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1.
Front Immunol ; 12: 807134, 2021.
Article in English | MEDLINE | ID: covidwho-1604257

ABSTRACT

ORF8 is a viral immunoglobulin-like (Ig-like) domain protein encoded by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome. It tends to evolve rapidly and interfere with immune responses. However, the structural characteristics of various coronavirus ORF8 proteins and their subsequent effects on biological functions remain unclear. Herein, we determined the crystal structures of SARS-CoV-2 ORF8 (S84) (one of the epidemic isoforms) and the bat coronavirus RaTG13 ORF8 variant at 1.62 Å and 1.76 Å resolution, respectively. Comparison of these ORF8 proteins demonstrates that the 62-77 residues in Ig-like domain of coronavirus ORF8 adopt different conformations. Combined with mutagenesis assays, the residue Cys20 of ORF8 is responsible for forming the covalent disulfide-linked dimer in crystal packing and in vitro biochemical conditions. Furthermore, immune cell-binding assays indicate that various ORF8 (SARS-CoV-2 ORF8 (L84), ORF8 (S84), and RaTG13 ORF8) proteins have different interaction capabilities with human CD14+ monocytes in human peripheral blood. These results provide new insights into the specific characteristics of various coronavirus ORF8 and suggest that ORF8 variants may influence disease-related immune responses.


Subject(s)
COVID-19/immunology , Chiroptera/immunology , Immunity/immunology , Immunoglobulin Domains/immunology , Viral Proteins/immunology , Animals , Binding Sites/genetics , COVID-19/virology , Cells, Cultured , Chiroptera/genetics , Chiroptera/metabolism , Crystallography, X-Ray , Humans , Immunity/genetics , Immunoglobulin Domains/genetics , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Models, Molecular , Monocytes/immunology , Monocytes/metabolism , Mutation , Protein Binding , Species Specificity , Viral Proteins/classification , Viral Proteins/genetics
2.
Microbiol Spectr ; 9(2): e0135221, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1526454

ABSTRACT

The emerging new lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have marked a new phase of coronavirus disease 2019 (COVID-19). Understanding the recognition mechanisms of potent neutralizing monoclonal antibodies (NAbs) against the spike protein is pivotal for developing new vaccines and antibody drugs. Here, we isolated several monoclonal antibodies (MAbs) against the SARS-CoV-2 spike protein receptor-binding domain (S-RBD) from the B cell receptor repertoires of a SARS-CoV-2 convalescent. Among these MAbs, the antibody nCoV617 demonstrates the most potent neutralizing activity against authentic SARS-CoV-2 infection, as well as prophylactic and therapeutic efficacies against the human angiotensin-converting enzyme 2 (ACE2) transgenic mouse model in vivo. The crystal structure of S-RBD in complex with nCoV617 reveals that nCoV617 mainly binds to the back of the "ridge" of RBD and shares limited binding residues with ACE2. Under the background of the S-trimer model, it potentially binds to both "up" and "down" conformations of S-RBD. In vitro mutagenesis assays show that mutant residues found in the emerging new lineage B.1.1.7 of SARS-CoV-2 do not affect nCoV617 binding to the S-RBD. These results provide a new human-sourced neutralizing antibody against the S-RBD and assist vaccine development. IMPORTANCE COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has posed a serious threat to global health and the economy, so it is necessary to find safe and effective antibody drugs and treatments. The receptor-binding domain (RBD) in the SARS-CoV-2 spike protein is responsible for binding to the angiotensin-converting enzyme 2 (ACE2) receptor. It contains a variety of dominant neutralizing epitopes and is an important antigen for the development of new coronavirus antibodies. The significance of our research lies in the determination of new epitopes, the discovery of antibodies against RBD, and the evaluation of the antibodies' neutralizing effect. The identified antibodies here may be drug candidates for the development of clinical interventions for SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , Binding Sites/immunology , COVID-19 Vaccines/immunology , Crystallography, X-Ray , Disease Models, Animal , Female , Humans , Immunization, Passive/methods , Immunoglobulin G/blood , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Interaction Domains and Motifs/immunology , Viral Load/drug effects
3.
Environ Pollut ; 292(Pt B): 118396, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1482582

