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

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dc.contributor.authorCallahan, Victoriaen
dc.contributor.authorHawks, Seth A.en
dc.contributor.authorCrawford, Matthew A.en
dc.contributor.authorLehman, Caitlin W.en
dc.contributor.authorMorrison, Holly A.en
dc.contributor.authorIvester, Hannah M.en
dc.contributor.authorAkhrymuk, Ivan V.en
dc.contributor.authorBoghdeh, Niloufaren
dc.contributor.authorFlor, Rafaelaen
dc.contributor.authorFinkielstein, Carla V.en
dc.contributor.authorAllen, Irving C.en
dc.contributor.authorWeger-Lucarelli, Jamesen
dc.contributor.authorDuggal, Nisha K.en
dc.contributor.authorHughes, Molly A.en
dc.contributor.authorKehn-Hall, Kyleneen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.contributor.departmentTranslational Biology, Medicine and Healthen
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentCenter for Drug Discoveryen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentVirginia Tech Carilion School of Medicineen
dc.contributor.departmentCenter for Emerging, Zoonotic, and Arthropod-borne Pathogensen
dc.date.accessioned2021-06-10T19:36:07Zen
dc.date.available2021-06-10T19:36:07Zen
dc.date.issued2021-06-03en
dc.date.updated2021-06-10T13:46:18Zen
dc.description.abstractSevere 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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationCallahan, V.; Hawks, S.; Crawford, M.A.; Lehman, C.W.; Morrison, H.A.; Ivester, H.M.; Akhrymuk, I.; Boghdeh, N.; Flor, R.; Finkielstein, C.V.; Allen, I.C.; Weger-Lucarelli, J.; Duggal, N.; Hughes, M.A.; Kehn-Hall, K. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses 2021, 13, 1062.en
dc.identifier.doihttps://doi.org/10.3390/v13061062en
dc.identifier.urihttp://hdl.handle.net/10919/103764en
dc.language.isoenen
dc.publisherMDPIen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectSARS-CoV-2en
dc.subjectbetacoronavirusen
dc.subjectCXCL10en
dc.subjectARDSen
dc.subjectALIen
dc.subjectcytokine stormen
dc.subjectCalu-3en
dc.subjecthACE2 miceen
dc.titleThe Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manneren
dc.title.serialVirusesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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