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Review
. 2022 Nov 18;23(22):14340.
doi: 10.3390/ijms232214340.

_targeting the Complement-Sphingolipid System in COVID-19 and Gaucher Diseases: Evidence for a New Treatment Strategy

Vyoma Snehal Trivedi  1 , Albert Frank Magnusen  1 , Reena Rani  1 , Luca Marsili  2 , Anne Michele Slavotinek  1   3 , Daniel Ray Prows  1   3 , Robert James Hopkin  1   3 , Mary Ashley McKay  1 , Manoj Kumar Pandey  1   3
Affiliations
Review

_targeting the Complement-Sphingolipid System in COVID-19 and Gaucher Diseases: Evidence for a New Treatment Strategy

Vyoma Snehal Trivedi et al. Int J Mol Sci. .

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.

Keywords: inflammation; innate and adaptive immunity; lipid; rare-genetic disease; viral infection.

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Conflict of interest statement

Author affirms that that this manuscript was completed in absence of any commercial or financial interactions that could be interpreted as a potential conflict of interest.

Figures

Figure 1
Figure 1
Legend. Complement-Glycosphingolipid Axis leads to the tissue inflammation in patients with Coronavirus Disease 2019 (COVID-19) and Gaucher Disease (GD). The interaction of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) with its cellular receptor (e.g., angiotensin converting enzyme-2; ACE2) triggers the massive generation of complement 5a (C5a) by SARS-CoV-2 and/or glycosphingolipid (GSL; glucosylceramide; GC)-specific immunoglobulin G1 immune complexes (SARS-CoV-2/GSL-IgG1-ICs)-mediated classical, SARS-CoV-2-IgM-ICs-mediated alternative, and crosslinking of SARS-CoV-2 mannose-binding lectin (MBL)-mediated lectin pathway of complement activation (A,B). The interaction of C5a and its C5aR1 receptor triggers glucosylceramide synthase (GCS)-mediated excess synthesis of GSLs, which ameliorates SARS-CoV-2 replication (C), as well as the overproduction of cytokines, chemokines and growth factors (D). These pro-inflammatory mediators cause excess tissue recruitment and activation of innate and adaptive immune cells, i.e., polymorphonuclear cell (PMN), monocytes (MO), macrophage (Mɸ), dendritic cell (DC), T cells, and the resulting excess production of pro-inflammatory cytokines (E; and listed in Table 1, Table 2, Table 3 and Table 4) and tissue destruction in patients with COVID-19 and GD patients with COVID-19 (F). Accordingly, the combined _targeting of C5a–C5aR1 and/or GSL synthesis pathway could stop the SARS-CoV-2-mediated tissue inflammation and organ damage in patients with COVID-19 and GD patients with COVID-19.
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References

    1. Wu D., Shu T., Yang X., Song J.-X., Zhang M., Yao C., Liu W., Huang M., Yu Y., Yang Q., et al. Plasma metabolomic and lipidomic alterations associated with COVID-19. Natl. Sci. Rev. 2020;7:1157–1168. doi: 10.1093/nsr/nwaa086. - DOI - PMC - PubMed
    1. Vitner E.B., Avraham R., Politi B., Melamed S., Israely T. Elevation in sphingolipid upon SARS-CoV-2 infection: Possible implications for COVID-19 pathology. Life Sci. Alliance. 2021;5:e202101168. doi: 10.26508/lsa.202101168. - DOI - PMC - PubMed
    1. Khodadoust M.M. Inferring a causal relationship between ceramide levels and COVID-19 respiratory distress. Sci. Rep. 2021;11:20866. doi: 10.1038/s41598-021-00286-7. - DOI - PMC - PubMed
    1. Torretta E., Garziano M., Poliseno M., Capitanio D., Biasin M., Santantonio T.A., Clerici M., Caputo S.L., Trabattoni D., Gelfi C. Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature. Int. J. Mol. Sci. 2021;22:10198. doi: 10.3390/ijms221910198. - DOI - PMC - PubMed
    1. Russo F.P., Burra P., Zanetto A. COVID-19 and liver disease: Where are we now? Nat. Rev. Gastroenterol. Hepatol. 2022;19:277–278. doi: 10.1038/s41575-022-00607-9. - DOI - PMC - PubMed

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