[Source: Journal of Virology, full text: (LINK). Abstract, edited.]
Plasmin-mediated activation of pandemic H1N1 influenza virus hemagglutinin independent of the viral neuraminidase
Longping V. Tse 1,2, Valerie C. Marcano 1, Weishan Huang 1, Misty S. Pocwierz 1 and Gary R. Whittaker 1,2,*
Author Affiliations: 1Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca NY 14853 2New York Center of Excellence for Influenza Research and Surveillance, University of Rochester Medical Center, Rochester NY 14627
Influenza virus is well recognized to modulate host tropism and pathogenesis based on mutations in the proteolytic cleavage site of the viral hemagglutinin (HA), which activates HA and exposes the fusion peptide for membrane fusion. Instead of the conventional trypsin-mediated cleavage event, modification of the cleavage site allows for extended use of host cell proteases and enhanced spread in vivo. For H1N1 influenza viruses, the mouse-adapted A/WSN/33 strain is known to replicate in the brain based on recruitment of plasminogen by the viral neuraminidase (NA), as well as a Ser-Tyr substitution at the P2 position of the HA cleavage site. Here, we show that an equivalent Ser-Tyr substitution has occurred in the HA of naturally occurring human H1N1 influenza viruses. We characterize one of these viruses (A/Beijing/718/2009), as well as the prototype A/California/04/2009 with a Ser-Tyr substitution in the cleavage site, and show that these HAs are preferentially cleaved by plasmin. Importantly, cleavage-activation by plasmin/plasminogen was independent of the viral NA, suggesting a novel mechanism for HA cleavage activation. We show that the viral HA itself can recruit plasminogen for HA cleavage. We further show that cellular factors, as well as streptokinase from bacteria commonly co-infecting the respiratory tract of influenza patients, can be a source of activated plasminogen for plasmin-mediated cleavage of influenza HAs that contain a Ser-Tyr substitution in the cleavage site.
*Address correspondence to: Gary R. Whittaker, C4127 VMC, Dept. Microbiology & Immunology, Cornell University, Ithaca NY 14853 USA. Tel: 607 253 4019. Fax: 607 253 3385 Email: firstname.lastname@example.org
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