Anti-Viral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein Against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models

Dhanushkodi, N.; Prakash, S.; Quadiri, A.; Zayou, L.; Srivastava, R.; Shaik, A. M.; Suzer, B.; Ibraim, I. C.; Landucci, G.; Tifrea, D. F.; Singer, M.; Jamal, L.; Edwards, R. A.; Vahed, H.; Brown, L.; BENMOHAMED, L.

doi:10.1101/2023.06.07.544133

bioRxiv · 10.1101/2023.06.07.544133

Anti-Viral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein Against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models

Dhanushkodi, N.·Prakash, S.·Quadiri, A.·Zayou, L.·Srivastava, R.·Shaik, A. M.·Suzer, B.·Ibraim, I. C.·Landucci, G.·Tifrea, D. F.·Singer, M.·Jamal, L.·Edwards, R. A.·Vahed, H.·Brown, L.·BENMOHAMED, L.

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Abstract

SignificanceSARS-CoV-2 Variants of Concern (VOCs) continue to evolve and re-emerge with chronic inflammatory long-COVID sequelae necessitating the development of anti-inflammatory therapeutic molecules. Therapeutic effects of the Receptor for Advanced Glycation End products (RAGE) were reported in many inflammatory diseases. However, a therapeutic effect of the RAGE in COVID-19 has not been reported. In the present study, we investigated whether and how the RAGE-Ig fusion protein would have an anti-viral and anti-inflammatory therapeutic effect in the COVID-19 system. MethodsThe protective therapeutic effect of RAGE-Ig was determined in vitro in K18-hACE2 transgenic mice and Syrian golden hamsters infected with six various VOCs of SARS-CoV-2. The underlying anti-viral mechanism of RAGE-Ig was determined in vitro in SARS-CoV-2-infected human lung epithelial cells (BEAS-2B). ResultsFollowing treatment of K18-hACE2 mice and hamsters infected with various SARS-CoV-2 VOCs with RAGE-Ig, we demonstrated: (i) significant dose-dependent protection (i.e. greater survival, less weight loss, lower virus replication in the lungs); (ii) a reduction of inflammatory macrophages (F4/80+/Ly6C+) and neutrophils (CD11b+/Ly6G+) infiltrating the infected lungs; (iii) a RAGE-Ig dose-dependent increase in the expression of type I interferons (IFN-, and IFN-{beta}) and type III interferon (IFN{lambda}2) and a decrease in the inflammatory cytokines (IL-6 and IL-8) in SARS-CoV-2-infected human lung epithelial cells; and (iv) a dose-dependent decrease in the expression of CD64 (FcgR1) on monocytes and lung epithelial cells from symptomatic COVID-19 patients. ConclusionOur pre-clinical findings revealed type I and III interferons-mediated anti-viral and anti-inflammatory therapeutic effects of RAGE-Ig protein against COVID-19 caused by multiple SARS-CoV-2 VOCs.

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Dhanushkodi, N., Prakash, S., Quadiri, A., Zayou, L., Srivastava, R., Shaik, A. M., Suzer, B., Ibraim, I. C., Landucci, G., Tifrea, D. F., Singer, M., Jamal, L., Edwards, R. A., Vahed, H., Brown, L., BENMOHAMED, L.. 2023-06-08. Anti-Viral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein Against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models. https://doi.org/10.1101/2023.06.07.544133

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