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Biochemistry data

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Published Data

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Data available on the European COVID-19 Data Portal

Data available from research groups in Sweden

The list below is curated manually and as such may not be exhaustive. If you would like to see your dataset here or correct information about your dataset, please get in touch with us. Projects sharing data where at least one author has an affiliation with a Swedish research institute are included. At this point, projects which share data openly or which explicitly promise to share data on request are included in this section. In the near future, only projects that either share data openly or have at least a metadata-only record with a clear data access procedure will be included.

Last updated: 2021-09-09

Project Last updated Available data
Simonetti M, Zhang N, Harbers L, Milia MG, Brossa S, [...], Crosetto N
Nat Commun 12 (1)
10.1038/s41467-021-24078-9
While mass-scale vaccination campaigns are ongoing worldwide, genomic surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to monitor the emergence and global spread of viral variants of concern (VOC). Here, we present a streamlined workflow—COVseq—which can be used to generate highly multiplexed sequencing libraries compatible with Illumina platforms from hundreds of SARS-CoV-2 samples in parallel, in a rapid and cost-effective manner. We benchmark COVseq against a standard library preparation method (NEBNext) on 29 SARS-CoV-2 positive samples, reaching 95.4% of concordance between single-nucleotide variants detected by both methods. Application of COVseq to 245 additional SARS-CoV-2 positive samples demonstrates the ability of the method to reliably detect emergent VOC as well as its compatibility with downstream phylogenetic analyses. A cost analysis shows that COVseq could be used to sequence thousands of samples at less than 15 USD per sample, including library preparation and sequencing costs. We conclude that COVseq is a versatile and scalable method that is immediately applicable for SARS-CoV-2 genomic surveillance and easily adaptable to other pathogens such as influenza viruses.
2021-12-00
Axfors C, Schmitt AM, Janiaud P, van’t Hooft J, Abd-Elsalam S, [...], Hemkens LG
Nat Commun 12 (1) 2349
10.1038/s41467-021-22446-z
Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
2021-12-00 Coded data from each included study and data analysis code
Högelin KA, Ruffin N, Pin E, Månberg A, Hober S, [...], Al Nimer F
iScience 103078
10.1016/j.isci.2021.103078
B-cell depleting therapies (BCDTs) are widely used as immunomodulating agents for autoimmune diseases such as multiple sclerosis. Their possible impact on development of immunity to SARS-CoV-2 has raised concerns with the COVID-19 pandemic. We here evaluated the frequency of COVID-19-like symptoms and determined immunological responses in participants of an observational trial comprising several multiple sclerosis disease modulatory drugs, (COMBAT-MS; NCT03193866) and in eleven patients after vaccination, with a focus on BCDT. Almost all seropositive and 17.9% of seronegative patients on BCDT, enriched for a history of COVID-19-like symptoms, developed anti-SARS-CoV-2 T-cell memory and T-cells displayed functional similarity to controls producing IFN-γ and TNF. Following vaccination, vaccine-specific humoral memory was impaired, while all patients developed a specific T-cell response. These results indicate that BCDTs do not abrogate SARS-CoV-2 cellular memory and provide a possible explanation as to why the majority of patients on BCDTs recover from COVID-19.
2021-09-02
Simnica D, Schultheiß C, Mohme M, Paschold L, Willscher E, [...], Binder M
Clin Transl Immunol 10 (9) e1340
10.1002/cti2.1340
T cells have an essential role in the antiviral defence. Public T-cell receptor (TCR) clonotypes are expanded in a substantial proportion of COVID-19 patients. We set out to exploit their potential use as read-out for COVID-19 T-cell immune responses. We searched for COVID-19-associated T-cell clones with public TCRs, as defined by identical complementarity-determining region 3 (CDR3) beta chain amino acid sequence that can be reproducibly detected in the blood of COVID-19 patients. Of the different clonotype identification algorithms used in this study, deep sequencing of brain tissue of five patients with fatal COVID-19 delivered 68 TCR clonotypes with superior representation across 140 immune repertoires of unrelated COVID-19 patients. Mining of immune repertoires from subjects not previously exposed to the virus showed that these clonotypes can be found in almost 20% of pre-pandemic immune repertoires of healthy subjects, with lower representation in repertoires from risk groups like individuals above the age of 60 years or patients with cancer. Together, our data show that at least a proportion of the SARS-CoV-2 T-cell response is mediated by public TCRs that are present in repertoires of unexposed individuals. The lower representation of these clones in repertoires of risk groups or failure to expand such clones may contribute to more unfavorable clinical COVID-19 courses.
