title: Features of Circulating Parainfluenza Virus Required for Growth in Human Airway.
abstract: Respiratory paramyxoviruses, including the highly prevalent human parainfluenza viruses, cause the majority of childhood croup, bronchiolitis, and pneumonia, yet there are currently no vaccines or effective treatments. Paramyxovirus research has relied on the study of laboratory-adapted strains of virus in immortalized cultured cell lines. We show that findings made in such systems about the receptor interaction and viral fusion requirements for entry and fitness-mediated by the receptor binding protein and the fusion protein-can be drastically different from the requirements for infection in vivo. Here we carried out whole-genome sequencing and genomic analysis of circulating human parainfluenza virus field strains to define functional and structural properties of proteins of circulating strains and to identify the genetic basis for properties that confer fitness in the field. The analysis of clinical strains suggests that the receptor binding-fusion molecule pairs of circulating viruses maintain a balance of properties that result in an inverse correlation between fusion in cultured cells and growth in vivo. Future analysis of entry mechanisms and inhibitory strategies for paramyxoviruses will benefit from considering the properties of viruses that are fit to infect humans, since a focus on viruses that have adapted to laboratory work provides a distinctly different picture of the requirements for the entry step of infection.
  
  
  OBJECTIVE
  Mechanistic information about viral infection-information that impacts antiviral and vaccine development-is generally derived from viral strains grown under laboratory conditions in immortalized cells. This study uses whole-genome sequencing of clinical strains of human parainfluenza virus 3-a globally important respiratory paramyxovirus-in cell systems that mimic the natural human host and in animal models. By examining the differences between clinical isolates and laboratory-adapted strains, the sequence differences are correlated to mechanistic differences in viral entry. For this ubiquitous and pathogenic respiratory virus to infect the human lung, modulation of the processes of receptor engagement and fusion activation occur in a manner quite different from that carried out by the entry glycoprotein-expressing pair of laboratory strains. These marked contrasts in the viral properties necessary for infection in cultured immortalized cells and in natural host tissues and animals will influence future basic and clinical studies.
authors.affiliation: Departments of Pediatrics, Microbiology and Immunology, and Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Palermo
authors.affiliation: Departments of Pediatrics, Microbiology and Immunology, and Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Manik
authors.initials: M
authors.lastname: Uppal
authors.affiliation: Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Skrabanek
authors.affiliation: Applied Bioinformatics Core, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Zumbo
authors.affiliation: New York Genome Center, New York, New York, USA.
authors.forename: Soren
authors.initials: S
authors.lastname: Germer
authors.affiliation: New York Genome Center, New York, New York, USA.
authors.forename: Nora C
authors.initials: NC
authors.lastname: Toussaint
authors.affiliation: Center for Infection and Immunity, Queens University, Belfast, Northern Ireland, UK.
authors.forename: Bert K
authors.initials: BK
authors.lastname: Rima
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Ohio, USA.
authors.forename: Devra
authors.initials: D
authors.lastname: Huey
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Ohio, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
authors.affiliation: Departments of Pediatrics, Microbiology and Immunology, and Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Porotto
authors.affiliation: Departments of Pediatrics, Microbiology and Immunology, and Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York, USA Am939@cumc.columbia.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Moscona
mesh_terms: D000818:Animals; D016679:Genome, Viral; D006801:Humans; D012137:Respiratory System / Q000821:virology*; D018108:Respirovirus / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology* / Q000648:ultrastructure; D010253:Respirovirus Infections / Q000821:virology; D017422:Sequence Analysis, DNA; D016205:Sigmodontinae; D014774:Virulence; D053586:Virus Internalization