Abstract
Although COVID-19 has become a major challenge to global health, there are currently no efficacious agents for effective treatment. Cytokine storm syndrome (CSS) can lead to acute respiratory distress syndrome (ARDS), which contributes to most COVID-19 mortalities. Research points to interleukin 6 (IL-6) as a crucial signature of the cytokine storm, and the clinical use of the IL-6 inhibitor tocilizumab shows potential for treatment of COVID-19 patient. In this study, we challenged wild-type and adenovirus-5/human angiotensin-converting enzyme 2-expressing BALB/c mice with a combination of polyinosinic-polycytidylic acid and recombinant SARS-CoV-2 spike-extracellular domain protein. High levels of TNF-α and nearly 100 times increased IL-6 were detected at 6 h, but disappeared by 24 h in bronchoalveolar lavage fluid (BALF) following immunostimulant challenge. Lung injury observed by histopathologic changes and magnetic resonance imaging at 24 h indicated that increased TNF-α and IL-6 may initiate CSS in the lung, resulting in the continual production of inflammatory cytokines. We hypothesize that TNF-α and IL-6 may contribute to the occurrence of CSS in COVID-19. We also investigated multiple monoclonal antibodies (mAbs) and inhibitors for neutralizing the pro-inflammatory phenotype of COVID-19: mAbs against IL-1α, IL-6, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and inhibitors of p38 and JAK partially relieved CSS; mAbs against IL-6, TNF-α, and GM-CSF, and inhibitors of p38, extracellular signal-regulated kinase, and myeloperoxidase somewhat reduced neutrophilic alveolitis in the lung. This novel murine model opens a biologically safe, time-saving avenue for clarifying the mechanism of CSS/ARDS in COVID-19 and developing new therapeutic drugs.
Highlights
In early December 2019, cases of viral pneumonia of unknown cause appeared in Wuhan, China
To investigate the molecular mechanism of SARS-CoV-2– induced acute respiratory distress syndrome (ARDS)/Cytokine storm syndrome (CSS) and find effective strategies to prevent and treat this highly infectious disease, we have developed a murine ARDS model that mimics the pathologic changes observed in COVID-19 patients
The receptor-binding domain (RBD) of the viral SP is critical for binding to human ACE2
Summary
In early December 2019, cases of viral pneumonia of unknown cause appeared in Wuhan, China. The causative viral strain was first isolated from patient samples on January 7, and the entire viral genome sequence was obtained by January 10, 2020 [1, 2]. The virus showed homology of 79% and 50% to the genomes of SARSCoV and MERS-CoV, respectively, and was named as the novel coronavirus SARS-CoV-2 [3]. The illness known as COVID19 was demonstrated to be caused by SARS-CoV-2 infection [4], and a total of 78,679,912 confirmed cases of COVID-19 had been reported globally as of December 22, 2020. The total number of deaths worldwide has exceeded 1 million, even the BioNTec/Pfizer vaccine has been approved in Europe, but for exists COVID19 patients, and we need more efficacious antiviral drugs. The COVID-19 pandemic is a threat to public health, and methods to control the spread of the virus and improve treatment have become urgent issues concerning the national security of governments all around the world
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