Molecular mechanism of SARS-CoV-2 components caused ARDS in murine model

Abstract

<jats:title>Abstract</jats:title><jats:p>COVID-19 has become a major challenge to global health, and until now, no efficient antiviral agents have been developed. The SARS-CoV-2 infection is characterized by pulmonary and systemic inflammation in severe patients, and acute respiratory distress syndrome (ARDS) caused respiratory failure contributes to most mortalities. There is an urgent need for developing effective drugs and vaccines against SARS-CoV-2 and COVID-19 caused ARDS. However, most researchers cannot perform SARS-CoV-2 related researches due to lacking P3 or P4 facility. We developed a non-infectious, highly safety, time-saving SARS-CoV-2 components induced murine model to study the SARS-CoV-2 caused ARDS and cytokine storm syndrome (CSS). We also investigated mAbs and inhibitors which potentially neutralize the pro-inflammatory phenotype of COVID-19, and found that anti-IL-1α, anti-IL-6, anti-TNFα, anti-GM-CSF mAbs, p38 inhibitor, and JAK inhibitor partially relieved CSS. Besides, anti-IL-6, anti-TNFα, anti-GM-CSF mAbs and inhibitors of p38, ERK, and MPO somewhat reduced neutrophilic alveolitis in the lung. In all, we established the murine model mimic of COVID-19, opening a biosafety and less time-consuming avenue for clarifying the mechanism of ARDS and CSS in COVID-19 and developing the therapeutic drugs.</jats:p>

Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

“…It has been reported that innate immune responses to components of SARS-CoV-2 are principal drivers of inflammation and alveolar tissue injury in COVID-19[26–28]. To elucidate mechanisms of alveolar epithelial cell death in COVID-19-induced ARDS, we established animal models of severe and mild COVID-19 by intratracheal instillation with the SARS-CoV-2 spike protein and poly (I:C), a synthetic analog of double-stranded RNA based on previous reports [15,16] and our preliminary experiments (Supplementary Fig. 3).…”

“…Several previous studies have also reported that circulating levels of DAMPs, such as HMGB-1 [47,48] or mitochondrial DNA [49] In the present study, an animal model mimicking COVID-19 was established by administering the SARS-CoV-2 spike protein combined with poly (I:C). The same approach has been used in some studies [15,16,50]. Animal models treated with infectious strains of SARS-CoV-2 are often ideal models for COVID-19; however, use of infectious viruses in animal experiments can be difficult.…”

“…A mouse model mimicking COVID-19 was established based on previous reports. [15,16] Intratracheal administration of polyinosinic:polycytidylic acid (poly (I:C)) (P1530, Sigma-Aldrich, St. Louis, MO, USA) and the SARS-CoV-2 spike protein (Z03481, Lot B2103045, GenScript, Piscataway, NJ) was performed via the exposed trachea through a small incision at the front of the neck. During the procedure, mice were placed under general anesthesia using intraperitoneal ketamine and xylazine.…”

“…Moreover, we analyzed the levels of CK18-M65 and CK18-M30 in broncho alveolar lavage fluids (BALF) from COVID-19-induced ARDS. Next, we investigated the detailed mechanisms of alveolar epithelial cell death using the animal model mimicking COVID-19-induced ARDS [15,16]. Finally, we evaluated whether blockade of HMGB-1, one of DAMPs released from necrotic cells, can attenuate alveolar tissue injury in the animal model.…”

Animal models for SARS‐CoV‐2 infection and pathology

“…This genetically unaltered mouse might be infected via a novel mechanism other than the canonical ACE2-mediated uptake route. Besides, some strategies, such as intratracheal instillation of Poly I:C and SARS-CoV-2 spike protein 90 and intravenous injection of SARS-CoV-2 envelope (2-E) protein, 91 have also been reported to induce ARDS-like pathological damages in genetically unaltered mice. Finally, the K18-hACE2 mice can develop lethal disease after SARS-CoV-2 infection as describe…”