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Targeting the Complement-Sphingolipid System in COVID-19 and Gaucher Diseases: Evidence for a New Treatment Strategy
Vyoma Snehal Trivedi1, Albert Frank Magnusen1, Reena Rani1
1Cincinnati Children's Hospital Medical Center, Division of Human Genetics, 3333 Burnet Avenue, Building R1, MLC 7016, Cincinnati, OH 45229, USA.
Abstract:
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced disease (COVID-19) and Gaucher disease (GD) exhibit upregulation of complement 5a (C5a) and its C5aR1 receptor, and excess synthesis of glycosphingolipids that lead to increased infiltration and activation of innate and adaptive immune cells, resulting in massive generation of pro-inflammatory cytokines, chemokines and growth factors. This C5a-C5aR1-glycosphingolipid pathway- induced pro-inflammatory environment causes the tissue damage in COVID-19 and GD. Strikingly, pharmaceutically targeting the C5a-C5aR1 axis or the glycosphingolipid synthesis pathway led to a reduction in glycosphingolipid synthesis and innate and adaptive immune inflammation, and protection from the tissue destruction in both COVID-19 and GD. These results reveal a common involvement of the complement and glycosphingolipid systems driving immune inflammation and tissue damage in COVID-19 and GD, respectively. It is therefore expected that combined targeting of the complement and sphingolipid pathways could ameliorate the tissue destruction, organ failure, and death in patients at high-risk of developing severe cases of COVID-19.
Insights
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Gaucher disease share a common inflammatory pathway involving complement 5a (C5a) and glycosphingolipids. Targeting this pathway may reduce inflammation and tissue damage in both conditions.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced disease (COVID-19) and Gaucher disease (GD) are characterized by elevated complement 5a (C5a) and its receptor C5aR1.
- Both conditions involve excessive glycosphingolipid synthesis, leading to immune cell activation and pro-inflammatory cytokine release, causing tissue damage.
Purpose of the Study:
- To investigate the shared molecular pathways underlying immune inflammation and tissue damage in COVID-19 and Gaucher disease.
- To explore the therapeutic potential of targeting the C5a-C5aR1 axis and glycosphingolipid synthesis.
Main Methods:
- Pharmaceutical targeting of the C5a-C5aR1 axis.
- Intervention in glycosphingolipid synthesis pathways.
- Assessment of immune cell infiltration, cytokine production, and tissue damage markers.
Main Results:
- Targeting the C5a-C5aR1 axis or glycosphingolipid synthesis reduced glycosphingolipid levels and immune inflammation.
- Therapeutic interventions protected against tissue destruction in both COVID-19 and Gaucher disease models.
- A common C5a-C5aR1-glycosphingolipid pathway was identified as a driver of inflammation and tissue damage.
Conclusions:
- The complement and glycosphingolipid systems are critically involved in driving immune inflammation and tissue damage in both COVID-19 and Gaucher disease.
- Combined targeting of complement and sphingolipid pathways offers a potential therapeutic strategy to mitigate severe outcomes, including organ failure and death, in high-risk COVID-19 patients.
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