A Novel Activation Mechanism of Avian Influenza Virus H9N2 by Furin

Tse, Longping V.; Hamilton, Alice M.; Friling, Tamar; Whittaker, Gary R.

doi:10.1128/jvi.02648-13

Cited by 78 publications

(72 citation statements)

References 51 publications

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“…In this regard, there are also parallels with influenza virus, where peptide insertions upstream of the cleavage site/fusion peptide modulate the fusion activity of H7 influenza viruses (Hamilton et al, 2012; Perdue, 2008). In addition, work on influenza virus HA have shown that glycosylations can have profound effects on cleavage activation, as bulky sugar moieties can create steric hindrance around the cleavage site, restricting access for proteases (Kawaoka et al, 1984; Tse et al, 2014). The role of glycosylations in modulating proteolytic activation of the coronavirus S protein, which is known to be heavily glycosylated, has been relatively unexplored and awaits further investigation.…”

Section: Discussion: Spike (S) Cleavage Motifs As Coronavirus Cellmentioning

confidence: 99%

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

2015

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Coronaviruses are a large group of enveloped, single-stranded positive-sense RNA viruses that infect a wide range of avian and mammalian species, including humans. The emergence of deadly human coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) have bolstered research in these viral and often zoonotic pathogens. While coronavirus cell and tissue tropism, host range, and pathogenesis are initially controlled by interactions between the spike envelope glycoprotein and host cell receptor, it is becoming increasingly apparent that proteolytic activation of spike by host cell proteases also plays a critical role. Coronavirus spike proteins are the main determinant of entry as they possess both receptor binding and fusion functions. Whereas binding to the host cell receptor is an essential first step in establishing infection, the proteolytic activation step is often critical for the fusion function of spike, as it allows for controlled release of the fusion peptide into target cellular membranes. Coronaviruses have evolved multiple strategies for proteolytic activation of spike, and a large number of host proteases have been shown to proteolytically process the spike protein. These include, but are not limited to, endosomal cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, and trypsin. This review focuses on the diversity of strategies coronaviruses have evolved to proteolytically activate their fusion protein during spike protein biosynthesis and the critical entry step of their life cycle, and highlights important findings on how proteolytic activation of coronavirus spike influences tissue and cell tropism, host range and pathogenicity.

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Section: Discussion: Spike (S) Cleavage Motifs As Coronavirus Cellmentioning

confidence: 99%

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

2015

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“…The hindrance could also be overcome by the addition of multiple basic amino acids to the cleavage site (11)(12)(13). A recent study showed a similar effect of the oligosaccharide on HA cleavage in an H9 LP avian IAV (14). The H9 HA contained an R-S-K-R cleavage motif, which was not cleavable by furin-like ubiquitous proteases when the oligosaccharide was present at the stalk region but became cleavable by these proteases when the oligosaccharide was removed (14).…”

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confidence: 84%

A Mutant H3N2 Influenza Virus Uses an Alternative Activation Mechanism in TMPRSS2 Knockout Mice by Loss of an Oligosaccharide in the Hemagglutinin Stalk Region

Sakai

Sekizuka

Ami

et al. 2015

J Virol

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e The host protease TMPRSS2 plays an essential role in proteolytic activation of the influenza A virus (IAV) hemagglutinin (HA) protein possessing a monobasic cleavage site. However, after passages in TMPRSS2 knockout mice, an H3N2 subtype IAV began to undergo cleavage activation of HA, showing high virulence in the mice due to the loss of an oligosaccharide at position 8 in the HA stalk region. Thus, the H3N2 IAV acquired cleavability by an alternative HA activation mechanism/protease(s). Influenza A virus (IAV), a member of the Orthomyxoviridae family, affects and kills many humans worldwide. The viral hemagglutinin (HA) glycoprotein, which is responsible for receptor binding and subsequent membrane fusion, is synthesized as the inactive precursor, HA 0 , and cleaved by a host cell protease(s) into HA 1 and HA 2 subunits. The cleavage is essential for HA to mediate membrane fusion.Using mouse models, three research groups recently demonstrated that a type II transmembrane serine protease, TMPRSS2, expressed in the airway epithelium, is critically important for HA cleavage in vivo (1-3). Mice lacking TMPRSS2 expression (TMPRSS2 knockout [tmprss2 KO ] mice) are highly tolerant of challenge infection by low-pathogenic (LP) IAVs possessing a monobasic cleavage site in HA. Our group (1) and Hatesuer et al.(2) showed that TMPRSS2 is essential for proteolytic activation of both H1N1 and H3N2 subtype IAVs. However, Tarnow et al. (3) reported that TMPRSS2 is not critical for activation of H3N2 IAV. Since the three groups used different H3N2 IAV strains, the discrepancy likely arose from possible variations in HA among the H3N2 IAV strains. The present study reveals a molecular determinant that modulates the TMPRSS2 dependency of H3N2 IAV in mouse lungs.A mouse-adapted human H3N2 IAV strain, MA-A/Guizhou-X (H3 WT ) (1), was used as a reference wild-type (WT) virus. The virus was a reassortant H3N2 virus of A/Guizhou/54/89 (H3N2), a Chinese human isolate from 1989, and A/Puerto Rico/8/34 (H1N1) (4). The H3WT virus was passaged 10 times in tmprss2 KO mice, and a tmprss2 KO mouse-adapted MA-A/Guizhou-X virus ( H3 p10 ) was obtained.The parental H3 WT and H3 p10 viruses were inoculated intranasally into tmprss2 KO mice (n ϭ 5). After challenge infection with 3.0 ϫ 10 3 PFU of H3 WT , tmprss2 KO mice showed no body weight loss, while all TMPRSS2 ϩ/ϩ wild-type mice (tmprss2 WT ) showed severe body weight loss (Fig. 1A). Conversely, both tmprss2 KO and tmprss2 WT mice infected with 1.7 ϫ 10 2 PFU of H3 p10 showed severe body weight loss and required euthanasia on day 6 postinfection (p.i.) (Fig. 1B). To compare the susceptibility between the two mouse strains in detail, both mouse strains were also infected with 1.7 ϫ 10, 1.7, and 0.17 PFU of H3 p10 ( Fig. 1C to E). The H3 p10 infections exhibited pathogenicity in both tmprss2 KO and tmprss2 WT mice, although the pathological changes were slightly less severe in tmprss2 KO mice than in tmprss2 WT mice. The 50% lethal doses of H3 p10 for tmprss2 WT and tmprss2 KO mice w...

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“…In recent years, there have been increasing concerns regarding virus transmission from birds to humans with the low pathogenic H9N2 AIV being implicated in sporadic outbreaks in Europe and Asia [5]. The H9N2 subtype that displays differences in the levels of pathogenicity [6], remains endemic in Asia and the Middle East [7].…”

Section: Introductionmentioning

confidence: 99%

Systemic immune responses to an inactivated, whole H9N2 avian influenza virus vaccine using class B CpG oligonucleotides in chickens

Singh

Alkie

Hodgins

et al. 2015

Vaccine

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A Novel Activation Mechanism of Avian Influenza Virus H9N2 by Furin

Cited by 78 publications

References 51 publications

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

A Mutant H3N2 Influenza Virus Uses an Alternative Activation Mechanism in TMPRSS2 Knockout Mice by Loss of an Oligosaccharide in the Hemagglutinin Stalk Region

Systemic immune responses to an inactivated, whole H9N2 avian influenza virus vaccine using class B CpG oligonucleotides in chickens

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