Abstract
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.
Highlights
Coronavirus disease 2019 (COVID-19) is generally caused by inhalation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus related to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) [1]
We show that oropharyngeal aspiration of ORN06 induces a cytokine storm and lung damage in mice with similarities to the cytokine storm and lung damage seen in patients infected with the single-stranded RNA (ssRNA) viruses SARS-CoV-2, including more severe effects in male mice than female mice
We observed that aspiration of ORN06 induced the accumulation of immune cells, alveolar wall thickening, and presence of lung exudates, as previously described when mice were treated with GU-rich ssRNA by tail vein injection [47]
Summary
Coronavirus disease 2019 (COVID-19) is generally caused by inhalation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA (ssRNA) virus related to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) [1]. Human patients and murine models of SARS-CoV, MERS, and SARS-CoV2 indicate that severe disease may be triggered by a cytokine storm, in which, as in other cytokine storm associated diseases, an over exuberant production of cytokines leads to the accumulation of immune cells in sensitive organs such as the lungs [2,3].
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