Japanese study reveals that Omicron variants prefer Endosomal Cathepsin L for viral entry over TMPRSS2
Nikhil Prasad Fact checked by:Thailand Medical News Team Aug 29, 2024 2 months, 2 weeks, 4 days, 20 hours, 28 minutes ago
Medical News: In a groundbreaking study, researchers from Nagasaki University in Japan have uncovered significant findings about how the Omicron variants of the SARS-CoV-2 virus, responsible for COVID-19, gain entry into human cells. Unlike previous variants such as Delta, which primarily utilized a protein called TMPRSS2, the Omicron variants have shown a preference for using a different protein, cathepsin L, to facilitate their entry into cells. This discovery could have crucial implications for understanding the virus's behavior including all the current circulating variants that are descendants of the Omicron and developing targeted treatments.
The Shift in Viral Entry Mechanism
The study was conducted by a team of researchers from the Department of Emerging Infectious Diseases at Nagasaki University, led by Yasuteru Sakurai and Jiro Yasuda. This
Medical News report will delve into the details of their research, which examined several Omicron subvariants, including BA.1, BA.2, BA.5, BQ.1.1, and XBB.1, in comparison to the Delta variant. The researchers focused on understanding how these subvariants enter human cells and how their entry mechanisms differ from previous strains.
The SARS-CoV-2 virus, like other coronaviruses, enters human cells through a process that involves the spike protein on its surface binding to receptors on the host cell. Once attached, the virus must undergo a series of steps that allow it to fuse with the host cell membrane and release its genetic material into the cell, initiating infection. In the case of earlier variants, this process heavily relied on the TMPRSS2 protein, which is found on the surface of cells, particularly in the lungs and respiratory tract.
However, the research by Nagasaki University revealed that Omicron variants have adapted to use a different pathway. Instead of depending on TMPRSS2, these variants preferentially utilize cathepsin L, a protease found within the endosomes of cells, to facilitate their entry. This shift in entry mechanism marks a significant evolution in the virus's ability to infect human cells.
Implications of the Findings
The study's findings have profound implications for understanding the transmission and pathogenicity of Omicron variants.
The use of cathepsin L for viral entry suggests that Omicron variants may have a broader range of target cells in the human body, including those in the nasal and gastrointestinal tracts. This could potentially explain the high transmissibility and altered symptom profile associated with Omicron infections.
Moreover, the shift away from TMPRSS2 could impact the effectiveness of existing treatments and preventative measures. Many antiviral drugs and therapeutic strategies developed early in the pandemic were designed to inhibit TMPRSS2 and block the virus's entry into cells. With Omicron's preference for cathepsin L, these treatments may be less effective, necessitating the development of new antiviral therapies that target the endosomal pathway.
Detailed Study Findings
The researchers conducted a series of experiments using human cell lines derived from different tissues, including the upper and lower airways and the intestinal tract. They compared the replication capacities and cell entry mechanisms of v
arious Omicron subvariants with those of the Delta variant.
One key observation was that while the Delta variant showed high efficiency in entering cells via the TMPRSS2 pathway, all tested Omicron variants demonstrated a preference for the endosomal cathepsin L pathway. This was confirmed through experiments using inhibitors that block either TMPRSS2 or cathepsin L. The results showed that inhibiting cathepsin L significantly reduced the entry of Omicron variants into cells, while inhibiting TMPRSS2 had little effect.
Additionally, the study found that the spike proteins of Omicron variants exhibit less efficient cleavage at the S1/S2 junction, a critical step for viral entry that is usually facilitated by host cell proteases like furin and TMPRSS2. However, recent Omicron subvariants such as BQ.1.1 and XBB.1.5 showed improved cleavage efficiency, which could contribute to their higher replication rates and increased fitness in human cells.
Evolution of the Omicron Variant
The study also highlighted the progressive adaptation of Omicron variants to human cells. Over time, these variants have evolved to optimize their use of the endosomal entry pathway, likely in response to selective pressures within the human population. This adaptation may have been driven by the widespread immunity from previous infections and vaccinations, which could have favored the emergence of variants with alternative entry mechanisms.
Moreover, the researchers observed that recent Omicron subvariants, particularly those in the BQ and XBB lineages, exhibit higher replication efficiency in a variety of human cell types. This suggests that these variants have become more adept at infecting different tissues, potentially leading to more severe or diverse clinical outcomes.
Conclusion
In conclusion, this study by researchers from Nagasaki University provides critical insights into the evolving nature of the SARS-CoV-2 virus, particularly the Omicron variants. The discovery that Omicron prefers endosomal cathepsin L over TMPRSS2 for viral entry not only deepens our understanding of the virus's biology but also underscores the need for updated therapeutic strategies. As the virus continues to evolve, ongoing research will be essential in developing effective treatments and preventing future outbreaks.
The study findings were published in the peer-reviewed journal mSphere.
https://journals.asm.org/doi/10.1128/msphere.00338-24
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