title: Genetic determinants of mouse hepatitis virus strain 1 pneumovirulence.
abstract: We report here investigation into the genetic basis of mouse hepatitis virus strain 1 (MHV-1) pneumovirulence. Sequencing of the 3' one-third of the MHV-1 genome demonstrated that the genetic organization of MHV-1 was similar to that of other strains of MHV. The hemagglutinin esterase (HE) protein was truncated, and reverse transcription-PCR (RT-PCR) studies confirmed previous work that suggested that the MHV-1 HE is a pseudogene. Targeted recombination was used to select chimeric viruses containing either the MHV-1 S gene or genes encoding all of the MHV-1 structural proteins, on an MHV-A59 background. Challenge studies in mice demonstrated that expression of the MHV-1 S gene within the MHV-A59 background (rA59/S(MHV-1)) increased the pneumovirulence of MHV-A59, and mice infected with this recombinant virus developed pulmonary lesions that were similar to those observed with MHV-1, although rA59/S(MHV-1) was significantly less virulent. Chimeras containing all of the MHV-1 structural genes on an MHV-A59 background were able to reproduce the severe acute respiratory syndrome (SARS)-like pathology observed with MHV-1 and reproducibly increased pneumovirulence relative to rA59/S(MHV-1), but were still much less virulent than MHV-1. These data suggest that important determinants of pneumopathogenicity are contained within the 3' one-third of the MHV-1 genome, but additional important virulence factors must be encoded in the genome upstream of the S gene. The severity of the pulmonary lesions observed correlates better with elevated levels of inflammatory cytokines than with viral replication in the lungs, suggesting that pulmonary disease has an important immunological component.
authors.affiliation: Department of Microbial and Molecular Pathogenesis Texas A&M University System-HSC, College of Medicine, 407 Reynolds Medical Building, 1114 TAMU, College Station, TX 77843-1114, USA. jleibowitz@tamu.edu
authors.forename: Julian L
authors.initials: JL
authors.lastname: Leibowitz
authors.forename: Rajiv
authors.initials: R
authors.lastname: Srinivasa
authors.forename: Shawn T
authors.initials: ST
authors.lastname: Williamson
authors.forename: Ming Ming
authors.initials: MM
authors.lastname: Chua
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Liu
authors.forename: Samantha
authors.initials: S
authors.lastname: Wu
authors.forename: Hyojeung
authors.initials: H
authors.lastname: Kang
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Ma
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Itay
authors.initials: I
authors.lastname: Shalev
authors.forename: Robert
authors.initials: R
authors.lastname: Smith
authors.forename: Melville J
authors.initials: MJ
authors.lastname: Phillips
authors.forename: Gary A
authors.initials: GA
authors.lastname: Levy
authors.forename: Susan R
authors.initials: SR
authors.lastname: Weiss
mesh_terms: D000818:Animals; D018352:Coronavirus Infections / Q000473:pathology / Q000821:virology; D005260:Female; D023061:Gene Order; D005814:Genes, Viral; D008168:Lung / Q000473:pathology* / Q000821:virology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D006517:Murine hepatitis virus / Q000235:genetics / Q000472:pathogenicity*; D011024:Pneumonia, Viral / Q000473:pathology / Q000821:virology; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; D012367:RNA, Viral; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D037521:Virulence Factors