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1.
Euro Surveill ; 25(28)2020 07.
Article in English | MEDLINE | ID: covidwho-647504

ABSTRACT

BackgroundA novel coronavirus, SARS-CoV-2, which emerged at the end of 2019 and causes COVID-19, has resulted in worldwide human infections. While genetically distinct, SARS-CoV-1, the aetiological agent responsible for an outbreak of severe acute respiratory syndrome (SARS) in 2002-2003, utilises the same host cell receptor as SARS-CoV-2 for entry: angiotensin-converting enzyme 2 (ACE2). Parts of the SARS-CoV-1 spike glycoprotein (S protein), which interacts with ACE2, appear conserved in SARS-CoV-2.AimThe cross-reactivity with SARS-CoV-2 of monoclonal antibodies (mAbs) previously generated against the S protein of SARS-CoV-1 was assessed.MethodsThe SARS-CoV-2 S protein sequence was aligned to those of SARS-CoV-1, Middle East respiratory syndrome (MERS) and common-cold coronaviruses. Abilities of mAbs generated against SARS-CoV-1 S protein to bind SARS-CoV-2 or its S protein were tested with SARS-CoV-2 infected cells as well as cells expressing either the full length protein or a fragment of its S2 subunit. Quantitative ELISA was also performed to compare binding of mAbs to recombinant S protein.ResultsAn immunogenic domain in the S2 subunit of SARS-CoV-1 S protein is highly conserved in SARS-CoV-2 but not in MERS and human common-cold coronaviruses. Four murine mAbs raised against this immunogenic fragment could recognise SARS-CoV-2 S protein expressed in mammalian cell lines. In particular, mAb 1A9 was demonstrated to detect S protein in SARS-CoV-2-infected cells and is suitable for use in a sandwich ELISA format.ConclusionThe cross-reactive mAbs may serve as useful tools for SARS-CoV-2 research and for the development of diagnostic assays for COVID-19.


Subject(s)
Antibodies, Monoclonal/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Sequence , Animals , Betacoronavirus/genetics , Blotting, Western , COS Cells , Chlorocebus aethiops , Conserved Sequence , Coronavirus Infections/genetics , Coronavirus Infections/virology , Cross Reactions/immunology , Enzyme-Linked Immunosorbent Assay/methods , Fluorescent Antibody Technique/methods , Genome, Viral , Mice , Pandemics , Peptidyl-Dipeptidase A/immunology , Plasmids , Pneumonia, Viral/genetics , Recombinant Proteins/immunology , SARS Virus/genetics , Sequence Alignment , Severe Acute Respiratory Syndrome/virology , Spike Glycoprotein, Coronavirus/genetics , Transfection , Vero Cells , Virus Integration
2.
Virol Sin ; 35(3): 290-304, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-618224

ABSTRACT

The recent outbreak of coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already affected a large population of the world. SARS-CoV-2 belongs to the same family of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). COVID-19 has a complex pathology involving severe acute respiratory infection, hyper-immune response, and coagulopathy. At present, there is no therapeutic drug or vaccine approved for the disease. There is an urgent need for an ideal animal model that can reflect clinical symptoms and underlying etiopathogenesis similar to COVID-19 patients which can be further used for evaluation of underlying mechanisms, potential vaccines, and therapeutic strategies. The current review provides a paramount insight into the available animal models of SARS-CoV-2, SARS-CoV, and MERS-CoV for the management of the diseases.


Subject(s)
Betacoronavirus , Coronavirus Infections/virology , Disease Models, Animal , Middle East Respiratory Syndrome Coronavirus , Pneumonia, Viral/virology , SARS Virus , Severe Acute Respiratory Syndrome/virology , Animals , Betacoronavirus/pathogenicity , Camelids, New World , Camelus , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Mice , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/physiopathology , Severe Acute Respiratory Syndrome/therapy , Swine
3.
Open Vet J ; 10(2): 164-177, 2020 08.
Article in English | MEDLINE | ID: covidwho-724486

