SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. Here we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1β, IL-6, IL-12p70, IL-23, and IL-27 in serum. SAP also reduced D-dimer levels in the lung fluid. In human peripheral blood mononuclear cells, SAP attenuated ORN06-induced extracellular accumulation of IL-6. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms and/or a cytokine storm.
【초록키워드】 COVID-19, SARS-CoV-2, Efficacy, Cytokine storm, IL-6, Genome, Infection, lung, clinical trials, fibrosis, D-dimer, animal model, cytokine, Symptom, animal models, virus, Symptoms, immune, RNA, Peripheral blood, innate immune system, Protein, serum, mice, therapeutic, male, female, Inflammatory cytokines, women, disease, Inflammatory cytokine, IL-1β, D-dimer level, Blood clots, mononuclear cells, inflammatory cells, Intraperitoneal injections, inflammatory cell, Serum protein, intraperitoneal injection, D-dimer levels, accumulation, sequence, serum amyloid, upregulation, serum cytokine, serum cytokine levels, aggregate, IL-12p70, Hyperactivation, ssRNA, aspiration, clot, IL-23, IL-27, inflammatory immune cells, alveolar, Extracellular, reduced, increase in, induce, cause, severe symptom, lung alveolar, severe COVID-19 symptom, 【제목키워드】 cytokine, mice, amyloid, Lung inflammation, lung damage, inhibit,