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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330735

ABSTRACT

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.

2.
Cell ; 185(4): 614-629.e21, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1676664

ABSTRACT

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.


Subject(s)
Adjuvants, Immunologic/pharmacology , Antigens, Viral/immunology , Candida albicans/chemistry , Mannans/immunology , Aluminum Hydroxide/chemistry , Animals , Antibodies, Neutralizing/immunology , Antibody Specificity/immunology , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Epitopes/immunology , Immunity, Innate , Immunization , Inflammation/pathology , Interferons/metabolism , Lectins, C-Type/metabolism , Ligands , Lung/immunology , Lung/pathology , Lung/virology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Macrophages/metabolism , Mice, Inbred C57BL , Paranasal Sinuses/metabolism , Protein Subunits/metabolism , Sialic Acid Binding Ig-like Lectin 1/metabolism , Solubility , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology , Transcription Factor RelB/metabolism , Vero Cells , beta-Glucans/metabolism
3.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295412

ABSTRACT

Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19 and this negatively affects T cell activation. The presence of functional effector T cells in mild patients and dysfunctional T cells in severely ill patients suggests that adequate T cell responses are needed to limit disease severity. Therefore, understanding how cDCs cope with SARS-CoV-2 infections can help elucidate the mechanism of generation of protective immune responses. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures with the up-regulation of interferon-stimulated genes and IL-6 signaling pathways. The main difference observed between DC2s and DC3s is the up-regulation of anti-apoptotic genes in DC3s, which explains their accumulation during infection. Furthermore, comparing cDCs between severe and mild patients, we find in the former a profound down-regulation of genes encoding molecules involved in antigen presentation, such as major histocompatibility complex class II (MHCII) molecules, β 2 microglobulin, TAP and costimulatory proteins, while an opposite trend is observed for proinflammatory molecules, such as complement and coagulation factors. Therefore, as the severity of the disease increases, cDC2s enhance their inflammatory properties and lose their main function, which is the antigen presentation capacity. In vitro, direct exposure of cDC2s to the virus recapitulates the type of activation observed in vivo. Our findings provide evidence that SARS-CoV-2 can interact directly with cDC2s and, by inducing the down-regulation of crucial molecules required for T cell activation, implements an efficient immune escape mechanism that correlates with disease severity.

4.
Cell ; 184(19): 4953-4968.e16, 2021 09 16.
Article in English | MEDLINE | ID: covidwho-1363913

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.


Subject(s)
COVID-19/pathology , Interferons/metabolism , Respiratory System/virology , Severity of Illness Index , Age Factors , Aging/pathology , COVID-19/genetics , COVID-19/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Gene Expression Regulation , Humans , Interferons/genetics , Leukocytes/pathology , Leukocytes/virology , Lung/pathology , Lung/virology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Viral Load
5.
Eur J Immunol ; 52(1): 109-122, 2022 01.
Article in English | MEDLINE | ID: covidwho-1332967

ABSTRACT

Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the upregulation of IFN-stimulated genes and IL-6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Lymphocyte Activation , SARS-CoV-2/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Humans
6.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Article in English | MEDLINE | ID: covidwho-1242054

ABSTRACT

The modulation of the transcriptome is among the earliest responses to infection. However, defining the transcriptomic signatures of disease is challenging because logistic, technical, and cost factors limit the size and representativeness of samples in clinical studies. These limitations lead to a poor performance of signatures when applied to new datasets. Although the study focuses on infection, the central hypothesis of the work is the generalization of sets of signatures across diseases. We use a machine learning approach to identify common elements in datasets and then test empirically whether they are informative about a second dataset from a disease or process distinct from the original dataset. We identify sets of genes, which we name transfer signatures, that are predictive across diverse datasets and/or species (e.g., rhesus to humans). We demonstrate the usefulness of transfer signatures in two use cases: the progression of latent to active tuberculosis and the severity of COVID-19 and influenza A H1N1 infection. This indicates that transfer signatures can be deployed in settings that lack disease-specific biomarkers. The broad significance of our work lies in the concept that a small set of archetypal human immunophenotypes, captured by transfer signatures, can explain a larger set of responses to diverse diseases.


Subject(s)
Communicable Diseases/genetics , Gene Expression Profiling , Transcriptome/genetics , Databases, Genetic , Humans , Tuberculosis/genetics , Virus Diseases/genetics
7.
Cell ; 184(5): 1171-1187.e20, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-1051523

ABSTRACT

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.


