The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner

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.

Antiviral and Immunomodulatory Effects of Pelargonium sidoides DC. Root Extract EPs® 7630 in SARS-CoV-2-Infected Human Lung Cells

“…Multiple studies reported the massive and dysregulated production of inflammatory cytokines and growth factors in patients with severe COVID-19. In line with previous reports, we detected the production of inflammatory cytokines and growth factors in SARS-CoV-2-infected Calu-3 epithelial lung cells (Callahan et al, 2021;Islam et al, 2021). Of note, key inflammatory factors and drivers of COVID-19-induced cytokine storm were included in our analysis (IL-6, IL-8, IL-13, TNF-α, CXCL9, CXCL10, PDGF, VEGF-A, CD40L, IL1RA) and showed robust upregulation in infected Calu-3 cells (see Figure 6 for graphical overview and details) (Cauchois et al, 2020;Donlan et al, 2021;Pang et al, 2021;Petrey et al, 2021;Sugiyama et al, 2021).…”

Diosmectite inhibits the interaction between SARS-CoV-2 and human enterocytes by trapping viral particles, thereby preventing NF-kappaB activation and CXCL10 secretion

“…Both viral components activated NF-kappaB and induced the expression of the pro-inflammatory chemokine CXCL10. An increase in CXCL10 has previously been reported in Calu-3 lung epithelial cells in mice lungs following SARS-CoV-2 infection 26 and in COVID-19 patients 27 , implicating this chemokine as a key contributor to SARS-CoV-2-related cytokine storm. In our experimental model the IFN-γ response was of limited magnitude; however, in an in vitro study, Yeruva et al .…”

Phillyrin for COVID-19 and Influenza Co-infection: A Potential Therapeutic Strategy Targeting Host Based on Bioinformatics Analysis

“…MMP-9 can cleave various proteins to regulate inflammation and injury responses ( Bradley et al, 2012 ). MMP-9 can mediate the migration of neutrophils into the airway in response to Toll-like receptor signals induced by influenza viruses ( Callahan et al, 2021 ). The main characteristics of SARS-CoV-2 induced pulmonary complications include the overexpression of pro-inflammatory chemokines and cytokines, which can lead to a “cytokine storm.” After SARS-CoV-2 infects Calu-3 human lung epithelial cells, the pro-inflammatory chemokines CXCL9, CXCL10, and CXCL11 are up-regulated in an AKT-dependent manner ( Li et al, 2021 ).…”