[Source: mBio, full page: (LINK). Abstract, edited.]
mBio. 2019 Nov 5;10(6):e02369-19. doi: 10.1128/mBio.02369-19.
A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus
Hyeok-Il Kwon 1 2, Young-Il Kim 1 2, Su-Jin Park 1 2, Eun-Ha Kim 1 2, Semi Kim 1 2, Young-Jae Si 1 2, Min-Suk Song 1 2, Philippe Noriel Q Pascua 1 3, Elena A Govorkova 3, Robert G Webster 3, Richard J Webby 4, Young Ki Choi 5 2
Affiliations: 1 College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Republic of Korea. 2 Zoonotic Infectious Diseases Research Center, Chungbuk National University, Cheongju, Republic of Korea. 3 Division of Virology, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. 4 Division of Virology, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA email@example.com firstname.lastname@example.org. 5 College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Republic of Korea email@example.com firstname.lastname@example.org.
PMID: 31690675 PMCID: PMC6831776 DOI: 10.1128/mBio.02369-19
In this study, we demonstrate a novel mechanism for hemagglutinin (HA) activation in a naturally occurring H7N6 avian influenza A virus strain, A/mallard duck/Korea/6L/2007 (A/Mdk/6L/07). This novel mechanism allows for systemic infection of chickens, ducks, and mice, and A/Mdk/6L/07 can replicate in vitro without exogenous trypsin and exhibits broad tissue tropism in animals despite the presence of a monobasic HA cleavage motif (PEIPKGR/G). The trypsin-independent growth phenotype requires the N6 neuraminidase and the specific recognition of glycine at the P2 position of the HA cleavage motif by a thrombin-like protease. Correspondingly, viral growth is significantly attenuated by the addition of a thrombin-like protease inhibitor (argatroban). These data provide evidence for a previously unrecognized virus replication mechanism and support the hypothesis that thrombin-mediated HA cleavage is an important virulence marker and potential therapeutic target for H7 influenza viruses.
The identification of virulence markers in influenza viruses underpins risk assessment programs and the development of novel therapeutics. The cleavage of the influenza virus HA is a required step in the viral life cycle, and phenotypic differences in viruses can be caused by changes in this process. Here, we describe a novel mechanism for HA cleavage in an H7N6 influenza virus isolated from a mallard duck. The mechanism requires the N6 protein and full activity of thrombin-like proteases and allows the virus to cause systemic infection in chickens, ducks, and mice. The thrombin-mediated cleavage of HA is thus a novel virulence determinant of avian influenza viruses.
Keywords: GRG motif; H7; N6 neuraminidase; influenza; pathogenicity; thrombin-like protease; trypsin-independent growth; virulence.
Copyright © 2019 Kwon et al.
Keywords: Avian Influenza; H7N6; Wild Birds; Viral pathogenesis.