Short Communication Experimental Human Metapneumovirus Infection of Cynomolgus Macaques (Macaca fascicularis) Results in Virus Replication in Ciliated Epithelial Cells and Pneumocytes with Associated Lesions throughout the Respiratory Tract

A substantial proportion of hitherto unexplained respiratory tract illnesses is associated with human metapneumovirus (hMPV) infection. This virus also was found in patients with severe acute respiratory syndrome (SARS). To determine the dynamics and associated lesions of hMPV infection, six cynomolgus macaques (Macaca fascicularis) were inoculated with hMPV and examined by pathological and virological assays. They were euthanized at 5 (n 2) or 9 (n 2) days post-infection (dpi), or monitored until 14 dpi (n 2). Viral excretion peaked at 4 dpi and decreased to zero by 10 dpi. Viral replication was restricted to the respiratory tract and associated with minimal to mild, multi-focal erosive and inflammatory changes in conducting airways, and increased numbers of macrophages in alveoli. Viral expression was seen mainly at the apical surface of ciliated epithelial cells throughout the respiratory tract, and less frequently in type 1 pneumocytes and alveolar macrophages. Both cell tropism and respiratory lesions were distinct from those of SARS-associated coronavirus infection, excluding hMPV as the primary cause of SARS. This study demonstrates that hMPV is a respiratory pathogen and indicates that viral replication is short-lived, polarized to the apical surface, and occurs primarily in ciliated respiratory epithelial cells. (Am J Pathol 2004, 164:1893–1900) A substantial proportion of hitherto unexplained respiratory tract illnesses in human beings is associated with infection by a recently discovered paramyxovirus, provisionally named human metapneumovirus (hMPV). It is most closely related to avian pneumovirus type C (APV), the etiological agent of rhinitis and sinusitis in turkeys. Human metapneumovirus was first identified in the Netherlands, where serological studies indicate that it has been circulating in the human population since at least 1958 and that most children are infected by 5 years of age. Since its discovery in the Netherlands, hMPV infection also has been reported elsewhere in Europe, North America, Asia, and Australia. Respiratory tract disease associated with hMPV infection occurs both in children and adults, suggesting that hMPV is capable of causing clinically important re-infection of individuals later in life. Clinically, hMPV-associated disease includes rhinitis, pharyngitis, bronchitis, bronchiolitis, and pneumonia, and resembles that of human respiratory syncytial virus (RSV) infection. Severity of disease varies from common cold to death, with very young children, the elderly, and immunocompromised patients being predisposed to severe lower respiratory tract disease. In the recent epidemic of severe acute respiratory syndrome (SARS), the role of hMPV as a primary pathogen or co-pathogen was considered. Although a newly discovered virus, SARS-associated coronavirus (SCV), proved to be the primary cause of the disease, 12% (41 of 335) of SARS patients also were infected with