Human matriptase/ST 14 proteolytically cleaves H7N9 hemagglutinin and facilitates the activation of influenza A/Shanghai/2/2013 virus in cell culture

Abstract

Background: Influenza is a zoonotic disease that infects millions of people each year resulting in hundreds of thousands of deaths, and in turn devastating pandemics.Influenza is caused by influenza viruses, including influenza A virus (IAV). There are many subtypes of IAV but only a few seem to be able to adapt to humans and to cause disease. In 2013, an H7N9 IAV subtype emerged in China that does not cause clinical symptoms in its chicken host but leads to severe infections when transmitted into humans. Since 2013, there have been six epidemic waves of H7N9 with 1567 laboratory-confirmed human infections and 615 deaths. Pathogenicity of IAV is complex, but a crucial feature contributing to virulence is the activation of the hemagglutinin (HA) fusion protein by host proteases that triggers membrane fusion and leads to subsequent virus propagation. Methods: 293T, VERO, and MDCK cells were used to conduct Western blot analysis, immunofluorescence assays, and pseudoparticle and live virus infections, and to evaluate H7N9 HA cleavage-activation. Results/Conclusions: We show that human matriptase/ST 14 is able to cleave H7N9 HA. Cleavage of H7N9 HA expressed in cell culture results in fusogenic HA and syncytia formation. In infection studies with viral pseudoparticles carrying matriptase/ ST 14-activated H7N9 HA, we observed a high infectivity of cells. Finally, human matriptase/ST 14 also activated H7N9 live virus which resulted in high infectivity.Our data demonstrate that human matriptase/ST 14 is a likely candidate protease to promote H7N9 infections in humans.

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

“…The reports demonstrating that TMPRSS2 is crucial for H1N1 and H7N9 virus propagation in mice and cell culture suggest that it also plays a major role in the human respiratory tract. So far, however, it is unclear whether the obtained results translate to humans and other studies have shown that for example human matriptase is able to process H1N1 and H7N9 (Hamilton and Whittaker, 2013;Whittaker and Straus, 2019). Our peptide assay suggests that SPINT2 has a wide variety of host protease specificity.…”

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

“…In addition to being novel drugs, selective TMRSS2 inhibitors can be used as valuable chemical probes to help elucidate mechanisms of viral pathogenesis, including host cellÀvirus interactions, Spike protein processing, and ACE2 receptor binding. Since TMPRSS2 plays a key role as a viral protein processing protease in the pathogenesis of other coronaviruses (SARS-CoV, MERS-CoV) as well as influenza viruses (25,(54)(55)(56)(57)(58), MM3122 and this new class of inhibitors may be effective not only against COVID-19 but for infections caused by most or all corona and influenza viruses. Thus, these small-molecule inhibitors of TMPRSS2 not only hold much promise as new drugs to treat SARS-CoV-2 infections but also potentially represent broad-spectrum antivirals.…”

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

“…In addition to being novel drugs, selective TMRSS2 inhibitors can be used as valuable chemical probes to help elucidate mechanisms of viral pathogenesis, including host cell-virus interactions, Spike protein processing and ACE2 receptor binding. Since TMPRSS2 plays a key role as a viral protein processing protease in the pathogenesis of other coronaviruses (SARS-CoV, MERS-CoV) as well as influenza viruses [47][48][49][50][51][52] , MM3122 and this new class of inhibitors may be effective not only against COVID-19 but for infections caused by most or all corona and influenza viruses. Thus, these small-molecule inhibitors of TMPRSS2 not only hold much promise as new drugs to treat SARS-CoV-2 infections but also potentially represent broad-spectrum antivirals.…”