How does MT1-MMP contribute to COVID-19 infectivity?

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MT1-MMP Facilitates SARS-CoV-2 Entry into Cells

The protease MT1-MMP plays a significant role in the infectivity of SARS-CoV-2 by mediating the release of soluble angiotensin-converting enzyme 2 (ACE2). This soluble ACE2 then binds to the virus's spike proteins, effectively carrying the virus to cells with lower ACE2 expression and facilitating its entry, a mechanism demonstrated to be crucial for infection in various human tissues.
Soluble ACE2 Aids Viral Transport

SARS-CoV-2 relies on ACE2, a protein found on cell membranes, to enter human cells. However, ACE2 expression is not uniform across all tissues, and previous research indicated that a soluble form of ACE2 is involved in infecting organs with limited ACE2. The identified mechanism shows that MT1-MMP, activated by SARS-CoV-2 infection, cleaves ACE2 from the cell surface, releasing this soluble form. This soluble ACE2 then acts as a carrier, binding to the SARS-CoV-2 spike proteins and transporting the virus to cells that do not express sufficient ACE2 on their surface, thereby enabling infection.
Antibody 3A2 Shows Therapeutic Potential

Research has shown that blocking MT1-MMP activity with a humanised antibody, known as 3A2, can significantly reduce SARS-CoV-2 infection. In laboratory experiments using human organoids derived from lung, heart, and liver tissues, the application of 3A2 led to a 60-80% reduction in SARS-CoV-2 infection rates. This effect was observed consistently across different variants of the virus, including Delta and Omicron, suggesting MT1-MMP's broad relevance as a host factor.
Reduced Viral Load and Lung Damage in Animal Models

The therapeutic potential of inhibiting MT1-MMP was further validated in a mouse model of COVID-19. When treated with the 3A2 antibody, infected mice exhibited a reduction in viral load by nearly 90%. Furthermore, the treatment significantly alleviated the lung tissue damage that resulted from the infection, highlighting the impact of MT1-MMP activity on disease severity and organ pathology.

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How does MT1-MMP contribute to COVID-19 infectivity?

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