Research led by SCM identifies new cell-entry mechanism of SARS-CoV-2 and therapeutic target for COVID-19

28 December 2022

 

A research team led by Dr. Xavier Wong, Assistant Professor of the Teaching and Research Division of SCM, in collaboration with Dr. Yuan Shuofeng, Assistant Professor of the Department of Microbiology at The University of Hong Kong, has identified a protease named MT1-MMP as a major host factor for SARS-CoV-2 infection and the mechanism by which this protease promotes viral cell entry by targeting a receptor protein called angiotensin-converting enzyme 2 (ACE2).  Their research findings were published in the internationally-renowned scientific journal Nature Communications.

SARS-CoV-2 is responsible for the global outbreak of coronavirus disease 2019 (COVID-19), associated with high mortality, especially among the elderly population.  Vaccines changed the course of the COVID-19 pandemic by training the immune system to recognise and clear the SARS-CoV-2 virus.  However, they are not always effective in individuals with a weak immune system, or against some viral variants.  Moreover, despite international efforts to boost vaccination coverage, not everyone has access to vaccines, owing to their cost and disparities in distribution across regions.  A huge challenge in managing COVID-19 in this post-vaccine era is preventing SARS-CoV-2 infection in high-risk unvaccinated groups.  Therefore, understanding the cell-entry mechanism of SARS-CoV-2 is of high priority to curb its spread. 
Found on the membrane of human cells, ACE2 acts as the main doorway through which SARS-CoV-2 enters and infects human cells.  Despite the lung being the major route of SARS-CoV-2 infection, only a small population of lung cells express ACE2.  It remains unknown how SARS-CoV-2 infects lung cells without the expression of ACE2.  In the study, the researchers found that SARS-CoV-2 infection leads to increased activation of MT1-MMP, which releases a soluble form of ACE2 from ACE2-expressing cells.  This soluble ACE2 in turn binds to SARS-CoV-2 and carries it into cells without ACE2 expression.  Their findings reveal a new mechanism by which the virus hijacks host enzymes to enhance its infectivity, triggering multiorgan infections. 

To study MT1-MMP’s functions and how it promotes viral infection, they used human cells to create organoids, a 3D tissue structure grown in vitro to resemble and model different organs in the laboratory. Through the organoid experiments, they discovered that blocking MT1-MMP activities with a specific antagonist (3A2) effectively reduced soluble ACE2 levels and the infection of SARS-CoV-2 including the original strain and variants of concerns in organoid models of the human lung, heart and liver. To confirm these findings in living animals in old age, a major risk factor of COVID-19, they treated aged mice with 3A2 and showed that the drug prevented the infection of virulent SARS-CoV-2 and dramatically alleviated tissue damages resulted from infection. 

Antivirals for SARS-CoV-2 should not only be efficacious in people with a well-functioning immune system.  Besides, they should not act on the virus directly as it can potentially mutate to overcome immune defenses.  3A2 - the drug identified by the team - meets both of these requirements.  It does not target the immune system or the virus itself.  In addition, in previous studies published in Nature Metabolism and Nature Communications, the team has demonstrated that 3A2 also offers protection against obesity and diabetes, two major risk factors of COVID-19.  Therefore, it could be effective in protecting people with weak immunity and metabolic dysfunctions against viral infections.  It could also be effective in managing future coronavirus pandemics, because ACE2 is a doorway for many such viruses.

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