ABSTRACT

Viruses are having great time as they seem to have bogged humans down. Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and novel coronavirus (COVID-19) are the three major coronaviruses of present-day global human and animal health concern. COVID-19 caused by SARS-CoV-2 is identified as the newest disease, presumably of bat origin. Different theories on the evolution of viruses are in circulation, yet there is no denying the fact that the animal source is the skeleton. The whole world is witnessing the terror of the COVID-19 pandemic that is following the same path of SARS and MERS, and seems to be more severe. In addition to humans, several species of animals are reported to have been infected with these life-threatening viruses. The possible routes of transmission and their zoonotic potentialities are the subjects of intense research. This review article aims to overview the link of all these three deadly coronaviruses among animals along with their phylogenic evolution and cross-species transmission. This is essential since animals as pets or food are said to pose some risk, and their better understanding is a must in order to prepare a possible plan for future havoc in both human and animal health. Although COVID-19 is causing a human health hazard globally, its reporting in animals are limited compared to SARS and MERS. Non-human primates and carnivores are most susceptible to SARS-coronavirus and SARS-CoV-2, respectively, whereas the dromedary camel is susceptible to MERS-coronavirus. Phylogenetically, the trio viruses are reported to have originated from bats and have special capacity to undergo mutation and genomic recombination in order to infect humans through its reservoir or replication host. However, it is difficult to analyze how the genomic pattern of coronaviruses occurs. Thus, increased possibility of new virus-variants infecting humans and animals in the upcoming days seems to be the biggest challenge for the future of the world. One health approach is portrayed as our best way ahead, and understanding the animal dimension will go a long way in formulating such preparedness plans.


Subject(s)
Betacoronavirus/classification , Coronavirus Infections/veterinary , Middle East Respiratory Syndrome Coronavirus/classification , Pandemics/veterinary , Pneumonia, Viral/veterinary , SARS Virus/classification , Severe Acute Respiratory Syndrome/veterinary , Animals , Animals, Wild , Betacoronavirus/genetics , Camelids, New World/virology , Camelus/virology , Cats , Chiroptera/virology , Coronavirus Infections/immunology , Coronavirus Infections/transmission , Disease Susceptibility/veterinary , Dogs , Eutheria/virology , Ferrets/virology , Humans , Lions/virology , Middle East Respiratory Syndrome Coronavirus/genetics , Phylogeny , Pneumonia, Viral/immunology , Pneumonia, Viral/transmission , Primates/virology , Raccoon Dogs/virology , SARS Virus/genetics , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/transmission , Snakes/virology , Tigers/virology , Viverridae/virology
4.
Viruses ; 12(8)2020 08 07.
Article in English | MEDLINE | ID: covidwho-712882

ABSTRACT

Seven years after the Middle East respiratory syndrome (MERS) outbreak, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) made its first appearance in a food market in Wuhan, China, drawing an entirely new course to our lives. As the virus belongs to the same genus of MERS and SARS, researchers have been trying to draw lessons from previous outbreaks to find a potential cure. Although there were five Phase I human vaccine trials against SARS and MERS, the lack of data in humans provided us with limited benchmarks that could help us design a new vaccine for Coronavirus disease 2019 (COVID-19). In this review, we showcase the similarities in structures of virus components between SARS-CoV, MERS-CoV, and SARS-CoV-2 in areas relevant to vaccine design. Using the ClinicalTrials.gov and World Health Organization (WHO) databases, we shed light on the 16 current approved clinical trials worldwide in search for a COVID-19 vaccine. The different vaccine platforms being tested are Bacillus Calmette-Guérin (BCG) vaccines, DNA and RNA-based vaccines, inactivated vaccines, protein subunits, and viral vectors. By thoroughly analyzing different trials and platforms, we also discuss the advantages and disadvantages of using each type of vaccine and how they can contribute to the design of an adequate vaccine for COVID-19. Studying past efforts invested in conducting vaccine trials for MERS and SARS will provide vital insights regarding the best approach to designing an effective vaccine against COVID-19.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Clinical Trials as Topic , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/immunology , Models, Animal , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/prevention & control , Severe Acute Respiratory Syndrome/virology , Vaccines, DNA/immunology , Viral Vaccines/administration & dosage
5.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Article in English | MEDLINE | ID: covidwho-709116

ABSTRACT

As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.


Subject(s)
Aging/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Macaca mulatta/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Age Factors , Aging/metabolism , Animals , Betacoronavirus/physiology , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Cytokines/metabolism , Inflammation/immunology , Inflammation/veterinary , Inflammation/virology , Lung/immunology , Lung/pathology , Lung/virology , Macaca mulatta/virology , Monkey Diseases/immunology , Monkey Diseases/virology , Pandemics/veterinary , Pneumonia, Viral/veterinary , Pneumonia, Viral/virology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/veterinary , Severe Acute Respiratory Syndrome/virology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Viral Load/immunology , Viral Load/veterinary , Virus Replication/immunology
6.
Clin Immunol ; 219: 108555, 2020 10.
Article in English | MEDLINE | ID: covidwho-696063

ABSTRACT

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.


