The protective effect of SARS-CoV-2 antibodies in Scottish healthcare workers

BACKGROUND: Healthcare workers (HCW) are believed to be at increased risk of SARS-CoV-2 infection. It is 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 HCW's in 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 local population, were studied for comparison. New infections (up to 2/12/2020) 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. At enrolment 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 were most likely to test positive. 97.3% of patients who had previously tested positive for SARS-CoV-2 by RT-PCR had positive antibodies. 18.7% had an asymptomatic infection. There were 38 new infections with SARS-CoV-2 in HCW who were previously antibody negative and one symptomatic RT-PCR positive 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: HCW were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all infected individuals developed an antibody response which was 85% effective in protecting against re-infection with SARS-CoV-2

Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography

Acknowledgements This work was supported by the Chief Scientist Office, Scottish Government, Grant COV/ABN/20/01 (Elasmogen, Ltd.), a 2018 Prostate Cancer Foundation Challenge Award (AML), a 2013 Prostate Cancer Foundation Young Investigator Award (AML), NCI R01s CA237272, CA233562, and CA245922 (AML). WEM was supported by the NIH T32 HL007741 and JMT by the NIH T32 AI055433. JSM was funded by NIGMS R01 GM088790. HA was funded by NIGMS R35 GM118047 and NCI P01 CA234228. X-ray diffraction data were collected at the Northeastern Collaborative Access Team beamlines, which are funded by the US National Institutes of Health (NIGMS P30 GM124165). The Pilatus 6M detector on 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10 RR029205). We thank the Marco Pravetoni lab for providing training and access to the OctetRED96e for BLI experiments.Peer reviewedPublisher PD

The International Bathymetric Chart of the Arctic Ocean Version 4.0

Funder: The Nippon Foundation of Japan, grant Seabed 2030Funder: Open access funding provided by Stockholm UniversityAbstract: Bathymetry (seafloor depth), is a critical parameter providing the geospatial context for a multitude of marine scientific studies. Since 1997, the International Bathymetric Chart of the Arctic Ocean (IBCAO) has been the authoritative source of bathymetry for the Arctic Ocean. IBCAO has merged its efforts with the Nippon Foundation-GEBCO-Seabed 2030 Project, with the goal of mapping all of the oceans by 2030. Here we present the latest version (IBCAO Ver. 4.0), with more than twice the resolution (200 × 200 m versus 500 × 500 m) and with individual depth soundings constraining three times more area of the Arctic Ocean (∼19.8% versus 6.7%), than the previous IBCAO Ver. 3.0 released in 2012. Modern multibeam bathymetry comprises ∼14.3% in Ver. 4.0 compared to ∼5.4% in Ver. 3.0. Thus, the new IBCAO Ver. 4.0 has substantially more seafloor morphological information that offers new insights into a range of submarine features and processes; for example, the improved portrayal of Greenland fjords better serves predictive modelling of the fate of the Greenland Ice Sheet

Functional and genetic dissection of anti-mycobacterial immunity

Tuberculosis (TB) is a major global health problem with an estimated 2 billion people worldwide infected with M. tuberculosis, the causative agent of TB, and 9.2 million new cases of active TB disease reported in 2008. Despite the enormity of the problem, little is known about the anti-mycobacterial immune responses used to detect TB infection. The aim of my studies was to investigate how host factors impact on anti-mycobacterial immune responses and to evaluate if these responses can provide clues about host susceptibility to infection and progression to disease. Healthy nuclear families were enrolled from a hyper-endemic TB region of Cape Town, South Africa. We measured in vivo tuberculin skin test (TST) responses, and used in vitro whole blood assays to determine antigen-specific IFNg cytokine release as well as the frequency of antigen-specific IFNg+CD4+ and IFNg+CD8+ cells. We showed that the in vivo TST and in vitro IFNg release assays, two assays used to detect M. tuberculosis infection, measure non-redundant pathways of anti-mycobacterial immunity. We observed a significant impact of age, but not sex, on all the immune phenotypes measured. We calculated the heritability of the immune phenotypes and observed high estimates. We performed the first genome-scan of the TST and identified a major locus on 11p14 (p = 0.000015) impacting on TST positivity (i.e. T-cell independent resistance to M. tuberculosis) and a second major locus on 5p15 (p < 0.00001) controlling the extent of the TST response. The results of the genome-scan suggested that host genetics confounds the use of TST in detection of TB infection and critically, modulates the protective immune response to M. tuberculosis infection. Finally, we provided evidence for the functional impact of NRAMP1 TB disease risk alleles on protein function. Together, the studies demonstrated the importance of host factors, in particular host geneticLa tuberculose reste un problème majeur de santé publique à travers le monde. On estime qu'environ 2 milliards de personnes dans le monde sont infectées par la bactérie M. tuberculosis, l'agent causal de la tuberculose, et on a rapporté 9,2 millions de nouveaux cas de tuberculose évolutive en 2008. Malgré l'énormité du problème, on en sait peu sur les réponses immunitaires anti-mycobactériennes utilisées pour dépister l'infection tuberculeuse. L'objectif de mon travail était de rechercher l'impact des facteurs de l'hôte sur les réponses immunitaires anti-mycobactériennes et de déterminer comment ces réponses peuvent fournir des indices sur la susceptibilité de l'hôte à développer une infection tuberculeuse et sa progression en maladie. Nous avons recruté des familles nucléaires en bonne santé vivant dans une zone hyperendémique tuberculeuse du Cap en Afrique du Sud. Nous avons interprété les réponses de l'intradermo-réaction (IDR) à la tuberculine in vivo et avons réalisé des essais immunologiques sanguins in vitro pour mesurer la production spécifique de cytokines IFNg vis-à-vis d'antigènes ainsi que la fréquence de production spécifique de cellules IFNg+CD4+ et IFNg+CD8+ vis-à-vis d'antigènes. Nous avons démontré que l'IDR à la tuberculine in vivo et les essais sanguins in vitro, deux essais servant au dépistage de l'infection tuberculeuse, mesurent les réponses immunitaires anti-mycobactériennes sans redondance. Nous avons observé que l'âge a un effet significatif, mais non le sexe, sur les essais immunitaires. Nous avons évalué l'héritabilité des phénotypes immunologiques et observé des taux élevés d'héritabilité. Nous avons effectué pour la première fois un balayage du génome à partir de l'IDR à la tuberculine et avons identifié un locus majeur sur 11p14 (p = 0.000015) ayant un impact sur la positivation de l'IDR à la tube

