Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.
Highlights
IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an emergent coronavirus first identified as causing widespread pneumonia in Wuhan, China in late 2019 [1,2,3]
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an emergent coronavirus first identified as causing widespread pneumonia in Wuhan, China in late 2019 [1,2,3].The etiologic cause of the widespread pneumonia was identified to be SARS-CoV-2 from bronchoalveolar lavage fluid (BALF) of three patients in December 2019 [1,3]
Towards understanding the mechanisms by which SARS-CoV-2 triggers destructive pulmonary inflammation, the current study investigates the expression of pro-inflammatory chemokines associated with SARS-CoV-2 infection in both in vitro and in vivo models
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an emergent coronavirus first identified as causing widespread pneumonia in Wuhan, China in late 2019 [1,2,3]. The etiologic cause of the widespread pneumonia was identified to be SARS-CoV-2 from bronchoalveolar lavage fluid (BALF) of three patients in December 2019 [1,3]. The novel coronavirus rapidly spread via human–human transmission and by March 2020 had infected over. Since the outbreak of SARS-CoV-2 the pandemic has been designated the Coronavirus disease 2019 (COVID-19) pandemic. According to the WHO, as of 26 April 2021, over 146 million people have been infected worldwide and over. 3.1 million people have succumbed to the disease. SARS-CoV-2 is a novel, emergent Betacoronavirus related to SARS-CoV and MERSCoV. SARS-CoV-2 shares about 80% sequence identity with SARS-CoV and about 50%
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