Subject(s)
Acute Kidney Injury/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/pathogenicity , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Acute Kidney Injury/complications , Acute Kidney Injury/drug therapy , Acute Kidney Injury/virology , Adult , Betacoronavirus/immunology , Biomarkers/metabolism , Complement Activation/drug effects , Complement C4b/antagonists & inhibitors , Complement C5/antagonists & inhibitors , Complement Membrane Attack Complex/antagonists & inhibitors , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Immunity, Humoral/drug effects , Male , Mannose-Binding Protein-Associated Serine Proteases/genetics , Mannose-Binding Protein-Associated Serine Proteases/immunology , Middle Aged , Neutrophils/immunology , Neutrophils/pathology , Pandemics , Peptide Fragments/antagonists & inhibitors , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology
7.
J Transl Med ; 18(1): 297, 2020 08 03.
Article in English | MEDLINE | ID: covidwho-692007

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome virus SARS-CoV-2, a close relative of the SARS-CoV virus, is the cause of the recent COVID-19 pandemic affecting, to date, over 14 million individuals across the globe and demonstrating relatively high rates of infection and mortality. A third virus, the H5N1, responsible for avian influenza, has caused infection with some clinical similarities to those in COVID-19 infections. Cytokines, small proteins that modulate immune responses, have been directly implicated in some of the severe responses seen in COVID-19 patients, e.g. cytokine storms. Understanding the immune processes related to COVID-19, and other similar infections, could help identify diagnostic markers and therapeutic targets. METHODS: Here we examine data of cytokine, immune cell types, and disease associations captured from biomedical literature associated with COVID-19, Coronavirus in general, SARS, and H5N1 influenza, with the objective of identifying potentially useful relationships and areas for future research. RESULTS: Cytokine and cell-type associations captured from Medical Subject Heading (MeSH) terms linked to thousands of PubMed records, has identified differing patterns of associations between the four corpuses of publications (COVID-19, Coronavirus, SARS, or H5N1 influenza). Clustering of cytokine-disease co-occurrences in the context of Coronavirus has identified compelling clusters of co-morbidities and symptoms, some of which already known to be linked to COVID-19. Finally, network analysis identified sub-networks of cytokines and immune cell types associated with different manifestations, co-morbidities and symptoms of Coronavirus, SARS, and H5N1. CONCLUSION: Systematic review of research in medicine is essential to facilitate evidence-based choices about health interventions. In a fast moving pandemic the approach taken here will identify trends and enable rapid comparison to the literature of related diseases.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Lung Diseases/immunology , Pneumonia, Viral/immunology , Publications , Cluster Analysis , Comorbidity , Cytokine Release Syndrome/virology , Cytokines/immunology , Hematopoietic Stem Cells/cytology , Humans , Immune System , Influenza A Virus, H5N1 Subtype , Influenza, Human/immunology , Pandemics , PubMed , Severe Acute Respiratory Syndrome/immunology
8.
Nature ; 584(7821): 443-449, 2020 08.
Article in English | MEDLINE | ID: covidwho-647154

ABSTRACT

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health1 and the medical countermeasures available so far are limited2,3. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-24. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein5, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (SRBD) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the SRBD, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Animals , Antibodies, Monoclonal/immunology , Betacoronavirus/chemistry , Binding, Competitive , Cell Line , Cross Reactions , Disease Models, Animal , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , Female , Humans , Macaca mulatta , Male , Mice , Middle Aged , Neutralization Tests , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pre-Exposure Prophylaxis , SARS Virus/chemistry , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
9.
Immunity ; 53(2): 248-263, 2020 08 18.
Article in English | MEDLINE | ID: covidwho-643222

ABSTRACT

A key goal to controlling coronavirus disease 2019 (COVID-19) is developing an effective vaccine. Development of a vaccine requires knowledge of what constitutes a protective immune response and also features that might be pathogenic. Protective and pathogenic aspects of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not well understood, partly because the virus has infected humans for only 6 months. However, insight into coronavirus immunity can be informed by previous studies of immune responses to non-human coronaviruses, common cold coronaviruses, and SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we review the literature describing these responses and discuss their relevance to the SARS-CoV-2 immune response.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Pneumonia, Viral/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Adaptive Immunity/immunology , Animals , Betacoronavirus/pathogenicity , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/prevention & control , Humans , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Severe Acute Respiratory Syndrome/prevention & control , Viral Vaccines/immunology
10.
Eur J Clin Invest ; 50(9): e13342, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-636108

