Nikhil Prasad Fact checked by:Thailand Medical News Team May 31, 2024 6 months, 1 week, 5 days, 45 minutes ago
COVID-19 News: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has presented a wide range of clinical outcomes, from mild symptoms to severe pneumonia and acute respiratory distress syndrome (ARDS). Understanding the molecular mechanisms that lead to severe COVID-19 cases is crucial for developing effective treatments. One area of research focuses on the enzyme a disintegrin and metalloproteinase-17 (ADAM-17) and its interaction with angiotensin-converting enzyme 2 (ACE2), the receptor used by SARS-CoV-2 to enter host cells. This
COVID-19 News report explores the implications of ADAM-17 activity in severe COVID-19, its relationship with ACE2, and potential therapeutic targets.
The estimated ADAM-17 activity in the relationship with COVID-19: (A) ADAM-17 substrate z-scores are higher in COVID-19 patients with severe disease on days 0 (n = 305, of whom n = 80 had severe COVID-19), 3 (n = 214, of whom n = 75 had severe COVID-19) and 7 (n = 138, of whom n = 68 had severe COVID-19). For the analyses of the present study, we defined patients with scores 1–3 as with severe illness, and scores 4–6 as non-severe illness, based on the WHO COVID-19 outcome scale; and (B) ADAM-17 substrate z-scores at baseline (day 0) are higher in patients who died from COVID-19 (n = 42) than COVID-19+ survivals (n = 263) until day 28. (C) ADAM-17 substrate z-scores positively correlate with soluble ACE2 on days 0, 3 and 7, respectively.
ADAM-17 and Its Substrates
ADAM-17 is an enzyme known for its role in shedding various membrane-bound proteins, including ACE2. This shedding process can trigger pro-inflammatory pathways, influencing the severity of COVID-19. Increased ADAM-17 activity has been associated with several chronic diseases that are also risk factors for severe COVID-19, such as cardiovascular disease and diabetes.
Study Overview
The study conducted by Lund University and Skåne University Hospital aimed to investigate the relationship between ADAM-17 activity and COVID-19 severity. Using data from the Massachusetts General Hospital COVID-19 study, researchers analyzed plasma levels of 33 different ADAM-17 substrates in 306 COVID-19 patients and 78 symptomatic controls. They calculated an ADAM-17 substrate score as a surrogate for cellular ADAM-17 activity and examined its association with disease severity, mortality, and levels of soluble ACE2 (sACE2).
Key Findings
-Increased ADAM-17 Activity in Severe COVID-19
The study found that increased ADAM-17 activity, as estimated by the ADAM-17 substrate score, was significantly associated with the severity of COVID-19 (p = 0.001). Although the association with mortality did not reach statistical significance (p = 0.06), the trend suggested a potential link. Soluble ACE2 levels showed a strong positive correlation with the ADAM-17 substrate score, followed by renin, interleukin-6
(IL-6), and lung injury biomarkers.
-Tissue-Specific Expression of ACE2 and ADAM-17
Using data from the Genotype-Tissue Expression (GTEx) database, researchers examined ACE2 and ADAM-17 gene expression across various tissues. They found that the ratio of ADAM-17 to ACE2 gene expression was highest in the lungs, which may explain why the lungs are particularly vulnerable to COVID-19. This tissue-specific expression pattern highlights the potential for differential impacts of SARS-CoV-2 infection in various organs.
-Age and Sex Differences
The study also explored age and sex differences in ACE2 and ADAM-17 gene expression. ACE2 expression decreased with age in the aorta and transverse colon for both sexes, while ADAM-17 expression increased with age in the kidneys and decreased in the colon. These findings suggest that the interaction between ADAM-17 and ACE2 may vary with age and sex, potentially influencing the risk and severity of COVID-19.
Mechanisms of ADAM-17 and ACE2 Interaction
The positive correlation between sACE2 levels and the ADAM-17 substrate score suggests a joint mechanism involving mACE2 shedding, dysregulated renin-angiotensin system (RAS) signaling, and immune regulation. Plasma sACE2 levels were also associated with markers of epithelial and lung injury, indicating that sACE2 levels may reflect both direct pulmonary injury and systemic inflammation.
Implications for Treatment
The findings of this study suggest that targeting ADAM-17 could be a promising therapeutic strategy for treating severe COVID-19. However, the timing and context of ADAM-17 inhibition are crucial. Some studies have shown that inhibiting ADAM-17 can reduce viral replication in cell cultures, while others indicate increased viral loads in the lungs of mice with inhibited ADAM-17 activity. This complexity underscores the need for further research to determine the optimal conditions for ADAM-17 inhibition in COVID-19 treatment.
Conclusion
This study highlights the significant role of ADAM-17 activity in the severity of COVID-19 and its potential as a therapeutic target. The tissue-specific expression patterns of ACE2 and ADAM-17, along with age and sex differences, provide valuable insights into the pathophysiology of COVID-19. Further research is needed to explore the therapeutic potential of ADAM-17 inhibition and to better understand the complex interactions between these molecules in the context of COVID-19.
By deepening our understanding of the molecular mechanisms underlying severe COVID-19, we can develop more targeted and effective treatments to combat this global pandemic.
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/25/11/5911
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