2021-08-28
Asano T, Boisson B, Onodi F, Matuozzo D, Moncada-Velez M, [...],
Sci Immunol 6 (62) eabl4348
10.1126/sciimmunol.abl4348
2021-08-19 GEO GSE181787: Database entry containing information on samples and some raw data.
Hoffmann D, Mereiter S, Jin Oh Y, Monteil V, Elder E, [...], Penninger JM
EMBO J e108375
10.15252/embj.2021108375
New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. The 22 N-glycan sites of Spike remain highly conserved among SARS-CoV-2 variants, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike and the receptor binding domain (RBD) of SARS-CoV-2. Two lectins, Clec4g and CD209c, were identified to strongly bind to Spike. Clec4g and CD209c binding to Spike was dissected and visualized in real time and at single molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD-ACE2 interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g and CD209c significantly reduced SARS-CoV-2 infections. These data report the first extensive map and 3D structural modelling of lectin-Spike interactions and uncovers candidate receptors involved in Spike binding and SARS-CoV-2 infections. The capacity of CLEC4G and mCD209c lectins to block SARS-CoV-2 viral entry holds promise for pan-variant therapeutic interventions.
2021-08-10 Structural models for used in virtual screening
Normark J, Vikström L, Gwon Y, Persson I, Edin A, [...], Forsell M
N Engl J Med
10.1056/NEJMc2110716
2021-07-14
Sandberg JT, Varnaitė R, Christ W, Chen P, Muvva JR, [...], Karolinska COVID‐19 Study Group
Clin Transl Immunol 10 (7) e1306
10.1002/cti2.1306
Humoral and cellular immunity to SARS-CoV-2 following COVID-19 will likely contribute to protection from reinfection or severe disease. It is therefore important to characterise the initiation and persistence of adaptive immunity to SARS-CoV-2 amidst the ongoing pandemic. Here, we conducted a longitudinal study on hospitalised moderate and severe COVID-19 patients from the acute phase of disease into convalescence at 5 and 9 months post-symptom onset. Utilising flow cytometry, serological assays as well as B cell and T cell FluoroSpot assays, we assessed the magnitude and specificity of humoral and cellular immune responses during and after human SARS-CoV-2 infection. During acute COVID-19, we observed an increase in germinal centre activity, a substantial expansion of antibody-secreting cells and the generation of SARS-CoV-2-neutralising antibodies. Despite gradually decreasing antibody levels, we show persistent, neutralising antibody titres as well as robust specific memory B cell responses and polyfunctional T cell responses at 5 and 9 months after symptom onset in both moderate and severe COVID-19 patients. Our findings describe the initiation and, importantly, persistence of cellular and humoral SARS-CoV-2-specific immunological memory in hospitalised COVID-19 patients long after recovery, likely contributing towards protection against reinfection.