ABSTRACT

A growing number of studies report associations between air pollution and COVID-19 mortality. Most were ecological studies at the county or regional level which disregard important local variability and relied on data from only the first few months of the pandemic. Using COVID-19 deaths identified from death certificates in California, we evaluated whether long-term ambient air pollution was related to weekly COVID-19 mortality at the census tract-level during the first ∼12 months of the pandemic. Weekly COVID-19 mortality for each census tract was calculated based on geocoded death certificate data. Annual average concentrations of ambient particulate matter <2.5 µm (PM2.5) and <10 µm (PM10), nitrogen dioxide (NO2), and ozone (O3) over 2014-2019 were assessed for all census tracts using inverse distance-squared weighting based on data from the ambient air quality monitoring system. Negative binomial mixed models related weekly census tract COVID-19 mortality counts to a natural cubic spline for calendar week. We included adjustments for potential confounders (census tract demographic and socioeconomic factors), random effects for census tract and county, and an offset for census tract population. Data were analyzed as two study periods: Spring/Summer (March 16-October 18, 2020) and Winter (October 19, 2020-March 7, 2021). Mean (standard deviation) concentrations were 10.3 (2.1) µg/m3 for PM2.5, 25.5 (7.1) µg/m3 for PM10, 11.3 (4.0) ppb for NO2, and 42.8 (6.9) ppb for O3. For Spring/Summer, adjusted rate ratios per standard deviation increase were 1.13 (95% confidence interval: 1.09, 1.17) for PM2.5, 1.16 (1.11, 1.21) for PM10, 1.06 (1.02, 1.10) for NO2, and 1.09 (1.04, 1.14) for O3. Associations were replicated in Winter, although they were attenuated for PM2.5 and PM10. Study findings support a relation between long-term ambient air pollution exposure and COVID-19 mortality. Communities with historically high pollution levels might be at higher risk of COVID-19 mortality.


Subject(s)
Air Pollutants , Air Pollution , COVID-19 , Air Pollutants/analysis , Air Pollution/analysis , California/epidemiology , Environmental Exposure , Humans , Mortality , Nitrogen Dioxide/analysis , Particulate Matter/analysis , SARS-CoV-2
4.
Ann Epidemiol ; 58: 69-75, 2021 06.
Article in English | MEDLINE | ID: covidwho-1144483

ABSTRACT

PURPOSE: To examine characteristics of coronavirus disease 2019 (COVID-19) decedents in California (CA) and evaluate for disproportionate mortality across race/ethnicity and ethnicity/nativity. METHODS: COVID-19 deaths were identified from death certificates. Age-adjusted mortality rate ratios (MRR) were compared across race/ethnicity. Proportionate mortality rates (PMR) were compared across race/ethnicity and by ethnicity/nativity. RESULTS: We identified 10,200 COVID-19 deaths in CA occurring February 1 through July 31, 2020. The most frequently observed characteristics among decedents were age 65 years or above, male, Hispanic, foreign-born, and educational attainment of High School or below. MRR indicated elevated COVID-19 morality rates among Asian/Pacific Islander, Black, and Hispanic groups compared with the White group, with Black and Hispanic groups having the highest MRR at 2.75 (95%CI: 2.54-2.97) and 4.18 (95%CI: 3.99-4.37), respectively. Disparities were larger at younger ages. Similar results were observed with PMR, and patterns of age-racial/ethnic disparities remained in analyses stratified by education. Elevated PMR were observed in all ethnicity/nativity groups, especially foreign-born Hispanic individuals, relative to U.S.-born non-Hispanic individuals. These were generally larger at younger ages and persisted after stratifying by education. CONCLUSIONS: Differential COVID-19 mortality was observed in California across racial/ethnic groups and by ethnicity/nativity groups with evidence of greater disparities among younger age groups. Identifying COVID-19 disparities is an initial step toward mitigating disease impacts in vulnerable communities.


Subject(s)
COVID-19 , Aged , California/epidemiology , Death Certificates , Humans , Male , SARS-CoV-2 , United States
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