ABSTRACT

COVID-19 pandemia is a major concern for patients and healthcare systems. The fear of infection by patients with concomitant rheumatic diseases (either adult or children) and connective tissue diseases is arising worldwide, because of their immunological background and immunological therapies. Analysing the basic biology of single diseases, the data suggest that there is an "immunological umbrella" that seems to protect against the infection, through IFN type 1 and NK cell function. To date, reports from China, United States and Europe did not reveal an higher risk of infection, either for rheumatoid arthritis, juvenile idiopathic arthritis nor for lupus erythematosus. Antimalarials, anti-IL6-Anti-IL6 receptor, anti-IL1, anti-GM-CSF receptor and JAK1/2/3 inhibitors, are under investigation in COVID-dedicated clinical trials to control the inflammation raised by SARS-CoV-2 infection. Initial reports on the occurrence of autoimmune phenomena in the convalescence phase of SARS-CoV-2 infection suggests that the immunological consequences of the infection need to be strictly understood. Reporting of the study conforms to broad EQUATOR guidelines (Simera et al January 2010 issue of EJCI).


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Immunosuppressive Agents/administration & dosage , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Rheumatic Diseases/epidemiology , Severe Acute Respiratory Syndrome/epidemiology , Adaptive Immunity/drug effects , Adaptive Immunity/immunology , Aged , Antirheumatic Agents/administration & dosage , Comorbidity , Coronavirus Infections/drug therapy , Disease Outbreaks/statistics & numerical data , Female , Humans , Hydroxychloroquine/administration & dosage , Immunity, Innate/drug effects , Immunity, Innate/immunology , Immunologic Factors/administration & dosage , Italy/epidemiology , Male , Middle Aged , Pandemics , Pneumonia, Viral/drug therapy , Rheumatic Diseases/drug therapy , Rheumatic Diseases/immunology , Risk Assessment , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/immunology
13.
Int Immunopharmacol ; 86: 106740, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-614079

ABSTRACT

BACKGROUND: There is no vaccine or specific antiviral treatment for HCoVs infection. The use of type I interferons for coronavirus is still under great debate in clinical practice. MATERIALS AND METHODS: A literature search of all relevant studies published on PubMed, Cochrane library, Web of Science database, Science Direct, Wanfang Data, and China National Knowledge Infrastructure (CNKI) until February 2020 was performed. RESULTS: Of the 1081 identified articles, only 15 studies were included in the final analysis. Comorbidities and delay in diagnosis were significantly associated with case mortality. Type I interferons seem to improve respiratory distress, relieve lung abnormalities, present better saturation, reduce needs for supplemental oxygen support. Type I interferons seem to be well tolerated, and don't increase life threating adverse effects. Data on IFNs in HCoVs are limited, heterogenous and mainly observational. CONCLUSIONS: Current data do not allow making regarding robust commendations for the use of IFNs in HCoVs in general or in specific subtype. But we still recommend type I interferons serving as first-line antivirals in HCoVs infections within local protocols, and interferons may be adopted to the treatments of the SARS-CoV-2 as well. Well-designed large-scale prospective randomized control trials are greatly needed to provide more robust evidence on this topic.


Subject(s)
Antiviral Agents/administration & dosage , Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Interferon Type I/administration & dosage , Pneumonia, Viral/drug therapy , Antiviral Agents/adverse effects , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Humans , Interferon Type I/adverse effects , Middle East Respiratory Syndrome Coronavirus , Observational Studies as Topic , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Survival Analysis , Treatment Outcome
14.
Clin Immunol ; 218: 108517, 2020 09.
Article in English | MEDLINE | ID: covidwho-612038

ABSTRACT

Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/prevention & control , Cytokines/antagonists & inhibitors , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Severe Acute Respiratory Syndrome/prevention & control , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/immunology , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Drug Dosage Calculations , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/genetics , Janus Kinase 1/immunology , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/genetics , Janus Kinase 2/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Lung/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/pharmacokinetics , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction/drug effects
15.
J Clin Virol ; 129: 104521, 2020 08.
Article in English | MEDLINE | ID: covidwho-610625