2021-07-05 Supplementary Information (contains visualisations on clinical chemistry values, Memory B cell and T cell FluoroSpots, and Flow cytometry gating strategy)
Altay O, Arif M, Li X, Yang H, Aydın M, [...], Mardinoglu A
Adv. Sci. 2101222
10.1002/advs.202101222
2021-06-28 Raw, patient-level characteristics and data
Krambrich J, Akaberi D, Ling J, Hoffman T, Svensson L, [...], Lundkvist Å
Virol J 18 (1) 109
10.1186/s12985-021-01556-6
The ongoing SARS-CoV-2 pandemic has spread rapidly worldwide and disease prevention is more important than ever. In the absence of a vaccine, knowledge of the transmission routes and risk areas of infection remain the most important existing tools to prevent further spread. Here we investigated the presence of the SARS-CoV-2 virus in the hospital environment at the Uppsala University Hospital Infectious Disease ward by RT-qPCR and determined the infectivity of the detected virus in vitro on Vero E6 cells. SARS-CoV-2 RNA was detected in several areas, although attempts to infect Vero E6 cells with positive samples were unsuccessful. However, RNase A treatment of positive samples prior to RNA extraction did not degrade viral RNA, indicating the presence of SARS-CoV-2 nucleocapsids or complete virus particles protecting the RNA as opposed to free viral RNA. Our results show that even in places where a moderate concentration (Ct values between 30 and 38) of SARS-CoV-2 RNA was found; no infectious virus could be detected. This suggests that the SARS-CoV-2 virus in the hospital environment subsides in two states; as infectious and as non-infectious. Future work should investigate the reasons for the non-infectivity of SARS-CoV-2 virions.
2021-06-02 Ct values for all collected samples at the Uppsala University infectious disease ward
Brueggemann AB, Jansen van Rensburg MJ, Shaw D, McCarthy ND, Jolley KA, [...], Zhou F
The Lancet Digital Health 3 (6) e360-e370
10.1016/S2589-7500(21)00077-7
Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27-0·37]) and 82% at 8 weeks (0·18 [0·14-0·23]) following the week in which significant changes in population movements were recorded. The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).
2021-06-00 Data processing, visualisation, analysis code
Mehregan A, Pérez-Conesa S, Zhuang Y, Elbahnsi A, Pasini D, [...], Delemotte L
bioRxiv
10.1101/2021.05.28.446179
2021-05-28 Input files and simulations
Chen X, Saccon E, Appelberg KS, Mikaeloff F, Rodriguez JE, [...], Gupta S
Cell Death Discov 7 (1) 114
10.1038/s41420-021-00487-z
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce the susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV, and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon-stimulated genes and their role in the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.
2021-05-18
Messner CB, Demichev V, Bloomfield N, Yu JSL, White M, [...], Ralser M
Nat Biotechnol
10.1038/s41587-021-00860-4
Accurate quantification of the proteome remains challenging for large sample series and longitudinal experiments. We report a data-independent acquisition method, Scanning SWATH, that accelerates mass spectrometric (MS) duty cycles, yielding quantitative proteomes in combination with short gradients and high-flow (800 µl min -1) chromatography. Exploiting a continuous movement of the precursor isolation window to assign precursor masses to tandem mass spectrometry (MS/MS) fragment traces, Scanning SWATH increases precursor identifications by ~70% compared to conventional data-independent acquisition (DIA) methods on 0.5-5-min chromatographic gradients. We demonstrate the application of ultra-fast proteomics in drug mode-of-action screening and plasma proteomics. Scanning SWATH proteomes capture the mode of action of fungistatic azoles and statins. Moreover, we confirm 43 and identify 11 new plasma proteome biomarkers of COVID-19 severity, advancing patient classification and biomarker discovery. Thus, our results demonstrate a substantial acceleration and increased depth in fast proteomic experiments that facilitate proteomic drug screens and clinical studies.
2021-03-25
Sherina N, Piralla A, Du L, Wan H, Kumagai-Braesch M, [...], Pan-Hammarström Q
Med (N Y)
10.1016/j.medj.2021.02.001
Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody levels and specific memory B- and T-cell responses in convalescent coronavirus disease-2019 (COVID-19) patients. Altogether 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain antibody levels over a period of eight months. In addition, level of SARS-CoV-2 neutralizing antibodies, specific memory B- and T-cell responses were tested in a subset of samples. Anti-SARS-CoV-2 antibodies were present in 85% of the samples collected within 4 weeks after onset of symptoms in COVID-19 patients. Levels of specific IgM/IgA antibodies declined after 1 month while levels of specific IgG antibodies and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG antibodies were still present, though at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B- and T-cell responses developed with time and were persistent in all patients followed up till 6-8 months. Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 might persist for at least 6-8 months, regardless of disease severity. Development of medium or long-term protective immunity through vaccination might thus be possible. EU-ATAC consortium, the Italian Ministry of Health and SciLife/KAW.
