ELV-N34, RvD6-Isomer, or NPD1 Halt Replication of SARS-CoV-2 Omicron BA.5 Virus in Human Lung and Nasal Cells

Current vaccines rely on the sequence of Spike (S) protein to induce immunity against the severe acute respiratory coronavirus-2 (SARS-CoV-2) virus. Because of the high mutation rate of the viral S protein, new mutant strains are developed to generate new infectivity profiles. Bioactive lipid mediators (LMs) derived from docosahexaenoic acid (DHA) are synthesized on demand to sustain homeostasis. The purpose of this study was to determine the action of selected LMs in the viral replication of SARS-CoV-2 Omicron BA.5 variant in human lung and nasal epithelial cells. Cells from healthy donors were infected with Omicron BA.5 for one hour and treated with 500 nM Elovanoid (ELV)-N32, ELV-N34, Resolvin D6 isomer (RvD6i), Neuroprotection D1 (NPD1), or vehicle before and after infection. Impedance was recorded to determine cell death by infectivity. Cells were then immunostained for nucleocapsid (N) protein, microtubule-associated protein 1B-light chain 3 (LC3B), and autophagic proteins. N and S RNA were measured to assess the synthesis of viral components. The addition of ELV-N34 or RvD6i decreased the synthesis of N RNA by 76.7% and 96.9%, respectively, in lung primary culture, while NPD1 exerted the same effect in nasal epithelial cells (61.7% reduction). In lung cells, transcription of autophagy-related gene-3 (ATG3) and Sequestosome 1 (SQSTM1/p62), components of the autophagy initiation process, decreased compared to the non-treated infected cells. The results suggest that specific LMs prevent viral autophagy machinery hijacking, leading to a decrease in BA.5 replication. This novel effect of the bioactive LMs as antivirals, regardless of the protein sequence, would potentially complement vaccination and other prevention and treatment therapeutics.