ABSTRACT

BACKGROUND: Knowledge of the COVID-19 epidemic extent and the level of herd immunity is urgently needed to help manage this pandemic. METHODS: We used a panel of 167 samples (77 pre-epidemic and 90 COVID-19 seroconverters) and SARS-CoV1, SARS-CoV2 and MERS-CoV Spike and/or Nucleopcapsid (NC) proteins to develop a high throughput multiplex screening assay to detect IgG antibodies in human plasma. Assay performances were determined by ROC curves analysis. A subset of the COVID-19+ samples (n = 36) were also tested by a commercial NC-based ELISA test and the results compared with those of the novel assay. RESULTS: On samples collected ≥14 days after symptoms onset, the accuracy of the assay is 100 % (95 % CI: 100-100) for the Spike antigen and 99.9 % (95 % CI:99.7-100) for NC. By logistic regression, we estimated that 50 % of the patients have seroconverted at 5.7 ± 1.6; 5.7 ± 1.8 and 7.9 ± 1.0 days after symptoms onset against Spike, NC or both antigens, respectively and all have seroconverted two weeks after symptoms onset. IgG titration in a subset of samples showed that early phase samples present lower IgG titers than those from later phase. IgG to SARS-CoV2 NC cross-reacted at 100 % with SARS-CoV1 NC. Twenty-nine of the 36 (80.5 %) samples tested were positive by the commercial ELISA while 31/36 (86.1 %) were positive by the novel assay. CONCLUSIONS: Our assay is highly sensitive and specific for the detection of IgG antibodies to SARS-CoV2 proteins, suitable for high throughput epidemiological surveys. The novel assay is more sensitive than a commercial ELISA.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Immunoglobulin G/blood , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/immunology , Serologic Tests/methods , Adult , Aged , Aged, 80 and over , Antigens, Viral/immunology , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Humans , Male , Middle Aged , Nucleocapsid Proteins/immunology , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , ROC Curve , Sensitivity and Specificity , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Spike Glycoprotein, Coronavirus/immunology , Time Factors
16.
Cell Rep ; 32(1): 107863, 2020 07 07.
Article in English | MEDLINE | ID: covidwho-610468

ABSTRACT

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is an unprecedented worldwide health problem that requires concerted and global approaches to stop the coronavirus 2019 (COVID-19) pandemic. Although SARS-CoV-2 primarily targets lung epithelium cells, there is growing evidence that the intestinal epithelium is also infected. Here, using both colon-derived cell lines and primary non-transformed colon organoids, we engage in the first comprehensive analysis of the SARS-CoV-2 life cycle in human intestinal epithelial cells (hIECs). Our results demonstrate that hIECs fully support SARS-CoV-2 infection, replication, and production of infectious de novo virus particles. We found that viral infection elicits an extremely robust intrinsic immune response where interferon-mediated responses are efficient at controlling SARS-CoV-2 replication and de novo virus production. Taken together, our data demonstrate that hIECs are a productive site of SARS-CoV-2 replication and suggest that the enteric phase of SARS-CoV-2 may participate in the pathologies observed in COVID-19 patients by contributing to increasing patient viremia and fueling an exacerbated cytokine response.


Subject(s)
Betacoronavirus/growth & development , Colon/virology , Epithelial Cells/immunology , Interferons/immunology , Intestinal Mucosa/immunology , Betacoronavirus/immunology , Caco-2 Cells , Cell Line, Tumor , Colon/cytology , Colon/immunology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/blood , Epithelial Cells/virology , Humans , Intestinal Mucosa/cytology , Intestinal Mucosa/virology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology , Virus Replication/immunology
17.
Cell Rep ; 32(1): 107863, 2020 07 07.
Article in English | MEDLINE | ID: covidwho-610159

ABSTRACT

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is an unprecedented worldwide health problem that requires concerted and global approaches to stop the coronavirus 2019 (COVID-19) pandemic. Although SARS-CoV-2 primarily targets lung epithelium cells, there is growing evidence that the intestinal epithelium is also infected. Here, using both colon-derived cell lines and primary non-transformed colon organoids, we engage in the first comprehensive analysis of the SARS-CoV-2 life cycle in human intestinal epithelial cells (hIECs). Our results demonstrate that hIECs fully support SARS-CoV-2 infection, replication, and production of infectious de novo virus particles. We found that viral infection elicits an extremely robust intrinsic immune response where interferon-mediated responses are efficient at controlling SARS-CoV-2 replication and de novo virus production. Taken together, our data demonstrate that hIECs are a productive site of SARS-CoV-2 replication and suggest that the enteric phase of SARS-CoV-2 may participate in the pathologies observed in COVID-19 patients by contributing to increasing patient viremia and fueling an exacerbated cytokine response.