2021-02-10 Demographic and clinical characteristics of the COVID-19 patients (N=122 Italian, N=12 Swedish)
Lourda M, Dzidic M, Hertwig L, Bergsten H, Palma Medina LM, [...], None
medRxiv
https://doi.org/10.1101/2021.01.27.21250591
2021-01-31 Karolinska KI/K Covid19 Immune atlas
Tomić D, Davidović D, Szasz AM, Rezeli M, Pirkić B, [...], Rogina BM
Inform Med Unlocked 23 100529
10.1016/j.imu.2021.100529
Spike glycoprotein is essential for the reproduction of the SARS-CoV-2 virus, and its inhibition using already approved antiviral drugs may open new avenues for treatment of patients with the COVID-19 disease. Because of that we analyzed the inhibition of SARS-CoV-2 spike glycoprotein with FDA-approved antiviral drugs and their double and triple combinations. We used the Vini in silico model of cancer to perform this virtual drug screening, showing HIV drugs to be the most effective. Besides, the combination of cobicistat-abacavir-rilpivirine HIV drugs demonstrated the highest in silico efficacy of inhibiting SARS-CoV-2 spike glycoprotein. Therefore, a clinical trial of cobicistat-abacavir-rilpivirine on a limited number of COVID-19 patients in moderately severe and severe condition is warranted.
2021-01-30
Persson BD, John L, Rafie K, Strebl M, Frängsmyr L, [...], Arnberg N
Proc Natl Acad Sci U S A 118 (3)
10.1073/pnas.2020732118
Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion-CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors.
2021-01-19 PDB 7AJP: Crystal Structure of Human Adenovirus 56 Fiber Knob
Tian JH, Patel N, Haupt R, Zhou H, Weston S, [...], Smith G
Nat Commun 12 (1) 372
10.1038/s41467-020-20653-8
The COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd protection and control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) from the full-length spike (S) protein that is stable in the prefusion conformation. NVX-CoV2373 S form 27.2-nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicit high titer anti-S IgG that blocks hACE2 receptor binding, neutralize virus, and protects against SARS-CoV-2 challenge with no evidence of vaccine-associated enhanced respiratory disease. NVX-CoV2373 also elicits multifunctional CD4 + and CD8+ T cells, CD4+ follicular helper T cells (Tfh), and antigen-specific germinal center (GC) B cells in the spleen. In baboons, low-dose levels of NVX-CoV2373 with Matrix-M was also highly immunogenic and elicited high titer anti-S antibodies and functional antibodies that block S-protein binding to hACE2 and neutralize virus infection and antigen-specific T cells. These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2373 with Matrix-M (NCT04368988).
2021-01-14 Various raw data
Iravani B, Peter MG, Arshamian A, Olsson MJ, Hummel T, [...], Lundström JN
bioRxiv
10.1101/2021.01.11.426175
2021-01-13 Available on request
Koenig PA, Das H, Liu H, Kümmerer BM, Gohr FN, [...], Schmidt FI
Science 371 (6530) eabe6230
10.1126/science.abe6230
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. Here, we generated four neutralizing nanobodies that target the receptor-binding domain of the SARS-CoV-2 spike protein. We defined two distinct binding epitopes using x-ray crystallography and cryo-electron microscopy. Based on the structures, we engineered multivalent nanobodies with more than 100-fold improved neutralizing activity than monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor-binding competition, while other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion, and rendered the virions non-infectious.
