The role of host cell glycans on virus infectivity: The SARS-CoV-2 case

Long and complex chains of sugars, called glycans, often coat both the cell and protein surface. Glycans both modulate specific interactions and protect cells. On the cell surface, these sugars form a cushion known as the glycocalyx. Here, we show that Heparan Sulfate (HS) chains - part of the glycocalyx - and other glycans - expressed on the surface of both host and virus proteins - have a critical role in modulating both attractive and repulsive potentials during viral infection. We analyse the SARS-CoV-2 virus, modelling its spike proteins binding to HS chains and two key entry receptors, ACE2 and TMPRSS2. We include the volume exclusion effect imposed on the HS chains impose during virus insertion into glycocalyx and the steric repulsion caused by changes in the conformation of the ACE2 glycans involved in binding to the spike. We then combine all these interactions, showing that the interplay of all these components is critical to the behaviour of the virus. We show that the virus tropism depends on the combinatorial expression of both HS chains and receptors. Finally, we demonstrate that when both HS chains and entry receptors express at high density, steric effects dominate the interaction, preventing infection.

A New Transmission Route for the Propagation of the SARS-CoV-2 Coronavirus

Background: Starting late 2019, a novel coronavirus spread from the capital of the Hubei province in China to the rest of the country, then to most of the world. To anticipate future trends in the development of the pandemic, we explore here, based on public records of infected persons, how variation in the virus tropism could end up in different patterns, warranting a specific strategy to handle the epidemic. Methods: We use a compartmental model to describe the evolution of an individual through several possible states: susceptible, infected, alternative infection, detected, and removed. We fit the parameters of the model to the existing data, taking into account significant quarantine changes where necessary. Results: The model indicates that Wuhan quarantine measures were effective, but that alternative virus forms and a second propagation route are compatible with available data. For the Hong Kong, Singapore, and Shenzhen regions, the secondary route does not seem to be active. Conclusions: Hypotheses of an alternative infection tropism (the gut tropism) and a secondary propagation route are discussed using a model fitted by the available data. Corresponding prevention measures that take into account both routes should be implemented to the benefit of epidemic control.

Hantavirus infection in type I interferon receptor-deficient (A129) mice

Type I interferon receptor knockout mice (strain A129) were assessed as a disease model of hantavirus infection. A range of infection routes (intramuscular, intraperitoneal and intranasal) were assessed using minimally passaged Seoul virus (strain Humber). Dissemination of virus to the spleen, kidney and lung was observed at 5 days after intramuscular and intraperitoneal challenge, which was resolved by day 14. In contrast, intranasal challenge of A129 mice demonstrated virus tropism to the lung, which was maintained to day 14 post-challenge. These data support the use of the A129 mouse model for future infection studies and the in vivo evaluation of interventions.

In plain sight: the role of alpha-1-antitrypsin in COVID-19 pathogenesis and therapeutics

ABSTRACTEntry of SARS-CoV-2 is facilitated by endogenous and exogenous proteases. These proteases proteolytically activate the SARS-CoV-2 spike glycoprotein and are key modulators of virus tropism. We show that SARS-CoV-2 naïve serum exhibits significant inhibition of SARS-CoV-2 entry. We identify alpha-1-antitrypsin (AAT) as the major serum protease inhibitor that potently restrict protease-mediated entry of SARS-CoV-2. AAT inhibition of protease-mediated SARS-CoV-2 entry in vitro occurs at concentrations far below what is present in serum and bronchoalveolar tissues, suggesting that AAT effects are physiologically relevant. Moreover, AAT deficiency affects up to 20% of the population and its symptomatic manifestations coincides with many risk factors associated with severe COVID-19 disease. In addition to the effects that AAT may have on viral entry itself, we argue that the anti-inflammatory and coagulation regulatory activity of AAT have implications for coronavirus disease 2019 (COVID-19) pathogenicity, SARS-CoV-2 tissue restriction, convalescent plasma therapies, and even potentially AAT therapy.

Recombinant SARS-CoV-2 spike proteins for sero-surveillance and epitope mapping

The newly emergent SARS-CoV-2 coronavirus is closely related to SARS-CoV which emerged in 2002. Studies on coronaviruses in general, and SARS in particular, have identified the virus spike protein (S) as being central to virus tropism, to the generation of a protective antibody response and to the unambiguous detection of past infections. As a result of this centrality SARS-CoV-2 S protein has a role in many aspects of research from vaccines to diagnostic tests. We describe a number of recombinant forms of SARS-CoV-2 S expressed in commonly available expression systems and their preliminary use in diagnostics and epitope mapping. These sources may find use in the current and future analysis of the virus and the Covid-19 disease it causes.

A new transmission route for the propagation of the SARS-CoV-2 coronavirus

Background: A novel coronavirus spread starting late 2019 from the capital of the Hubei province in China to the rest of the country, then to most of the world. To anticipate future trends in the development of the epidemic, we explore here, based on public records of infected persons how variation in the virus tropism could end up in different patterns, warranting specific way to handle the epidemic. Methods: We use a compartmental model to describe the evolution of an individual through several possible states: susceptible, infected, alternative infection, detected and removed. We t the parameters of the model to the existing data taking into account significant quarantine changes where necessary. Results: The model indicates that Wuhan quarantine measures were effective but that alternative virus forms and a second propagation route are compatible with available data. For Hong Kong, Singapore and Shenzhen region the secondary route does not seem to be active yet and the epidemic size limited. Conclusions: The alternative infection tropism (the gut tropism) and a secondary propagation route hypotheses are validated using a model fitted by the available data. Corresponding prevention measures that take into account both routes should be implemented to the benefit of epidemic control.

A new transmission route for the propagation of the SARS-CoV-2 coronavirus

BackgroundA novel coronavirus (SARS-CoV-2) spread from the capital of the Hubei province in China to the rest of the country, then to most of the world. To anticipate future trends in the development of the epidemic, we explore here, based on public records of infected persons how variation in the virus tropism could end up in different patterns, warranting specific way to handle the epidemic.MethodsWe use a compartmental model to describe the evolution of an individual through several possible states: susceptible, infected, alternative infection, detected and removed. We fit the parameters of the model to the existing data taking into account significant quarantine changes where necessary.ResultsThe model indicates that Wuhan quarantine measures were effective but that alternative virus forms and a second propagation route are compatible with available data. For Singapore and Shenzhen region the secondary route does not seem to be active yet and the epidemic size limited.ConclusionsThe alternative infection tropism (the gut tropism) and a secondary propagation route are validated hypotheses using a model fitted by the available data. Corresponding prevention measures that take into account both routes should be implemented to the benefit of epidemic control.