Subject(s)
Betacoronavirus/growth & development , Colon/virology , Epithelial Cells/immunology , Interferons/immunology , Intestinal Mucosa/immunology , Betacoronavirus/immunology , Caco-2 Cells , Cell Line, Tumor , Colon/cytology , Colon/immunology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/blood , Epithelial Cells/virology , Humans , Intestinal Mucosa/cytology , Intestinal Mucosa/virology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology , Virus Replication/immunology
19.
Science ; 369(6504): 731-736, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-599033

ABSTRACT

Broadly protective vaccines against known and preemergent human coronaviruses (HCoVs) are urgently needed. To gain a deeper understanding of cross-neutralizing antibody responses, we mined the memory B cell repertoire of a convalescent severe acute respiratory syndrome (SARS) donor and identified 200 SARS coronavirus 2 (SARS-CoV-2) binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the non-neutralizing antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of preexisting memory B cells elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a target for the rational design of pan-sarbecovirus vaccines.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Broadly Neutralizing Antibodies/immunology , SARS Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Antibody Affinity , B-Lymphocyte Subsets/immunology , Binding Sites , Cross Reactions , Epitopes , Female , Humans , Immunologic Memory , Male , Middle Aged , Neutralization Tests , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Protein Domains , Receptors, Virus/chemistry , Receptors, Virus/metabolism , Severe Acute Respiratory Syndrome/immunology , Somatic Hypermutation, Immunoglobulin , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Young Adult
20.
Clin Immunol ; 217: 108509, 2020 08.
Article in English | MEDLINE | ID: covidwho-597932

ABSTRACT

BACKGROUND: National health-system hospitals of Lombardy faced a heavy burden of admissions for acute respiratory distress syndromes associated with coronavirus disease (COVID-19). Data on patients of European origin affected by COVID-19 are limited. METHODS: All consecutive patients aged ≥18 years, coming from North-East of Milan's province and admitted at San Raffaele Hospital with COVID-19, between February 25th and March 24th, were reported, all patients were followed for at least one month. Clinical and radiological features at admission and predictors of clinical outcomes were evaluated. RESULTS: Of the 500 patients admitted to the Emergency Unit, 410 patients were hospitalized and analyzed: median age was 65 (IQR 56-75) years, and the majority of patients were males (72.9%). Median (IQR) days from COVID-19 symptoms onset was 8 (5-11) days. At hospital admission, fever (≥ 37.5 °C) was present in 67.5% of patients. Median oxygen saturation (SpO2) was 93% (range 60-99), with median PaO2/FiO2 ratio, 267 (IQR 184-314). Median Radiographic Assessment of Lung Edema (RALE) score was 9 (IQR 4-16). More than half of the patients (56.3%) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. The probability of overall survival at day 28 was 66%. Multivariable analysis showed older age, coronary artery disease, cancer, low lymphocyte count and high RALE score as factors independently associated with an increased risk of mortality. CONCLUSION: In a large cohort of COVID-19 patients of European origin, main risk factors for mortality were older age, comorbidities, low lymphocyte count and high RALE.


Subject(s)
Coronary Disease/diagnosis , Coronavirus Infections/diagnosis , Diabetes Mellitus/diagnosis , Hypertension/diagnosis , Kidney Failure, Chronic/diagnosis , Pneumonia, Viral/diagnosis , Pulmonary Edema/diagnosis , Severe Acute Respiratory Syndrome/diagnosis , Age Factors , Aged , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Comorbidity , Coronary Disease/epidemiology , Coronary Disease/immunology , Coronary Disease/mortality , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Diabetes Mellitus/mortality , Female , Hospitalization , Humans , Hypertension/epidemiology , Hypertension/immunology , Hypertension/mortality , Infectious Disease Incubation Period , Italy/epidemiology , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/mortality , Lymphocyte Count , Lymphocytes/immunology , Lymphocytes/pathology , Lymphocytes/virology , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pulmonary Edema/epidemiology , Pulmonary Edema/immunology , Pulmonary Edema/mortality , Risk Factors , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/mortality , Severity of Illness Index , Survival Analysis
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