Human metapneumovirus (HMPV) has been identified as a worldwide agent of serious upper and lower respiratory tract infections in infants and young children. HMPV is second only to respiratory syncytial virus (RSV) as a leading cause of bronchiolitis, and, like RSV, consists of two major genotypes that cocirculate and vary among communities year to year. Children who have experienced acute HMPV infection may develop sequelae of wheezing and asthma; however, the features contributing to this pathology remain unknown. A possible mechanism for postbronchiolitis disease is that HMPV might persist in the lung providing a stimulus that could contribute to wheezing and asthma. Using immunohistochemistry to identify HMPV-infected cells in the lungs of mice, we show that HMPV mediates biphasic replication in respiratory epithelial cells then infection migrates to neuronal processes that innervate the lungs where the virus persists with no detectable infection in epithelial cells. After glucocorticoid treatment, the virus is reactivated from neural fibers and reinfects epithelial cells. The findings show that HMPV persists in neural fibers and suggest a mechanism for disease chronicity that has important implications for HMPV disease intervention strategies.Human metapneumovirus (HMPV), a recently recognized paramyxovirus in the Pneumovirus genus, was first isolated in 2001 from nasopharyngeal aspirates of young children with respiratory disease (73). HMPV is a ubiquitous and important respiratory pathogen causing upper and lower respiratory tract disease in infants and young children, but infection may also cause disease in the elderly and immunocompromised (15, 26, 38, 45,73,75). It is recognized that severe respiratory viral infections in childhood are associated with the development of asthma later in life (47), and HMPV disease has been implicated as a trigger for bronchiolitis and asthma in infants and young children (38, 45). These features related to HMPV infection can be severe with prolonged recovery times, a feature that is not well understood.HMPV replication initiates in the upper respiratory tract; however, it can spread to the lower airways involving the bronchi, bronchioles, and alveoli. Evidence from experimental infection in cynomolgus macaques indicates that HMPV replication is short-lived and limited to the apical surface of ciliated respiratory epithelial cells (42). However, the various cell types that may be susceptible to HMPV infection are not completely understood. The HMPV G protein is considered to be the principal means for virus attachment to host cells, and F protein is required for penetration mediated by fusion with the plasma membrane (11, 59). Penetration requires proteolytic cleavage of the F protein, incorporation of the viral envelope into the cell membrane, nucleocapsid release into the cytoplasm, and L protein initiation of viral transcription where replication proceeds in the cytoplasm without nuclear involvement (11,59). Virions assemble at the plasma membrane, where inclusion bod...