2021-01-12
Kermani NZ, None , Song WJ, Badi Y, Versi A, [...], Chung KF
Respir Res 22 (1) 101876
10.1186/s12931-020-01605-8
Bats are reservoirs for a large number of viruses which have potential to cause major human disease outbreaks, including the current coronavirus disease 2019 (COVID-19) pandemic. Major efforts are underway to understand bat immune response to viruses, whereas much less is known about their immune responses to bacteria. In this study, MR1-restricted T (MR1T) cells were detected through the use of MR1 tetramers in circulation and tissues of Pteropus alecto (Pa) bats. Pa MR1T cells exhibited weak responses to MR1-presented microbial metabolites at resting state. However, following priming with MR1-presented agonist they proliferated, upregulated critical transcription factors and cytolytic proteins, and gained transient expression of Th1/17-related cytokines and antibacterial cytotoxicity. Collectively, these findings show that the Pa bat immune system encompasses an abundant and functionally conserved population of MR1T cells with mucosal-associated invariant T-like characteristics, suggesting that MR1 and MR1T cells also play a significant role in bat immune defense.
2021-01-07 Available on request
Pilotto A, Masciocchi S, Volonghi I, De Giuli V, Caprioli F, [...], Padovani A
Clin Infect Dis
10.1093/cid/ciaa1933
2021-01-04
  • Available in paper: Clinical features, imaging and CSF biochemical analyses of SARS-CoV-2 encephalitis cases
  • Available in paper: Clinical features, imaging and CSF biochemical analyses of COV-Enc cases
Pettke A, Tampere M, Pronk R, Wallner O, Falk A, [...], Puumalainen MR
Viruses 13 (1) 37
10.3390/v13010037
RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in several cell models and rescued ZIKV-induced neurotoxicity in brain organoids. The compound's mechanism-of-action was pinpointed to late steps in the virus life cycle, impairing the formation of new virus particles. Collectively, in this study, we expand the antiviral activity of new small molecule inhibitors to a new virus class of Flaviviruses, but also uncover compounds' mechanism of action, which are important for the further development of antivirals.
2020-12-29 The effect of novel antiviral compounds against ZIKV in several cell models; other supporting data
Tampere M, Pettke A, Salata C, Wallner O, Koolmeister T, [...], Puumalainen MR
Viruses 12 (12) 1423
10.3390/v12121423
2020-12-10
Robertson J, Gostner JM, Nilsson S, Andersson L, Fuchs D, [...], Gisslen M
Infect Dis . 2020 Dec 10;20(1):942. Dec 10; 20 (1) 942
10.1186/s12879-020-05671-7
Background The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is rapidly spreading worldwide. There is limited information about prognostic markers that could help clinicians to identify COVID-19 patients with a poor prognosis. Serum levels of the immune activation marker neopterin has shown to be of prognostic value in patients with SARS. The aim of this study was to investigate whether serum neopterin is associated with the severity of COVID-19. Methods We included 34 patients with confirmed COVID-19 between March 3 and March 30, 2020. Fifteen patients had mild disease and did not require hospitalization, whereas 19 patients developed severe COVID-19 requiring intensive care. Concentrations of serum neopterin, tryptophan, and kynurenine were measured at and repeatedly after inclusion. Results We found a more than two-fold higher mean concentration of neopterin in severely ill patients (mean value 42.0 nmol/L (SD 18.2)) compared to patients with mild symptoms (16.9 nmol/L (SD 11.0)). All of the severe cases had elevated neopterin concentrations (>9.1 nmol/L) at the initial sampling with values ranging from 17.2 to 86.7 nmol/L. In comparison, 10 of 15 patients with mild disease had neopterin levels above 9.1 nmol/L, with concentrations in the range from 4.9 to 31.6 nmol/L. Neopterin levels gradually decreased during the course of COVID-19, but severe cases maintained elevated levels for a longer period. Moreover, lower levels of tryptophan and higher levels of kynurenine, indicating an increased tryptophan catabolism, were seen in the group with severe cases. Conclusions In conclusion, we found that serum neopterin levels are associated with the severity of COVID-19. Our findings suggest that neopterin could be used as a prognostic marker, but further studies are needed to elucidate how it can be used in clinical praxis.
