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Cell ; 184(17): 4392-4400.e4, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1300647


The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission.

COVID-19/virology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Substitution , Angiotensin-Converting Enzyme 2 , Animals , Cell Line , Chiroptera/virology , Chlorocebus aethiops , Disease Reservoirs , Evolution, Molecular , Genome, Viral , Humans , Models, Molecular , Mutation , Phylogeny , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
Viruses ; 13(6)2021 06 03.
Article in English | MEDLINE | ID: covidwho-1259622


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.

COVID-19/immunology , Chemokine CXCL10/genetics , Chemokine CXCL11/genetics , Chemokine CXCL9/genetics , Proto-Oncogene Proteins c-akt/metabolism , Up-Regulation , Angiotensin-Converting Enzyme 2/genetics , Animals , Cell Line , Chemokine CXCL10/immunology , Chemokine CXCL11/immunology , Chemokine CXCL9/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Epithelial Cells/immunology , Epithelial Cells/virology , Female , Humans , Inflammation , Lung/cytology , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics , Signal Transduction/immunology
Viruses ; 13(6)2021 05 25.
Article in English | MEDLINE | ID: covidwho-1244147


SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl2 (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.

Antiviral Agents/pharmacology , Organometallic Compounds/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , COVID-19/virology , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Humans , Molecular Structure , Organometallic Compounds/chemistry , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects