| Abstract: |
Paramyxoviruses, a family of RNA enveloped viruses that includes human parainfluenza virus type 3 (HPIV3), cause the majority of childhood croup, bronchiolitis, and pneumonia worldwide. Infection starts with host cell receptor binding and fusion of the viral envelope with the cell membrane at the cell surface. The fusion process requires interaction of the two viral surface glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). We have previously shown that viruses with an HN/F pair that is highly fusogenic in monolayers of immortalized cells due to mutations in HN's secondary sialic acid binding site are growth impaired in differentiated human airway epithelium (HAE) cultures and in vivo. Here we have shown that adaptation of HPIV3 to growth in the lung is determined by specific features of HN and F that are different from those required for growth in cultured immortalized cells. An HPIV3 virus bearing a mutated HN (H552Q), which is fit and fusogenic in immortalized cells but unfit for growth in the lung, evolved into a less-fusogenic but viable virus in differentiated human airway epithelium. Stepwise evolution led to a progressive decrease in efficiency of fusion activation by the HN/F pair, with a mutation in F first decreasing the activation of F by HN and a mutation in HN's secondary sialic acid binding site decreasing fusion activation further and producing a stable virus. Adaptation of HPIV3 to successful growth in HAE is determined by specific features of HN and F that lead to a less easily activated fusion mechanism. © 2012 Palmer et al. |
| Keywords: |
controlled study; human tissue; human cell; mutation, missense; nonhuman; protein conformation; protein function; animals; protein protein interaction; cell line; cercopithecus aethiops; evolution, molecular; epithelial cells; binding site; models, molecular; mutant proteins; temperature sensitivity; receptor binding; parainfluenza virus; virus survival; virus identification; respiratory epithelium; viral fusion proteins; virogenesis; virus entry; virus mutation; virus cell interaction; virus internalization; parainfluenza virus 3; hn protein; virus fusion protein; viral phenomena and functions; virus adaptation; virus fusion; adaptation, biological; parainfluenza virus 3, human; human parainfluenza virus 3
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