Acquisition of a novel eleven amino acid insertion directly N-terminal to a tetrabasic cleavage site confers intracellular cleavage of an H7N7 influenza virus hemagglutinin

Hamilton, Brian S.; Sun, Xiangjie; Chung, Changik; Whittaker, Gary R.

doi:10.1016/j.virol.2012.09.004

Cited by 8 publications

(12 citation statements)

References 54 publications

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“…Notably, MHV S contains what appears to be an insertion of a stretch of residues upstream of the cleavage site (table 3), which are clearly linked to fusion activity (Taguchi and Shimazaki, 2000). 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).…”

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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“…173 However, the intracellular cleavage of the equine H7N7 lineage was found to be due to an 11 amino acid motif adjacent to the MBCS that, when inserted into an LPAI H7N3 virus, increased the pathogenicity of infection. 175 In contrast, the H3N8 equine lineage may have originated wholly from an avian IAV source, and these viruses have been shown to undergo frequent intersubtype and intrasubtype reassortments. [178][179][180] Interestingly, the H3N8 virus in equine hosts preferentially binds to avian-like α-2,3-SA, where the receptors are abundantly present in the upper respiratory tract of horses.…”

Section: Equine Iavmentioning

confidence: 99%

The ecology and adaptive evolution of influenza A interspecies transmission

Joseph

Vijaykrishna

et al. 2016

Influenza Resp Viruses

102

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Since 2013, there have been several alarming influenza‐related events; the spread of highly pathogenic avian influenza H5 viruses into North America, the detection of H10N8 and H5N6 zoonotic infections, the ongoing H7N9 infections in China and the continued zoonosis of H5N1 viruses in parts of Asia and the Middle East. The risk of a new influenza pandemic increases with the repeated interspecies transmission events that facilitate reassortment between animal influenza strains; thus, it is of utmost importance to understand the factors involved that promote or become a barrier to cross‐species transmission of Influenza A viruses (IAVs). Here, we provide an overview of the ecology and evolutionary adaptations of IAVs, with a focus on a review of the molecular factors that enable interspecies transmission of the various virus gene segments.

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“…In addition to the polybasic cleavage site, HPAI H7 HAs contain a peptide insert upstream of the HA cleavage site to increase the accessibility of the cleavage site to proteases (22). In other situations (most notably with equine H7N7 viruses), the addition of 11 amino acids adjacent to the cleavage site allowed increased cleavage and fusion activation (34,35), presumably by repositioning and increasing accessibility of the cleavage site motif. The impact of these types of modifications for H9 influenza virus has not been evaluated.…”

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A Novel Activation Mechanism of Avian Influenza Virus H9N2 by Furin

Tse

Hamilton

Friling

et al. 2014

J Virol

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bAvian influenza virus H9N2 is prevalent in waterfowl and has become endemic in poultry in Asia and the Middle East. H9N2 influenza viruses have served as a reservoir of internal genes for other avian influenza viruses that infect humans, and several cases of human infection by H9N2 influenza viruses have indicated its pandemic potential. Fortunately, an extensive surveillance program enables close monitoring of H9N2 influenza viruses worldwide and has generated a large repository of virus sequences and phylogenetic information. Despite the large quantity of sequences in different databases, very little is known about specific virus isolates and their pathogenesis. Here, we characterize a low-pathogenicity avian influenza virus, A/chicken/Israel/810/2001 (H9N2) (Israel810), which is representative of influenza virus strains that have caused severe morbidity and mortality in poultry farms. We show that under certain circumstances the Israel810 hemagglutinin (HA) can be activated by furin, a hallmark of highly pathogenic avian influenza virus. We demonstrate that Israel810 HA can be cleaved in cells with high levels of furin expression and that a mutation that eliminates a glycosylation site in HA 1 allows the Israel810 HA to gain universal cleavage in cell culture. Pseudoparticles generated from Israel810 HA, or the glycosylation mutant, transduce cells efficiently. In contrast, introduction of a polybasic cleavage site into Israel810 HA leads to pseudoviruses that are compromised for transduction. Our data indicate a mechanism for an H9N2 evolutionary pathway that may allow it to gain virulence in a distinct manner from H5 and H7 influenza viruses.

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Acquisition of a novel eleven amino acid insertion directly N-terminal to a tetrabasic cleavage site confers intracellular cleavage of an H7N7 influenza virus hemagglutinin

Cited by 8 publications

References 54 publications

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

The ecology and adaptive evolution of influenza A interspecies transmission

A Novel Activation Mechanism of Avian Influenza Virus H9N2 by Furin

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