metapneumovirus (HMPV) is a leading cause of acute upper and lower respiratory infections. Although nearly everyone is infected during early childhood, re-infections occur often, highlighting difficulty in building long-term immunity. We employed a mouse model of HMPV infection to elucidate differences in upper and lower tract immune responses, and address why upper airway infection does not establish durable protective immunity. We found HMPV burden was higher in nasal airways and exhibited delayed clearance compared to lung. Additionally, there was low nasal expression of antiviral interferons (IFN) and inflammatory cytokines. Key innate immune cells, including macrophages, monocytes, and dendritic cells, were present in the nose at baseline but were not upregulated by infection. We previously showed HMPV-specific lung CD8 +T cells (T CD8) are impaired, exhibiting sustained high PD-1 levels and reduced functionality. Despite higher HMPV viral load, there were few HMPV-specific nasal T CD8and they did not exhibit impairment. To test whether low nasal IFN led to this phenotype, we administered type I IFN in an upper airway-restricted fashion early post-infection. This led to lower HMPV nose titers, increased cell number, higher PD-1 expression, and reduced functionality in HMPV-specific nasal T CD8. Despite the subdued nasal immune response, intranasal vaccination with a small-volume HMPV dose elicited modest reduction of lung and nose titers on challenge but no improvement in clinical disease. Our findings reveal a quiescent nasal immune landscape despite high HMPV burden that contributed to slow clearance and was modulated, in part, by low IFN expression. Supported by NIH R01 AI085062-06 (JVW), T32 AI138954-4 (JS), and UPMC Children's Hospital of Pittsburgh Research Advisory Council Graduate Fellowship (JS).