Abstract
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.
Highlights
Coronaviruses are a wide-ranging family of viruses that infect many species of birds and mammals, including humans (Woo et al, 2009). They possess a remarkable ability for interspecies transmission as exemplified by the emergence of the deadly human virus severe acute respiratory syndrome coronavirus (SARS-CoV) (Drosten et al, 2003; Peiris et al, 2003, 2004), and more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), both of which are thought to have originated in bats (Li et al, 2005b; Wang et al, 2014), followed by an intermediate host stage (Alagaili et al, 2014; Haagmans et al, 2013; Hemida et al, 2014; Wang and Eaton, 2007), before crossing into the human population (Drexler et al, 2014)
It was shown for bovine respiratory syncytial virus (RSV) that the dual cleavage events generated a small peptide fragment, the virokinin, which is released upon activation and entry and has bioactive properties implicated in exacerbating pathogenesis (Valarcher et al, 2006; Zimmer et al, 2003)
It has become more appreciated that the protease-mediated activation of membrane fusion is a versatile process that can be exploited by coronaviruses for the basic requirement of entry into host cells, and to modulate this entry process and allow changes in cell, tissue and species tropism
Summary
Coronaviruses are a wide-ranging family of viruses that infect many species of birds and mammals, including humans (Woo et al, 2009). Certain viruses harboring class I viral fusion proteins, like influenza virus and Newcastle disease virus, display characteristically expanded or modified cell and tissue tropism, and altered viral pathogenesis following mutation of the cleavage site that results in a change in proteolytic activation (Klenk and Garten, 1994b) This is very well exemplified by the hemagglutinin (HA) protein of highly pathogenic avian influenza (HPAI) virus strains, where transition from a monobasic site, typically cleaved by trypsin-like proteases, to a polybasic site, allows cleavage by ubiquitously expressed furin-like proteases, enabling systemic spread of the virus within an infected host. We propose using protease sequence recognition motifs on coronavirus S protein as a novel marker to assess pathogenicity and host range, as well as forming the basis for effective therapeutic intervention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
