Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first six months of the COVID-19 pandemic

Three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the first six months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48,000 viral proteome sequences showed how each one of the 29 viral study proteins have undergone amino acid changes. Structural models computed for every unique sequence variant revealed that most substitutions map to protein surfaces and boundary layers with a minority affecting hydrophobic cores. Conservative changes were observed more frequently in cores versus boundary layers/surfaces. Active sites and protein-protein interfaces showed modest numbers of substitutions. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for six drug discovery targets and four structural proteins comprising the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and functional interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

Prevalence of SARS-CoV-2 infection in previously undiagnosed health care workers at the onset of the U.S. COVID-19 epidemic

ImportanceHealthcare workers are presumed to be at increased risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection due to occupational exposure to infected patients. However, no epidemiological study has examined the prevalence of SARS-CoV-2 infection in a cohort of healthcare workers during the early phase of community transmission. ObjectiveTo determine the baseline prevalence of SARS-CoV-2 infection in a cohort of previously undiagnosed healthcare workers and a comparison group of non-healthcare workers. DesignProspective cohort study SettingA large U.S. university and two affiliated university hospitals Participants546 health care workers and 283 non-health care workers with no known prior SARS-CoV-2 infection ExposureHealthcare worker status and role Main outcome(s) and measure(s)SARS-CoV-2 infection status as determined by presence of SARS-CoV-2 RNA in oropharyngeal swabs. ResultsAt baseline, 41 (5.0%) of participants tested positive for SARS-CoV-2 infection, of whom 14 (34.2%) reported symptoms. The prevalence of SARS-CoV-2 infection was higher among healthcare workers (7.3%) than in non-healthcare workers (0.4%), representing a 7.0% greater absolute risk (95% confidence interval for risk difference 4.7%, 9.3%). The majority of infected healthcare workers (62.5%) worked as nurses. Positive tests increased across the two weeks of cohort recruitment in line with rising confirmed cases in the hospitals and surrounding counties. Conclusions and relevanceIn a prospective cohort conducted in the early phases of community transmission, healthcare workers had a higher prevalence of SARS-CoV-2 infection than non-healthcare workers, attesting to the occupational hazards of caring for patients in this crisis. Baseline data reported here will enable us to monitor the spread of infection and examine risk factors for transmission among healthcare workers. These results will inform optimal strategies for protecting the healthcare workforce, their families, and their patients. Clinicaltrials.gov registration number:NCT04336215 Key pointsO_ST_ABSQuestionC_ST_ABSAmong previously undiagnosed individuals, is the prevalence of SARS-CoV-2 infection higher in U.S. healthcare workers compared to non-healthcare workers in the early phase of the U.S. COVID-19 epidemic? FindingsThe prevalence of SARS-CoV-2 infection was 7.3% in healthcare workers and 0.4% in non-healthcare workers, representing 7.0% greater absolute risk in the former (95% confidence interval for risk difference 4.7%, 9.3%). Infections were most common among nursing staff. MeaningHealth care workers, particularly those with high levels of close patient contact, may be particularly vulnerable to SARS-CoV-2 infection. Additional strategies are needed to protect these critical frontline workers.