2020-12-10 Available on request
Cagigi A, Yu M, Falck-Jones S, Vangeti S, Österberg B, [...], Smed-Sörensen A
medRxiv
10.1101/2020.11.25.20238592
2020-12-06 Available on request
Nyman E, Lindh M, Lövfors W, Simonsson C, Persson A, [...], Cedersund G
CPT Pharmacometrics Syst. Pharmacol. 9 (12) 707-717
10.1002/psp4.12568
Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g., asthma and atherosclerosis. Anti-inflammatory drugs come with side effects that may be aggravated by high and fluctuating drug concentrations. To remedy this, an anti-inflammatory drug should have an appropriate pharmacokinetic half-life or better still, a sustained anti-inflammatory drug response. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti-inflammatory response to a common glucocorticoid drug, dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism-a slow release of dexamethasone from the receptor-drug complex. The developed model is in agreement with time-resolved training and testing data and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge-driven drug development to find sustained anti-inflammatory responses and fewer side effects.
2020-12-00 Experimental data and data analysis code
Stebbing J, Sánchez Nievas G, Falcone M, Youhanna S, Richardson P, [...], Lauschke VM
Sci Adv 7 (1)
10.1126/sciadv.abe4724
Using AI we identified baricitinib as possessing anti-viral and anti-cytokine efficacy. We now show a 71% (95% CI 0.15-0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age 81 years). A further 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold. RNA-Seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and super-resolution microscopy, baricitinib exerts activity rapidly through the inhibition of host proteins (numb associated kinases), uniquely amongst anti-virals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivizes further randomized controlled trials.
2020-11-13
Wacker A, Weigand JE, Akabayov SR, Altincekic N, Bains JK, [...], Zetzsche H
Nucleic Acids Res 48 (22) 12415-12435
10.1093/nar/gkaa1013
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5' end, the ribosomal frameshift segment and the 3'-untranslated region (3'-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
2020-11-10
García M, Kokkinou E, Carrasco García A, Parrot T, Palma Medina LM, [...], Group tKKCS
Clin Transl Immunol 9 (12)
10.1002/cti2.1224
Objectives The role of innate lymphoid cells (ILCs) in coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unknown. Understanding the immune response in COVID-19 could contribute to unravel the pathogenesis and identification of treatment targets. To describe the phenotypic landscape of circulating ILCs in COVID-19 patients and to identify ILC phenotypes correlated to serum biomarkers, clinical markers, and laboratory parameters relevant in COVID-19. Methods Blood samples collected from moderately (n=11) and severely ill (n=12) COVID-19 patients as well as healthy control donors (n=16), were analyzed with 18-parameter flow cytometry. Using supervised and unsupervised approaches, we examined the ILC activation status and homing profile. Clinical and laboratory parameters were obtained from all COVID-19 patients and serum biomarkers were analyzed with multiplex immunoassays. Results ILCs were largely depleted from the circulation of COVID-19 patients compared with healthy controls. Remaining circulating ILCs from patients revealed increased frequencies of ILC2 in moderate COVID-19, with a concomitant decrease of ILC precursors (ILCp), as compared with controls. ILC2 and ILCp showed an activated phenotype with increased CD69 expression, whereas expression levels of the chemokine receptors CXCR3 and CCR4 were significantly altered in ILC2 and ILCp, and ILC1, respectively. The activated ILC profile of COVID-19 patients was associated with soluble inflammatory markers, while frequencies of ILC subsets were correlated with laboratory parameters that reflect the disease severity. Conclusion This study provides insights into the potential role of ILCs in immune responses against SARS-CoV-2, particularly linked to the severity of COVID-19.
2020-11-04 Karolinska KI/K Covid19 Immune atlas
Custódio TF, Das H, Sheward DJ, Hanke L, Pazicky S, [...], Löw C
Nat Commun 11 (1)
10.1038/s41467-020-19204-y
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC50 of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed an unusual conformation of the spike where two RBDs are in the ‘up’ ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.
2020-11-04
Marklund E, Leach S, Axelsson H, Nyström K, Norder H, [...], Gisslén M
PLoS One 15 (10) e0241104
10.1371/journal.pone.0241104
To accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset. SARS-CoV-2-specific IgG antibody levels were quantified using two clinically validated and widely used commercial serological assays (Architect, Abbott Laboratories and iFlash 1800, YHLO), detecting antibodies against the spike and nucleocapsid proteins. Forty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P = 0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset. Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys.
