Microbiota-Derived Corisin Increases Procoagulant Activity During SARS-CoV-2 Infection!

COVID-19 News: The ongoing COVID-19 pandemic caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with millions of infections and deaths reported worldwide. Coagulopathy, characterized by abnormal blood clotting, has emerged as a critical contributor to morbidity and mortality in COVID-19 patients. Understanding the complex interplay between the microbiota and coagulation system activation during SARS-CoV-2 infection is crucial for developing targeted therapeutic interventions.


Microbiota-Derived Corisin Increases Procoagulant Activity During SARS-CoV-2 Infection
Anticorisin antibody reduces markers of coagulation activation in mice with ALI. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected and the levels of tissue factor, fibrinogen, thrombin-antithrombin complex (TAT), and D-dimer were measured by enzyme immunoassays (A). Lung tissue was stained for fibrinogen/fibrin and the stained area was quantified. To quantify the fibrinogen/fibrin840 positive stained area, an investigator blinded to the treatment group randomly took microphotographs of five microscopic fields from the lung of each mouse and measured the fibrinogen/fibrin-stained area. (B, C). Scale bar 50 µm. Number of mice in A panel: n=3 in the SAL/SAL, Poly-IC/SAL and SARS/SAL groups, n=9 in the Poly845 IC/SARS/IgG group, and n=8 in the Poly-IC/SARS/anticorisin group. Number of mice in B and C panels: n=3 in the SAL/SAL, Poly-IC/SAL and SARS/SAL groups, n=4 in the Poly-IC/SARS/IgG group, and Poly-IC/SARS/anticorisin groups.

A new study that is covered in this COVID-19 News report, that was conducted by researchers from Mie University, Edobashi-Japan, University of Illinois at Urbana-Champaign-USA and Tosei General Hospital, Aichi-Japan has found that microbiota-derived Corisin increases procoagulant activity during SARS-CoV-2 infection!
 
Coagulation Challenges in COVID-19
COVID-19 patients often experience hypercoagulability, leading to severe complications such as deep vein thrombosis, thromboembolic events, and disseminated intravascular coagulation. The coagulation abnormalities observed in COVID-19 have been attributed to increased activation of platelets and elevated levels of various procoagulant factors. This imbalance in the coagulation system can result in life-threatening complications affecting multiple organs.
 
Microbiota Dysbiosis and its Impact
The microbiota, a diverse community of microorganisms inhabiting the human body, plays a crucial role in maintaining overall health. Dysbiosis, an imbalance in the microbiota composition, has been linked to the severity of various diseases, including COVID-19. Studies have shown associations between dysbiosis and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), both severe complications of COVID-19. The dysbiosis observed in COVID-19 patients involves alterations in the gut and respiratory microbiota, contributing to disease severity.
 
t; Corisin: A Microbiota-Derived Player
Recent research has identified a microbiota-derived proapoptotic peptide named corisin, which has been implicated in the exacerbation of pulmonary fibrosis and ALI in experimental animal models. Corisin levels have been found to be significantly elevated in the bronchoalveolar lavage fluid and serum of patients with idiopathic pulmonary fibrosis experiencing acute exacerbation. Moreover, treatment with an anticorisin monoclonal neutralizing antibody has shown promise in ameliorating lipopolysaccharide-induced ALI in experimental models.
 
The Correlation Between Corisin and Coagulation Activation
Building on these findings, a recent cross-sectional study involving 47 COVID-19 patients sought to investigate the role of corisin in coagulation system activation during SARS-CoV-2 infection. The study revealed that COVID-19 patients exhibited significantly elevated circulating levels of corisin, along with increased levels of thrombin-antithrombin complex, D-dimer, soluble thrombomodulin, tumor necrosis factor-α, and monocyte-chemoattractant protein-1. Simultaneously, the levels of free protein S were reduced compared to healthy subjects.
 
Corisin and Thrombin-Antithrombin Complex: A Strong Connection
Remarkably, the study found a significant correlation between the levels of thrombin-antithrombin complex, D-dimer, and corisin in COVID-19 patients. To further investigate this relationship, a monoclonal anticorisin neutralizing antibody was employed in a SARS-CoV-2 spike protein-associated acute lung injury mouse model. The results demonstrated that the antibody significantly inhibited the inflammatory response and coagulation system activation. Additionally, the levels of corisin and thrombin-antithrombin complex were found to be significantly correlated in the animal model.
 
Corisin's Direct Impact on Coagulation
In vitro experiments were conducted to delve deeper into the mechanisms underlying corisin's role in coagulation activation. The findings revealed that corisin increased tissue factor activity while decreasing the anticoagulant activity of thrombomodulin in various cell types, including alveolar epithelial cells, endothelial cells, and monocytic cells. These results suggest that corisin may directly enhance the procoagulant activity in these cell types, contributing to the coagulopathy observed in COVID-19 patients.
 
Corisin Release in SARS-CoV-2 Infection
The significant increase in circulating levels of corisin in COVID-19 patients represents a novel and noteworthy finding. This observation was further validated in a mouse acute lung injury model induced by a combination of SARS-CoV-2 spike protein and poly-IC. The model exhibited markedly elevated corisin levels compared to control mice, highlighting the potential contribution of corisin to the pathological processes associated with SARS-CoV-2 infection.
 
Potential Sources of Corisin and Dysbiosis
The origin of corisin during SARS-CoV-2 infection remains a subject of exploration. While corisin was initially isolated from the lung microbiome, it is unclear whether the lung microbiome is the primary source during SARS-CoV-2 infection. Previous studies suggest that transglycosylases containing corisin may be secreted by various commensal or opportunistic bacteria found in the gut, oral, lung, or skin microbiota. Dysbiosis in these microbiota populations, observed in COVID-19 patients, may contribute to the elevated corisin levels in systemic circulation.
 
Corisin and Dysbiosis - A Vicious Cycle
The mechanism by which dysbiosis leads to increased corisin release during SARS-CoV-2 infection remains unclear. However, it is plausible that SARS-CoV-2 infection induces an abnormal host cell response, triggering a "cytokine storm" and potentially overactivating microbiome-associated organisms secreting corisin. This scenario could lead to the heightened systemic release of corisin, exacerbating coagulation activation.
 
Therapeutic Implications and Future Directions
The study's findings support the notion that corisin plays a crucial and direct role in the activation of the coagulation system during SARS-CoV-2 infection. Therapeutically targeting corisin with the use of an anticorisin monoclonal neutralizing antibody demonstrated promising outcomes in mitigating both the inflammatory response and coagulation system activation in the animal model. This suggests a potential avenue for therapeutic intervention to alleviate the dual impact of corisin on inflammation and coagulation.
 
Conclusion
In summary, the intricate relationship between microbiota-derived corisin and coagulation activation during SARS-CoV-2 infection sheds light on a previously underexplored aspect of COVID-19 pathogenesis. The study's findings underscore the importance of understanding the role of dysbiosis and microbiota-derived factors in the complexities of COVID-19-associated coagulopathy. Further research in larger patient cohorts is needed to validate these results and explore the potential of corisin-targeted therapies as a novel approach to managing coagulation abnormalities in COVID-19 patients.
 
The study findings were published in the peer reviewed journal: Journal of Thrombosis and Haemostasis.
https://www.jthjournal.org/article/S1538-7836(24)00118-1/pdf
 
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https://pubmed.ncbi.nlm.nih.gov/38453025/
 
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