SARS-CoV-2 is activated for fusion by a broad range of proteases, finds study

NewsGuard 100/100 Score

It is well known that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds with the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface. This process facilitates host-virus membrane fusion, with cell entry achieved by host proteases.

The particular host protease utilized varies amongst betacoronaviruses, though SARS-CoV-2 appears to use cathepsins primarily, usually found in the late endosome, suggesting that SARS-CoV-2 enters the cell by the endocytotic pathway. MERS-CoV, by comparison, is thought to be activated predominantly by TMPRSS2, allowing entry directly at the cell surface, though SARS-CoV-2 has also been observed to use this mechanism.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

It is possible that multiple triggers are required to allow entry, or that multiple routes are equally possible depending on cell type, but studies that utilize targeted proteolytic inhibitors to investigate these mechanisms may disturb ordinary membrane composition and function.

In a new study recently released on the bioRxiv* preprint server, a team of researchers from the University of Virginia, USA, used single-virus fusion experiments with exogenously controlled proteases to investigate the mechanism of activation directly. They found that the subcellular location of entry depends on the protease activity of the various components, and parallel pathways are possible.

How was the study performed?

The group immobilized a host cell plasma membrane expressing ACE2 and low levels of TMPRSS2 in a microfluidic flow cell, and labeled the virus with a lipid-phase fluorophore. Proteases were then added to the flow cell, and where they facilitated cell entry, the fluorophores became dequenched to highlight the subcellular location. Vero cell membranes were used for this purpose, and minimal fusion was observed between these cells and the pseudoviruses employed in the absence of exogenous protease.

For comparison, Calu-3 cells, which express higher levels of TMPRSS2 and similar levels of ACE2, could be more easily entered by the pseudoviruses. The pseudoviruses consisted of a viral membrane sourced from either HIV, Indiana vesiculovirus (VSV), or murine leukemia viruses (MLV) expressing the SARS-CoV-2 spike protein. The group notes that the VSV membrane was able to support a greater density of the spike protein, and thus entered the cell more quickly than the others.

The group tested four exogenously introduced proteases in combination with the pseudoviruses: TMPRSS11D, also known as human airway trypsin-like (HAT) protease, a serine protease found in airway tissues; Cathepsins B and L, late endosomal proteases; and TMPRSS2, the cell surface protease found on alveolar cells. Each of these proteases was able to activate the SARS-CoV-2 spike protein for fusion, and they each showed similar fusion times.

Based on this, the group suggests that proteolytic activation can occur at any point, prior to or following bonding with ACE2: in the extracellular medium by HAT, at the cell surface by TMPRSS2, or within an endosome by the Cathepsins. One route of cell entry is likely to be favored in tissues or cells with a greater concentration of any of the particular proteases studied here.

Protease inhibitors are well-explored as drug leads against SARS-CoV-2. While often demonstrating impressive virus inhibition in vitro, often fall short at the in vivo stage, to which the authors attribute these multiple opportunistic pathways.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Journal references:

Article Revisions

  • Apr 8 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
Michael Greenwood

Written by

Michael Greenwood

Michael graduated from the University of Salford with a Ph.D. in Biochemistry in 2023, and has keen research interests towards nanotechnology and its application to biological systems. Michael has written on a wide range of science communication and news topics within the life sciences and related fields since 2019, and engages extensively with current developments in journal publications.  

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Greenwood, Michael. (2023, April 08). SARS-CoV-2 is activated for fusion by a broad range of proteases, finds study. News-Medical. Retrieved on May 24, 2024 from https://www.news-medical.net/news/20210506/SARS-CoV-2-is-activated-for-fusion-by-a-broad-range-of-proteases-finds-study.aspx.

  • MLA

    Greenwood, Michael. "SARS-CoV-2 is activated for fusion by a broad range of proteases, finds study". News-Medical. 24 May 2024. <https://www.news-medical.net/news/20210506/SARS-CoV-2-is-activated-for-fusion-by-a-broad-range-of-proteases-finds-study.aspx>.

  • Chicago

    Greenwood, Michael. "SARS-CoV-2 is activated for fusion by a broad range of proteases, finds study". News-Medical. https://www.news-medical.net/news/20210506/SARS-CoV-2-is-activated-for-fusion-by-a-broad-range-of-proteases-finds-study.aspx. (accessed May 24, 2024).

  • Harvard

    Greenwood, Michael. 2023. SARS-CoV-2 is activated for fusion by a broad range of proteases, finds study. News-Medical, viewed 24 May 2024, https://www.news-medical.net/news/20210506/SARS-CoV-2-is-activated-for-fusion-by-a-broad-range-of-proteases-finds-study.aspx.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Study reveals ferroptosis as a major driver of severe COVID-19 lung damage