Abstract
Human metapneumovirus (HMPV) is a leading cause of respiratory infection that causes upper airway and severe lower respiratory tract infections. HMPV infection is initiated by viral surface glycoproteins that attach to cellular receptors and mediate virus membrane fusion with cellular membranes. Most paramyxoviruses use two viral glycoproteins to facilitate virus entry—an attachment protein and a fusion (F) protein. However, membrane fusion for the human paramyxoviruses in the Pneumovirus subfamily, HMPV and respiratory syncytial virus (hRSV), is unique in that the F protein drives fusion in the absence of a separate viral attachment protein. Thus, pneumovirus F proteins can perform the necessary functions for virus entry, i.e., attachment and fusion. In this review, we discuss recent advances in the understanding of how HMPV F mediates both attachment and fusion. We review the requirements for HMPV viral surface glycoproteins during entry and infection, and review the identification of cellular receptors for HMPV F. We also review our current understanding of how HMPV F mediates fusion, concentrating on structural regions of the protein that appear to be critical for membrane fusion activity. Finally, we illuminate key unanswered questions and suggest how further studies can elucidate how this clinically important paramyxovirus fusion protein may have evolved to initiate infection by a unique mechanism.
Highlights
Human metapneumovirus (HMPV) was first isolated in 2001 in the Netherlands [1].Dutch investigators discovered an unknown virus in respiratory secretions collected from young children with lower respiratory illness
We review our current understanding of how HMPV F mediates fusion, concentrating on structural regions of the protein that appear to be critical for membrane fusion activity
We recently found that blocking HMPV F interaction with RGD-binding integrins did not alter virus-cell hemifusion kinetics, and virus-like particles bearing an F-RAE mutation fused with the same hemifusion kinetics as wild type F particles [65]
Summary
Human metapneumovirus (HMPV) was first isolated in 2001 in the Netherlands [1]. Dutch investigators discovered an unknown virus in respiratory secretions collected from young children with lower respiratory illness. PCR and sequence analysis revealed a single-stranded, negative-sense RNA genome with close resemblance to avian metapneumovirus (AMPV), an avian virus that causes serious respiratory disease in chickens and turkeys [3]. HMPV causes a clinical spectrum of illness from upper airway infection to severe lower respiratory tract infections (e.g., bronchiolitis and pneumonia) [5,26]. Experimental studies in nonhuman primates and small animal models (hamsters, cotton rats, and mice) indicate that HMPV replicates in the upper and lower respiratory tract epithelium and demonstrate no evidence of viral dissemination, indicating a distinct tissue tropism for HMPV which is consistent with clinical illness observed during human infection [28,29,30]
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