A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus
ABSTRACT 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 re...
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American Society for Microbiology
2019
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oai:doaj.org-article:d01f741f62bf4fb48865c8cb4b0e7d962021-11-15T15:54:46ZA Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus10.1128/mBio.02369-192150-7511https://doaj.org/article/d01f741f62bf4fb48865c8cb4b0e7d962019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02369-19https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Hyeok-il KwonYoung-Il KimSu-Jin ParkEun-Ha KimSemi KimYoung-Jae SiMin-Suk SongPhilippe Noriel Q. PascuaElena A. GovorkovaRobert G. WebsterRichard J. WebbyYoung Ki ChoiAmerican Society for MicrobiologyarticleH7N6 neuraminidasethrombin-like proteaseGRG motiftrypsin-independent growthinfluenzaMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
H7 N6 neuraminidase thrombin-like protease GRG motif trypsin-independent growth influenza Microbiology QR1-502 |
| spellingShingle |
H7 N6 neuraminidase thrombin-like protease GRG motif trypsin-independent growth influenza Microbiology QR1-502 Hyeok-il Kwon Young-Il Kim Su-Jin Park Eun-Ha Kim Semi Kim Young-Jae Si Min-Suk Song Philippe Noriel Q. Pascua Elena A. Govorkova Robert G. Webster Richard J. Webby Young Ki Choi A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus |
| description |
ABSTRACT 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. IMPORTANCE 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. |
| format |
article |
| author |
Hyeok-il Kwon Young-Il Kim Su-Jin Park Eun-Ha Kim Semi Kim Young-Jae Si Min-Suk Song Philippe Noriel Q. Pascua Elena A. Govorkova Robert G. Webster Richard J. Webby Young Ki Choi |
| author_facet |
Hyeok-il Kwon Young-Il Kim Su-Jin Park Eun-Ha Kim Semi Kim Young-Jae Si Min-Suk Song Philippe Noriel Q. Pascua Elena A. Govorkova Robert G. Webster Richard J. Webby Young Ki Choi |
| author_sort |
Hyeok-il Kwon |
| title |
A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus |
| title_short |
A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus |
| title_full |
A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus |
| title_fullStr |
A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus |
| title_full_unstemmed |
A Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza Virus |
| title_sort |
novel neuraminidase-dependent hemagglutinin cleavage mechanism enables the systemic spread of an h7n6 avian influenza virus |
| publisher |
American Society for Microbiology |
| publishDate |
2019 |
| url |
https://doaj.org/article/d01f741f62bf4fb48865c8cb4b0e7d96 |
| work_keys_str_mv |
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