martes, 31 de julio de 2012

Adaptation of Human Parainfluenza Virus to Airway Epithelium Reveals Fusion Properties Required for Growth in Host Tissue

Adaptation of Human Parainfluenza Virus to Airway Epithelium Reveals Fusion Properties Required for Growth in Host Tissue


Adaptation of Human Parainfluenza Virus to Airway Epithelium Reveals Fusion Properties Required for Growth in Host Tissue

  1. Anne Mosconaa
+ Author Affiliations
  1. Departments of Pediatrics and Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, USAa;
  2. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USAb; and
  3. Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USAc
  1. Address correspondence to Anne Moscona, anm2047@med.cornell.edu.
  1. Editor Diane Griffin, Johns Hopkins University School of Public Health

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.
IMPORTANCE Human parainfluenza viruses (HPIVs) are paramyxoviruses that cause the majority of childhood cases of croup, bronchiolitis, and pneumonia worldwide, but there are currently no vaccines or antivirals available for treatment. Enveloped viruses must fuse their membrane with the target cell membrane in order to initiate infection. Parainfluenza virus fusion proceeds via a multistep reaction orchestrated by the two glycoproteins that make up its fusion machine. The receptor-binding hemagglutinin-neuraminidase (HN), upon receptor engagement, activates the fusion protein (F) to penetrate the target cell and mediate viral entry. In this study, we show that the precise balance of fusion activation properties of these two glycoproteins during entry is key for infection. In clinically relevant tissues, viruses evolve to acquire a set of fusion features that provide key clues about requirements for infection in human beings.

Footnotes

  • Citation Palmer SG, et al. 2012. Adaptation of human parainfluenza virus to airway epithelium reveals fusion properties required for growth in host tissue. mBio 3(3):e00137-12. doi:10.1128/mBio.00137-12.
  • Received 4 May 2012
  • Accepted 8 May 2012
  • Published 5 June 2012
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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