The emergence of the COVID-19 pandemic prompted an intense effort to understand how the SARS-CoV-2 virus infects human cells. Research identified a protein on the surface of our cells, Transmembrane Serine Protease 2 (TMPRSS2), as a significant factor in this process. Understanding the function of TMPRSS2 became a focus for developing a response to the health challenge.
The Function of the TMPRSS2 Protein
Transmembrane Serine Protease 2 is a serine protease, a type of protein expressed on the surface of cells. These proteins function as molecular scissors, cleaving, or cutting, other proteins at specific sites as part of many normal biological processes. While its exact physiological role is still under investigation, TMPRSS2 is present in various tissues.
TMPRSS2 is found on epithelial cells, which line the surfaces of organs and cavities. It is expressed in the respiratory tract, including the nasal cavity, bronchial passages, and lungs, as well as in the digestive tract. Before the COVID-19 pandemic, studies had already shown its involvement in infections with other viruses.
The Viral Entry Mechanism
The entry of SARS-CoV-2 into a human cell is a multi-step process relying on two proteins on the host cell’s surface: ACE2 and TMPRSS2. The initial contact is made when the virus’s spike protein binds to the Angiotensin-Converting Enzyme 2 (ACE2) receptor. This binding acts as a docking mechanism that secures the virus to the cell.
Following this attachment, TMPRSS2 acts as molecular scissors, cutting the virus’s spike protein. This cleavage, or “priming,” activates the spike protein, causing it to change shape. This structural change allows the viral membrane to fuse with the human cell membrane.
Once the membranes are fused, the virus releases its genetic material into the cell’s interior, hijacking the cell’s machinery to produce more copies. While ACE2 serves as the docking point, or “doorknob,” the action of TMPRSS2 “turns the key,” unlocking the door for the virus.
This dependence on TMPRSS2 for entry is a feature shared with other respiratory viruses, including the original SARS-CoV and various influenza viruses. However, some variants of SARS-CoV-2, like Omicron, have shown a reduced dependence on this pathway in laboratory settings, preferring an alternative. Studies in animal models indicate that TMPRSS2 still plays a part in the efficient spread of Omicron within the respiratory tract, suggesting the pathway remains a significant contributor to infection.
Impact on COVID-19 Severity and Symptoms
The amount of TMPRSS2 expressed in tissues like the lungs and airways is thought to influence the course of a COVID-19 infection. Higher levels of TMPRSS2 could lead to more efficient viral entry and faster replication, potentially resulting in more severe disease. The abundance of both ACE2 and TMPRSS2 in respiratory cells helps explain why the respiratory system is the primary site of infection for SARS-CoV-2.
The expression of TMPRSS2 is not uniform among all individuals and may be influenced by factors including genetics and hormonal regulation. For instance, research has explored if sex steroids could modulate TMPRSS2 expression, which might contribute to observed differences in disease severity between sexes. These variations in protein levels could be a factor in the wide spectrum of clinical outcomes seen in patients.
Therapeutic Strategies Targeting TMPRSS2
The role of TMPRSS2 in viral entry has made it a target for therapeutic intervention. The primary strategy involves developing drugs known as TMPRSS2 inhibitors. These molecules are designed to block the protein’s enzymatic action, disabling the “molecular scissors” before they can activate the SARS-CoV-2 spike protein. This prevents the virus from fusing with the cell membrane and initiating infection.
Inhibiting TMPRSS2 appears to have minimal negative effects, as animal models where the gene for TMPRSS2 was knocked out did not show significant health problems. This suggests that blocking its function pharmacologically could be a safe approach, which has encouraged research into various compounds.
Several potential TMPRSS2 inhibitors have been studied, including repurposed drugs. One example is camostat mesylate, a protease inhibitor used in Japan for other conditions, which was shown in cell culture studies to partially block SARS-CoV-2 entry. Research into these inhibitors continues, but the emergence of viral variants with different entry preferences has complicated the therapeutic landscape.