tetano
Editor, Senior Moderator
J Virol. 2010 Jun 16. [Epub ahead of print]
Modifications to the hemagglutinin cleavage site control virulence of a neurotropic H1N1 influenza virus.
Sun X, Tse LV, Ferguson AD, Whittaker GR.
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca NY 14853 and New York Center of Excellence for Influenza Research and Surveillance, University of Rochester Medical Center, Rochester NY 14627.
Abstract
A key determinant of influenza pathogenesis is mutation in the proteolytic cleavage site of the hemagglutinin (HA). Typically, low pathogenicity forms of influenza are cleaved by trypsin-like proteases, whereas highly pathogenic forms are cleaved by different proteases (e.g. furin). Influenza A/WSN/33 is a well-studied H1N1 strain that is trypsin-independent in vitro and has the ability to replicate in mouse brain. Previous studies have indicated that mutations in the neuraminidase (NA) gene allow the recruitment of an alternate protease (plasminogen/plasmin) for HA activation. In this study we have identified an additional mutation in the P2 position of the WSN HA cleavage site (S328Y) that appears to control virus spread in a plasmin-dependent manner. We reconstructed recombinant WSN viruses containing tyrosine (Y), phenylalanine (F) or serine (S) in the P2 position of the cleavage site. The Y328 and F328 viruses allowed plaque formation in the absence of trypsin, whereas the S328 virus was unable to form plaques under these conditions. In mice, Y328 and F328 viruses were able to efficiently spread following intracranial inoculation; in contrast the S328 virus showed only limited infection of mouse brain. Following intranasal inoculation all viruses could replicate efficiently, but with Y328 and F328 viruses showing a limited growth defect. We also show that wild type HA (Y328) was more efficiently cleaved by plasmin than S328 HA. Our studies form the foundation for a more complete understanding of the molecular determinants of influenza virus pathogenesis and the role of the plasminogen/plasmin system in activating HA.
PMID: 20554779 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20554779
Modifications to the hemagglutinin cleavage site control virulence of a neurotropic H1N1 influenza virus.
Sun X, Tse LV, Ferguson AD, Whittaker GR.
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca NY 14853 and New York Center of Excellence for Influenza Research and Surveillance, University of Rochester Medical Center, Rochester NY 14627.
Abstract
A key determinant of influenza pathogenesis is mutation in the proteolytic cleavage site of the hemagglutinin (HA). Typically, low pathogenicity forms of influenza are cleaved by trypsin-like proteases, whereas highly pathogenic forms are cleaved by different proteases (e.g. furin). Influenza A/WSN/33 is a well-studied H1N1 strain that is trypsin-independent in vitro and has the ability to replicate in mouse brain. Previous studies have indicated that mutations in the neuraminidase (NA) gene allow the recruitment of an alternate protease (plasminogen/plasmin) for HA activation. In this study we have identified an additional mutation in the P2 position of the WSN HA cleavage site (S328Y) that appears to control virus spread in a plasmin-dependent manner. We reconstructed recombinant WSN viruses containing tyrosine (Y), phenylalanine (F) or serine (S) in the P2 position of the cleavage site. The Y328 and F328 viruses allowed plaque formation in the absence of trypsin, whereas the S328 virus was unable to form plaques under these conditions. In mice, Y328 and F328 viruses were able to efficiently spread following intracranial inoculation; in contrast the S328 virus showed only limited infection of mouse brain. Following intranasal inoculation all viruses could replicate efficiently, but with Y328 and F328 viruses showing a limited growth defect. We also show that wild type HA (Y328) was more efficiently cleaved by plasmin than S328 HA. Our studies form the foundation for a more complete understanding of the molecular determinants of influenza virus pathogenesis and the role of the plasminogen/plasmin system in activating HA.
PMID: 20554779 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20554779