Subject(s)
COVID-19/immunology , Genetic Fitness , Immune Evasion , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/chemistry , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Humans , Mutation , Phylogeny , SARS-CoV-2/chemistry , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Virulence
8.
Science ; 370(6519): 950-957, 2020 11 20.
Article in English | MEDLINE | ID: covidwho-796948

ABSTRACT

Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Amino Acid Motifs/immunology , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/administration & dosage , Antibodies, Viral/isolation & purification , CHO Cells , COVID-19 , Coronavirus Infections/therapy , Cricetinae , Cricetulus , Cryoelectron Microscopy , HEK293 Cells , Humans , Immunodominant Epitopes/chemistry , Immunodominant Epitopes/immunology , Microscopy, Electron , Pneumonia, Viral/therapy , Protein Domains/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
9.
Science ; 369(6504): 706-712, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-717344

ABSTRACT

Viral infections of the lower respiratory tract are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. In this study, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report that IFN-λ is present in the lower, but not upper, airways of patients with coronavirus disease 2019 (COVID-19). In mice, we demonstrate that IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in clinical practice against endemic viruses, such as influenza virus as well as the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Dendritic Cells/metabolism , Interferons/physiology , Lung/metabolism , Lung/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Animals , Bronchoalveolar Lavage Fluid/immunology , COVID-19 , Cell Proliferation , Cytokines/metabolism , Humans , Interferon Type I/metabolism , Interferons/metabolism , Lung/immunology , Mice , Mice, Inbred C57BL , Nasopharynx/immunology , Pandemics , Poly I-C/administration & dosage , Respiratory Mucosa/pathology , SARS-CoV-2 , Signal Transduction , Staphylococcal Infections/metabolism , Superinfection , Toll-Like Receptor 3/metabolism
10.
Nature ; 584(7821): 353-363, 2020 08.
Article in English | MEDLINE | ID: covidwho-643609

ABSTRACT

Antibody-dependent enhancement (ADE) of disease is a general concern for the development of vaccines and antibody therapies because the mechanisms that underlie antibody protection against any virus have a theoretical potential to amplify the infection or trigger harmful immunopathology. This possibility requires careful consideration at this critical point in the pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we review observations relevant to the risks of ADE of disease, and their potential implications for SARS-CoV-2 infection. At present, there are no known clinical findings, immunological assays or biomarkers that can differentiate any severe viral infection from immune-enhanced disease, whether by measuring antibodies, T cells or intrinsic host responses. In vitro systems and animal models do not predict the risk of ADE of disease, in part because protective and potentially detrimental antibody-mediated mechanisms are the same and designing animal models depends on understanding how antiviral host responses may become harmful in humans. The implications of our lack of knowledge are twofold. First, comprehensive studies are urgently needed to define clinical correlates of protective immunity against SARS-CoV-2. Second, because ADE of disease cannot be reliably predicted after either vaccination or treatment with antibodies-regardless of what virus is the causative agent-it will be essential to depend on careful analysis of safety in humans as immune interventions for COVID-19 move forward.


Subject(s)
Antibodies, Viral/adverse effects , Antibodies, Viral/immunology , Antibody-Dependent Enhancement/immunology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Animals , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/prevention & control , Dengue Virus/immunology , Disease Models, Animal , HEK293 Cells , Humans , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/immunology , Macaca mulatta , Mice , Middle East Respiratory Syndrome Coronavirus/immunology , Orthomyxoviridae/immunology , Pandemics , Rats , SARS Virus/immunology , SARS-CoV-2 , Viral Vaccines/adverse effects , Viral Vaccines/immunology
11.
Nature ; 583(7815): 290-295, 2020 07.
Article in English | MEDLINE | ID: covidwho-291856

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe several monoclonal antibodies that target the S glycoprotein of SARS-CoV-2, which we identified from memory B cells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-electron microscopy and binding assays, we show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , Cross Reactions/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antibodies, Viral/pharmacology , Antibody-Dependent Cell Cytotoxicity/drug effects , Antibody-Dependent Cell Cytotoxicity/immunology , B-Lymphocytes/immunology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Coronavirus Infections/virology , Cross Reactions/drug effects , Cryoelectron Microscopy , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , HEK293 Cells , Humans , Immune Evasion/immunology , Immunoglobulin Fab Fragments/chemistry , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/pharmacology , Immunologic Memory/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Models, Molecular , Neutralization Tests , Pandemics/prevention & control , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS Virus/chemistry , SARS Virus/drug effects , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells
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