2020-10-21 Raw data
Castro Dopico X, Hanke L, Sheward DJ, Muschiol S, Aleman S, [...], Karlsson Hedestam GB
medRxiv
10.1101/2020.07.17.20155937
Serology is critical for understanding pathogen-specific immune responses, but is fraught with difficulty, not least because the strength of antibody (Ab) response varies greatly between individuals and mild infections generally generate lower Ab titers (1-3). We used robust IgM, IgG and IgA Ab tests to evaluate anti-SARS-CoV-2 responses in individuals PCR+ for virus RNA (n=105) representing different categories of disease severity, including mild cases. All PCR+ individuals in the study became IgG-positive against pre-fusion trimers of the virus spike (S) glycoprotein, but titers varied greatly. Elevated IgA, IL-6 and neutralizing responses were present in intensive care patients. Additionally, blood donors and pregnant women (n=2,900) sampled throughout the first wave of the pandemic in Stockholm, Sweden, further demonstrated that anti-S IgG titers differed several orders of magnitude between individuals, with an increase of low titer values present in the population at later time points (4,5). To improve upon current methods to identify low titers and extend the utility of individual measures (6,7), we used our PCR+ individual data to train machine learning algorithms to assign likelihood of past infection. Using these tools that assigned probability to individual responses against S and the receptor binding domain (RBD), we report SARS-CoV-2-specific IgG in 13.7% of healthy donors five months after the peak of spring COVID-19 deaths, when mortality and ICU occupancy in the country due to the virus were at low levels. These data further our understanding of antibody responses to the virus and provide solutions to problems in serology data analysis.
2020-10-19 Inferring seroprevalence from ELISA data, without choosing a cutoff
Frithiof R, Bergqvist A, Järhult JD, Lipcsey M, Hultström M
Crit Care 24 (1) 587
10.1186/s13054-020-03302-w
2020-09-29 Available on request
Kanberg N, Ashton NJ, Andersson LM, Yilmaz A, Lindh M, [...], Gisslén M
Neurology 95 (12) e1754-e1759
10.1212/WNL.0000000000010111
To test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury. We recruited 47 patients with mild (n = 20), moderate (n = 9), or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort. The patients with severe COVID-19 had higher plasma concentrations of GFAp ( p = 0.001) and NfL (p < 0.001) than controls, while GFAp was also increased in patients with moderate disease (p = 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (p < 0.01), while NfL showed a sustained increase from first to last follow-up (p < 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury. We show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19-related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients.
2020-09-22 Researchers can apply for access to anonymized data
Bryant P, Elofsson A
PeerJ 8 e9879
10.7717/peerj.9879
As governments across Europe have issued non-pharmaceutical interventions (NPIs) such as social distancing and school closing, the mobility patterns in these countries have changed. Most states have implemented similar NPIs at similar time points. However, it is likely different countries and populations respond differently to the NPIs and that these differences cause mobility patterns and thereby the epidemic development to change. We build a Bayesian model that estimates the number of deaths on a given day dependent on changes in the basic reproductive number, R0, due to differences in mobility patterns. We utilise mobility data from Google mobility reports using five different categories: retail and recreation, grocery and pharmacy, transit stations, workplace and residential. The importance of each mobility category for predicting changes in R0 is estimated through the model. The changes in mobility have a considerable overlap with the introduction of governmental NPIs, highlighting the importance of government action for population behavioural change. The shift in mobility in all categories shows high correlations with the death rates 1 month later. Reduction of movement within the grocery and pharmacy sector is estimated to account for most of the decrease in R0. Our model predicts 3-week epidemic forecasts, using real-time observations of changes in mobility patterns, which can provide governments with direct feedback on the effects of their NPIs. The model predicts the changes in a majority of the countries accurately but overestimates the impact of NPIs in Sweden and Denmark and underestimates them in France and Belgium. We also note that the exponential nature of all epidemiological models based on the basic reproductive number, R0 cause small errors to have extensive effects on the predicted outcome.
