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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.
Victoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses 2021, 13, 1062 .
AMA StyleVictoria Callahan, Seth Hawks, Matthew Crawford, Caitlin Lehman, Holly Morrison, Hannah Ivester, Ivan Akhrymuk, Niloufar Boghdeh, Rafaela Flor, Carla Finkielstein, Irving Allen, James Weger-Lucarelli, Nisha Duggal, Molly Hughes, Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses. 2021; 13 (6):1062.
Chicago/Turabian StyleVictoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. 2021. "The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner." Viruses 13, no. 6: 1062.
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), became a pandemic in early 2020. Lateral flow immunoassays for antibody testing have been viewed as a cheap and rapidly deployable method for determining previous infection with SARS-CoV-2; however, these assays have shown unacceptably low sensitivity. We report on nine lateral flow immunoassays currently available and compare their titer sensitivity in serum to a best-practice enzyme-linked immunosorbent assay (ELISA) and viral neutralization assay. For a small group of PCR-positive, we found two lateral flow immunoassay devices with titer sensitivity roughly equal to the ELISA; these devices were positive for all PCR-positive patients harboring SARS-CoV-2 neutralizing antibodies. One of these devices was deployed in Northern Italy to test its sensitivity and specificity in a real-world clinical setting. Using the device with fingerstick blood on a cohort of 27 hospitalized PCR-positive patients and seven hospitalized controls, ROC curve analysis gave AUC values of 0.7646 for IgG. For comparison, this assay was also tested with saliva from the same patient population and showed reduced discrimination between cases and controls with AUC values of 0.6841 for IgG. Furthermore, during viral neutralization testing, one patient was discovered to harbor autoantibodies to ACE2, with implications for how immune responses are profiled. We show here through a proof-of-concept study that these lateral flow devices can be as analytically sensitive as ELISAs and adopted into hospital protocols; however, additional improvements to these devices remain necessary before their clinical deployment.
Amanda Haymond; Claudius Mueller; Hannah Steinberg; K. Alex Hodge; Caitlin W Lehman; Shih-Chao Lin; Lucia Collini; Heather Branscome; Tuong Vi Nguyen; Sally Rucker; Lauren Panny; Rafaela Flor; Raouf Guirguis; Richard Hoefer; Giovanni Lorenzin; Emanuel Petricoin; Fatah Kashanchi; Kylene Kehn-Hall; Paolo Lanzafame; Lance Liotta; Alessandra Luchini. Clinical Utility of a Highly Sensitive Lateral Flow Immunoassay as determined by Titer Analysis for the Detection of anti-SARS-CoV-2 Antibodies at the Point-of-Care. 2020, 1 .
AMA StyleAmanda Haymond, Claudius Mueller, Hannah Steinberg, K. Alex Hodge, Caitlin W Lehman, Shih-Chao Lin, Lucia Collini, Heather Branscome, Tuong Vi Nguyen, Sally Rucker, Lauren Panny, Rafaela Flor, Raouf Guirguis, Richard Hoefer, Giovanni Lorenzin, Emanuel Petricoin, Fatah Kashanchi, Kylene Kehn-Hall, Paolo Lanzafame, Lance Liotta, Alessandra Luchini. Clinical Utility of a Highly Sensitive Lateral Flow Immunoassay as determined by Titer Analysis for the Detection of anti-SARS-CoV-2 Antibodies at the Point-of-Care. . 2020; ():1.
Chicago/Turabian StyleAmanda Haymond; Claudius Mueller; Hannah Steinberg; K. Alex Hodge; Caitlin W Lehman; Shih-Chao Lin; Lucia Collini; Heather Branscome; Tuong Vi Nguyen; Sally Rucker; Lauren Panny; Rafaela Flor; Raouf Guirguis; Richard Hoefer; Giovanni Lorenzin; Emanuel Petricoin; Fatah Kashanchi; Kylene Kehn-Hall; Paolo Lanzafame; Lance Liotta; Alessandra Luchini. 2020. "Clinical Utility of a Highly Sensitive Lateral Flow Immunoassay as determined by Titer Analysis for the Detection of anti-SARS-CoV-2 Antibodies at the Point-of-Care." , no. : 1.