ABSTRACT
RationaleNeutrophils are important in the pathophysiology of COVID19 but the molecular changes contributing to altered neutrophil phenotypes following SARS-CoV-2 infection are not fully understood. ObjectivesTo use quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes following acute SARS-CoV-2 infection and during recovery. MethodsProspective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May 2020-December 2020). Patients were enrolled within 96 hours of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID19 acute lower respiratory tract infection (LRTI) and age-matched non-infected controls. Neutrophils isolated from peripheral blood were processed for mass spectrometry. COVID19 severity and recovery were defined using the WHO ordinal scale. Measurements and Main Results84 COVID19 patients were included and compared to 91 LRTI patients and 42 controls. 5,800 neutrophil proteins were identified and 1,748 proteins were significantly different (q-value<0.05) in neutrophils from COVID19 patients compared to those of non-infected controls, including a robust interferon response at baseline, which was lost in severe patients one week after enrolment. Neutrophil changes associated with COVID19 disease severity and prolonged illness were characterized and candidate targets for modulation of neutrophil function were identified. Delayed recovery from COVID19 was associated with changes in metabolic and signalling proteins, complement, chemokine and leukotriene receptors, integrins and inhibitory receptors. ConclusionsSARS-CoV-2 infection results in the sustained presence of recirculating neutrophils with distinct metabolic profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines. Scientific Knowledge on the SubjectInflammation is the primary driver of morbidity and mortality in severe COVID19. Type I interferon responses, T-cell exhaustion, cytokine storm, emergency myelopoiesis, myeloid compartment dysregulation and procoagulant pathway activation are well established contributors to COVID19 disease severity. Neutrophils play an important role in COVID19, with elevated neutrophil-to-lymphocyte ratios and the emergence of a circulating immature neutrophil population in individuals with severe symptoms. Neutrophil infiltration in the lungs coupled with the release of neutrophil extracellular traps has also been reported in severe and fatal COVID19. The aim of this study was to quantitatively map the proteomes of peripheral blood neutrophils from a cohort of hospitalised COVID19 patients to understand how SARS-CoV-2 infection changes neutrophil phenotypes and functional capacity. What this study adds to the fieldHigh-resolution mass spectrometry was used to characterise the proteomes of peripheral blood neutrophils from >200 individuals at different stages of disease. This work has comprehensively mapped neutrophil molecular changes associated with mild and severe COVID19 and identified significant quantitative changes in more than 1700 proteins in neutrophils from patients hospitalised with COVID19 versus patients with non-COVID19 acute respiratory infections. The study identifies neutrophil protein signatures associated with COVID19 disease severity. The data also show that alterations in neutrophil proteomes can persist in fully recovered patients and identify distinct neutrophil proteomes in recovered versus non recovered patients. Our study provides novel insights into neutrophil responses during acute COVID19 and reveals that altered neutrophil phenotypes persist in convalescent COVID19 patients.
Subject(s)
Infections , Chronobiology Disorders , Respiratory Tract Infections , COVID-19ABSTRACT
Background: Healthcare workers (HCW) are believed to be at increased risk of SARS-CoV-2 infection. The extent of that increased risk compared to the general population and the groups most at risk have not been extensively studied. It is also not known to what extent the natural production of antibodies to SARS-CoV-2 is protective against re-infection.Methods: A prospective observational study of health and social care workers in NHS Tayside (Scotland, UK) from May to September 2020. The Siemens SARS-CoV-2 total antibody assay was used to establish seroprevalence in this cohort. Controls, matched for age and sex to the general Tayside population, were studied for comparison. New infections post antibody testing were recorded to determine if the presence of SARS-CoV-2 antibodies protect against re-infection.Results: A total of 2063 health and social care workers were recruited for this study. 300 HCW had a positive antibody test (14.5%). 11/231 control sera tested positive (4.8%). HCW therefore had an increased likelihood of a positive test (Odds ratio 3.4 95% CI 1.85-6.16, p<0.0001). Dentists, healthcare assistants and porters were the job roles most likely to test positive. Those working in front-line roles with COVID-19 patients were more likely to test positive (17.4% vs. 13.4%, p=0.02). 97.3% of patients who had previously tested positive for SARS-CoV-2 by RT-PCR had positive antibodies. 18.7% of HCW had an asymptomatic infection. There were 38 new infections with SARS-CoV-2 in HCW who were previously antibody negative and 1 symptomatic RT-PCR positive re-infection in a HCW who had detectable antibodies 76 days prior to re-infection. The presence of antibodies was therefore associated with an 85% reduced risk of re-infection with SARS-CoV-2 (HR 0.15, 95% CI 0.06 to 0.35, p=0.026).Conclusion: In this study, HCW were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all of the infected individuals developed an antibody response and this was 85% effective in protecting against re-infection with SARS-CoV-2.Funding Statement: NHS Tayside COVID-19 Research Fund, JDC is supported by the British Lung Foundation Chair of Respiratory Research.Declaration of Interests: JDC reports grants and personal fees from GlaxoSmithKline, Boehringer-Ingelheim, Astrazeneca, Pfizer, Bayer Healthcare, Grifols, Napp, Insmed and Zambon outside the submitted work; All other authors report no conflicts of interest.Ethics Approval Statement: West of Scotland Research Ethics committee, approval number 20/WS/0078.
Subject(s)
COVID-19 , Williams SyndromeABSTRACT
By 29th April 2020, COVID-19 had caused more than 3 million cases across more than 200 countries. And most countries with significant outbreaks had introduced social distancing or "lockdown" measures to reduce viral transmission. So the key question now is when, how, and to what extent, these measures can be lifted. By fitting regression models to publically available data on daily numbers of newly-confirmed cases and mortality, trajectories, doubling times and reproduction number (R0) were estimated both before and under the control measures. These data ran up to 29th April 2020, and covered 73 countries that had provided sufficient data for modelling. The estimates of R0, before lockdown, based on these data were broadly consistent with those previously published at between 2.0 and 3.7 in the countries with the largest number of cases available for analysis (USA, Italy, Spain, France and UK). There was little evidence to suggest that the restrictions had reduced R far below 1 in many places, with France having the most rapid reductions - R0 0.77 (95%CI 0.68-0.87), based on cases and 0.78 (95%CI 0.68-0.88) based on mortality. Intermittent lockdown has been proposed as a means of controlling the outbreak while allowing periods of increase freedom and economic activity. These data suggest that few countries could have even one week per month unrestricted without seeing resurgence of the epidemic. Similarly, restoring 20% of the activity that has been prevented by the lockdowns looks difficult to reconcile with preventing the resurgence of the disease in most countries.