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Victoria Callahan
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA

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Journal article
Published: 03 June 2021 in Viruses
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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.

ACS Style

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 Style

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 (6):1062.

Chicago/Turabian Style

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. 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.

Journal article
Published: 02 March 2021 in Pathogens
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Alphaviruses are a genus of the Togaviridae family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are currently no approved therapeutics or vaccines available for alphaviruses. In order to identify novel therapeutics, a V5 epitope tag was inserted into the N-terminus of the VEEV E2 glycoprotein and used to identify host-viral protein interactions. Host proteins involved in protein folding, metabolism/ATP production, translation, cytoskeleton, complement, vesicle transport and ubiquitination were identified as VEEV E2 interactors. Multiple inhibitors targeting these host proteins were tested to determine their effect on VEEV replication. The compound HA15, a GRP78 inhibitor, was found to be an effective inhibitor of VEEV, EEEV, CHIKV, and SINV. VEEV E2 interaction with GRP78 was confirmed through coimmunoprecipitation and colocalization experiments. Mechanism of action studies found that HA15 does not affect viral RNA replication but instead affects late stages of the viral life cycle, which is consistent with GRP78 promoting viral assembly or viral protein trafficking.

ACS Style

Michael Barrera; Victoria Callahan; Ivan Akhrymuk; Nishank Bhalla; Weidong Zhou; Catherine Campbell; Aarthi Narayanan; Kylene Kehn-Hall. Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections. Pathogens 2021, 10, 283 .

AMA Style

Michael Barrera, Victoria Callahan, Ivan Akhrymuk, Nishank Bhalla, Weidong Zhou, Catherine Campbell, Aarthi Narayanan, Kylene Kehn-Hall. Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections. Pathogens. 2021; 10 (3):283.

Chicago/Turabian Style

Michael Barrera; Victoria Callahan; Ivan Akhrymuk; Nishank Bhalla; Weidong Zhou; Catherine Campbell; Aarthi Narayanan; Kylene Kehn-Hall. 2021. "Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections." Pathogens 10, no. 3: 283.