Sensitive Measurement of Drug-Target Engagement by a Cellular Thermal Shift Assay with Multiplex Proximity Extension Readout

The ability to monitor target engagement in cellular contexts is a key for successful drug discovery and also valuable in clinical routine. A cellular thermal shift assay (CETSA) provides realistic information about drug binding in cells and tissues, revealing drug-target engagement in clinically relevant samples. The CETSA combined with mass spectrometry (MS) detection can be applied in the early hit identification phase to generate target engagement data for large sets of proteins. However, the analysis is slow, requires substantial amounts of the sample material, and often misses proteins of specific interest. Here, we combined the CETSA and the multiplex proximity extension assay (PEA) for analysis of target engagement of a set of 67 proteins from small amounts of the sample material treated with kinase inhibitors. The results were concordant with the corresponding analyses read out via MS. Our approach allows analyses of large numbers of specific target proteins at high sensitivity in limited sample aliquots. Highly sensitive multiplex CETSA-PEA assays are therefore promising for monitoring drug-target engagement in small sample aliquots in the course of drug development and potentially in clinical settings

Social networks, the ‘Work’ and work force of chronic illness self-management: a survey analysis of personal communities

Self-management support forms a central aspect of chronic Illness management nationally and globally. Evidence for the success of self-management support has mainly focussed on individually-centred outcomes of behavioural change. While it is recognised that social network members play an important role there is currently a gap in knowledge regarding who provides what type of support and under what circumstances. This is relevant for understanding the division of labour and the meeting of needs for those living with a long-term condition. We therefore took a network approach to explore self-management support conceptualising it as types of illness ‘work’ undertaken within peoples’ social networks. 300 people from deprived areas and with chronic illnesses took part in a survey conducted in 2010 in the North West of England. A concentric circles diagram was used as a research tool with which participants identified 2,544 network members who contributed to illness management. The results provide an articulation of how social network members are substantially involved in illness management. Whilst partners and close family make the highest contributions there is evidence of inputs from a wide range of relationships. Network member characteristics (type of relationship, proximity, frequency of contact) impact on the amount of illness work undertaken in peoples’ networks. In networks with ‘no partner’ other people tend to contribute more in the way of illness related work than in networks with a partner. This indicates a degree of substitutability between differently constituted networks, and that the level and type of input by different members of a network might change according to circumstances. A network perspective offers an opportunity to redress the balance of an exclusively individual focus on self-management because it addresses the broader set of contributions and resources available to people in need of chronic illness management and suppor

A combined approach for single-cell mRNA and intracellular protein expression analysis

Combined measurements of mRNA and protein expression in single cells enable in-depth analysis of cellular states. We present SPARC, an approach that combines single-cell RNA-sequencing with proximity extension essays to simultaneously measure global mRNA and 89 intracellular proteins in individual cells. We show that mRNA expression fails to accurately reflect protein abundance at the time of measurement, although the direction of changes is in agreement during neuronal differentiation. Moreover, protein levels of transcription factors better predict their downstream effects than do their corresponding transcripts. Finally, we highlight that protein expression variation is overall lower than mRNA variation, but relative protein variation does not reflect the mRNA level. Our results demonstrate that mRNA and protein measurements in single cells provide different and complementary information regarding cell states. SPARC presents a state-of-the-art co-profiling method that overcomes current limitations in throughput and protein localization, including removing the need for cell fixation.De tre första författarna delar förstaförfattarskapet</p

Leukocytes with chromosome Y loss have reduced abundance of the cell surface immunoprotein CD99

Mosaic loss of chromosome Y (LOY) in immune cells is a male-specific mutation associated with increased risk for morbidity and mortality. The CD99 gene, positioned in the pseudoautosomal regions of chromosomes X and Y, encodes a cell surface protein essential for several key properties of leukocytes and immune system functions. Here we used CITE-seq for simultaneous quantification of CD99 derived mRNA and cell surface CD99 protein abundance in relation to LOY in single cells. The abundance of CD99 molecules was lower on the surfaces of LOY cells compared with cells without this aneuploidy in all six types of leukocytes studied, while the abundance of CD proteins encoded by genes located on autosomal chromosomes were independent from LOY. These results connect LOY in single cells with immune related cellular properties at the protein level, providing mechanistic insight regarding disease vulnerability in men affected with mosaic chromosome Y loss in blood leukocytes