Abstract
Treatment options for COVID-19 are currently limited. Drugs reducing both viral loads and SARS-CoV-2-induced inflammatory responses would be ideal candidates for COVID-19 therapeutics. Previous in vitro and clinical studies suggest that the proprietary Pelargonium sidoides DC. root extract EPs 7630 has antiviral and immunomodulatory properties, limiting symptom severity and disease duration of infections with several upper respiratory viruses. Here we assessed if EPs 7630 affects SARS-CoV-2 propagation and the innate immune response in the human lung cell line Calu-3. In direct comparison to other highly pathogenic CoV (SARS-CoV, MERS-CoV), SARS-CoV-2 growth was most efficiently inhibited at a non-toxic concentration with an IC50 of 1.61 μg/ml. Particularly, the cellular entry step of SARS-CoV-2 was significantly reduced by EPs 7630 pretreatment (10–100 μg/ml) as shown by spike protein-carrying pseudovirus particles and infectious SARS-CoV-2. Using sequential ultrafiltration, EPs 7630 was separated into fractions containing either prodelphinidins of different oligomerization degrees or small molecule constituents like benzopyranones and purine derivatives. Prodelphinidins with a low oligomerization degree and small molecule constituents were most efficient in inhibiting SARS-CoV-2 entry already at 10 μg/ml and had comparable effects on immune gene regulation as EPs 7630. Downregulation of multiple pro-inflammatory genes (CCL5, IL6, IL1B) was accompanied by upregulation of anti-inflammatory TNFAIP3 at 48 h post-infection. At high concentrations (100 μg/ml) moderately oligomerized prodelphinidins reduced SARS-CoV-2 propagation most efficiently and exhibited pronounced immune gene modulation. Assessment of cytokine secretion in EPs 7630-treated and SARS-CoV-2-coinfected Calu-3 cells showed that pro-inflammatory cytokines IL-1β and IL-6 were elevated whereas multiple other COVID-19-associated cytokines (IL-8, IL-13, TNF-α), chemokines (CXCL9, CXCL10), and growth factors (PDGF, VEGF-A, CD40L) were significantly reduced by EPs 7630. SARS-CoV-2 entry inhibition and the differential immunomodulatory functions of EPs 7630 against SARS-CoV-2 encourage further in vivo studies.
Highlights
The ongoing SARS-CoV-2 pandemic has presented challenges to health systems worldwide due to the limited availability of vaccines and effective antiviral drugs
To verify the antiviral activity of EPs 7630 against newly emerging SARS-CoV-2 variants, we analyzed its impact on SARS-CoV-2 Alpha and SARS-CoV-2 Beta propagation, both of which were classified as variants of concern (VOC) by the World Health Organization (Abdool Karim and de Oliveira, 2021; Konings et al, 2021)
At low concentrations of 10 μg/ml EPs 7630, we did not detect a significant reduction of viral RNA levels, possibly as a consequence of increased replicative fitness reported for the analyzed VOCs (Pyke et al, 2021; Rosenke et al, 2021; Touret et al, 2021)
Summary
The ongoing SARS-CoV-2 pandemic has presented challenges to health systems worldwide due to the limited availability of vaccines and effective antiviral drugs. The upper respiratory tract is the primary location of SARS-CoV-2 replication, especially during the early phase post-infection (Wolfel et al, 2020). Rapid disease progression results in severe COVID-19, which is accompanied by overt immunological dysregulations (Ghazavi et al, 2021; Petrey et al, 2021). SARS-CoV-2-specific antiviral drugs have shown limited effects in large clinical trials, which might partially be associated with delayed administration when virus replication has already waned (Consortium et al, 2021; Group et al, 2021; Zhang and Mylonakis, 2021). Reduction of viral loads might limit immunological dysregulation, severe disease progression, and human-tohuman transmission
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