2020-09-15 Modelling code and data
Ling J, Hickman RA, Li J, Lu X, Lindahl JF, [...], Järhult JD
Viruses 12 (9)
10.3390/v12091026
During the COVID-19 pandemic, the virus evolved, and we therefore aimed to provide an insight into which genetic variants were enriched, and how they spread in Sweden. We analyzed 348 Swedish SARS-CoV-2 sequences freely available from GISAID obtained from 7 February 2020 until 14 May 2020. We identified 14 variant sites ≥5% frequency in the population. Among those sites, the D936Y substitution in the viral Spike protein was under positive selection. The variant sites can distinguish 11 mutational profiles in Sweden. Nine of the profiles appeared in Stockholm in March 2020. Mutational profiles 3 (B.1.1) and 6 (B.1), which contain the D936Y mutation, became the predominant profiles over time, spreading from Stockholm to other Swedish regions during April and the beginning of May. Furthermore, Bayesian phylogenetic analysis indicated that SARS-CoV-2 could have emerged in Sweden on 27 December 2019, and community transmission started on February 1st with an evolutionary rate of 1.5425 × 10 -3 substitutions per year. Our study provides novel knowledge on the spatio-temporal dynamics of Swedish SARS-CoV-2 variants during the early pandemic. Characterization of these viral variants can provide precious insights on viral pathogenesis and can be valuable for diagnostic and drug development approaches.
2020-09-14 Spatial temporal appearance of each variant and their mutation profile and clade information; Other supplementary materials.
Bortz RH, Florez C, Laudermilch E, Wirchnianski AS, Lasso G, [...], Chandran K
mSphere 6 (2)
10.1128/mSphere.00224-21
The COVID-19 global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to place an immense burden on societies and healthcare systems. A key component of COVID-19 control efforts is serologic testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test makes it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.
2020-09-11 Available on request
Hanke L, Vidakovics Perez L, Sheward DJ, Das H, Schulte T, [...], McInerney GM
Nat Commun 11 (1) 4420
10.1038/s41467-020-18174-5
SARS-CoV-2 enters host cells through an interaction between the spike glycoprotein and the angiotensin converting enzyme 2 (ACE2) receptor. Directly preventing this interaction presents an attractive possibility for suppressing SARS-CoV-2 replication. Here, we report the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. Ty1 binds the RBD with high affinity, occluding ACE2. A cryo-electron microscopy structure of the bound complex at 2.9 Å resolution reveals that Ty1 binds to an epitope on the RBD accessible in both the 'up' and 'down' conformations, sterically hindering RBD-ACE2 binding. While fusion to an Fc domain renders Ty1 extremely potent, Ty1 neutralizes SARS-CoV-2 spike pseudovirus as a 12.8 kDa nanobody, which can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Ty1 is therefore an excellent candidate as an intervention against COVID-19.
2020-09-04
Maucourant C, Filipovic I, Ponzetta A, Aleman S, Cornillet M, [...], Karolinska COVID-19 Study Group
Sci Immunol 5 (50)
10.1126/sciimmunol.abd6832
Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56 bright NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease.
2020-08-21
Hultström M, von Seth M, Frithiof R
J Hypertens 38 (8) 1613-1614
10.1097/HJH.0000000000002531
No abstract available
2020-08-00 Provided in the article: biochemistry of patients in intensive care (N=9)
Pang J, Xu F, Aondio G, Li Y, Fumagalli A, [...], Cao Y
Nat Commun 12 (1) 814
10.1038/s41467-021-21085-8
On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O 2 ratio (PaO2/FiO2) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO2/FiO2 ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.
2020-07-29
Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, [...], Lindskog C
Mol Syst Biol 16 (7)
10.15252/msb.20209610
2020-07-00
Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, [...], Penninger JM
Cell 181 (4) 905-913.e7
10.1016/j.cell.2020.04.004
We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
2020-05-14