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1.
Science ; 376(6590): eabi9591, 2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1731250

ABSTRACT

In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

2.
Sci Transl Med ; 14(634): eabn7842, 2022 03 02.
Article in English | MEDLINE | ID: covidwho-1723505

ABSTRACT

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wild-type (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses, whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , Adult , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , Female , Humans , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/prevention & control , Pregnancy Complications, Infectious/virology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , /immunology
3.
Cell ; 185(6): 1025-1040.e14, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1649487

ABSTRACT

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.


Subject(s)
COVID-19 , Antibodies, Viral , COVID-19/prevention & control , Germinal Center , Humans , RNA, Messenger , SARS-CoV-2 , Vaccination
4.
Sci Transl Med ; 14(635): eabm7853, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1630954

ABSTRACT

A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc-gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-FcγR interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19.


Subject(s)
COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , COVID-19 Vaccines , Humans , Prospective Studies , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
7.
Nat Biotechnol ; 40(1): 110-120, 2022 01.
Article in English | MEDLINE | ID: covidwho-1397879

ABSTRACT

A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets. This integrated analysis reveals a robust interplay between plasma metabolites and cell-type-specific metabolic reprogramming networks that is associated with disease severity and could predict survival.


Subject(s)
COVID-19/blood , COVID-19/immunology , Monocytes/metabolism , Single-Cell Analysis , T-Lymphocytes/metabolism , COVID-19/diagnosis , COVID-19/metabolism , Humans , Prognosis
8.
Nature ; 596(7872): 410-416, 2021 08.
Article in English | MEDLINE | ID: covidwho-1305364

ABSTRACT

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14+CD16+ inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization.


Subject(s)
Adaptive Immunity , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Immunity, Innate , T-Lymphocytes/immunology , Vaccinology , Adult , Aged , Antibodies, Neutralizing/immunology , Autoantibodies/immunology , COVID-19 Vaccines/administration & dosage , Female , Humans , Immunization, Secondary , Male , Middle Aged , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/immunology , Transcription, Genetic , Transcriptome/genetics , Young Adult
9.
Sci Immunol ; 6(61)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1295163

ABSTRACT

A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic. Here we report development of an improved multimeric αß T cell staining reagent platform, with each maxi-ferritin "spheromer" displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC. Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a "memory" phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8+ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Severity of Illness Index , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Male
10.
Nat Cell Biol ; 23(6): 620-630, 2021 06.
Article in English | MEDLINE | ID: covidwho-1263492

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often causes severe complications and even death. However, asymptomatic infection has also been reported, highlighting the difference in immune responses among individuals. Here we performed single-cell chromatin accessibility and T cell-receptor analyses of peripheral blood mononuclear cells collected from individuals convalescing from COVID-19 and healthy donors. Chromatin remodelling was observed in both innate and adaptive immune cells in the individuals convalescing from COVID-19. Compared with healthy donors, recovered individuals contained abundant TBET-enriched CD16+ and IRF1-enriched CD14+ monocytes with sequential trained and activated epigenomic states. The B-cell lineage in recovered individuals exhibited an accelerated developmental programme from immature B cells to antibody-producing plasma cells. Finally, an integrated analysis of single-cell T cell-receptor clonality with the chromatin accessibility landscape revealed the expansion of putative SARS-CoV-2-specific CD8+ T cells with epigenomic profiles that promote the differentiation of effector or memory cells. Overall, our data suggest that immune cells of individuals convalescing from COVID-19 exhibit global remodelling of the chromatin accessibility landscape, indicative of the establishment of immunological memory.


Subject(s)
COVID-19/genetics , Epigenesis, Genetic , Epigenomics , Genes, T-Cell Receptor , Immunologic Memory , Lymphocyte Subsets/immunology , Monocytes/immunology , SARS-CoV-2/immunology , Single-Cell Analysis , Adaptive Immunity , Adolescent , Adult , Aged , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Case-Control Studies , Cell Differentiation , Chromatin Assembly and Disassembly , Female , Gene Expression Profiling , Host-Pathogen Interactions , Humans , Immunity, Innate , Lymphocyte Subsets/metabolism , Lymphocyte Subsets/virology , Male , Middle Aged , Monocytes/metabolism , Monocytes/virology , SARS-CoV-2/pathogenicity , Young Adult
11.
iScience ; 24(4): 102311, 2021 Apr 23.
Article in English | MEDLINE | ID: covidwho-1129054

ABSTRACT

We describe a physics-based learning model for predicting the immunogenicity of cytotoxic T lymphocyte (CTL) epitopes derived from diverse pathogens including SARS-CoV-2. The model was trained and optimized on the relative immunodominance of CTL epitopes in human immunodeficiency virus infection. Its accuracy was tested against experimental data from patients with COVID-19. Our model predicts that only some SARS-CoV-2 epitopes predicted to bind to HLA molecules are immunogenic. The immunogenic CTL epitopes across all SARS-CoV-2 proteins are predicted to provide broad population coverage, but those from the SARS-CoV-2 spike protein alone are unlikely to do so. Our model also predicts that several immunogenic SARS-CoV-2 CTL epitopes are identical to seasonal coronaviruses circulating in the population and such cross-reactive CD8+ T cells can indeed be detected in prepandemic blood donors, suggesting that some level of CTL immunity against COVID-19 may be present in some individuals before SARS-CoV-2 infection.

12.
Nat Med ; 27(1): 125-135, 2021 01.
Article in English | MEDLINE | ID: covidwho-1023963

ABSTRACT

Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.


Subject(s)
Influenza Vaccines/immunology , Palatine Tonsil/immunology , Adjuvants, Immunologic , B-Lymphocytes/cytology , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Germinal Center/cytology , Hemagglutinin Glycoproteins, Influenza Virus , Humans , In Vitro Techniques , Lymphoid Tissue/immunology , Measles-Mumps-Rubella Vaccine/immunology , Organoids/cytology , Organoids/immunology , Rabies Vaccines/immunology , T-Lymphocytes/immunology
13.
Nature ; 588(7839): 670-675, 2020 12.
Article in English | MEDLINE | ID: covidwho-943910

ABSTRACT

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5+ cells in basal organoids revealed a distinct population of ITGA6+ITGB4+ mitotic cells, whose offspring further segregated into a TNFRSF12Ahi subfraction that comprised about ten per cent of KRT5+ basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.


Subject(s)
COVID-19/virology , Lung/cytology , Models, Biological , Organoids/cytology , Organoids/virology , SARS-CoV-2/physiology , Tissue Culture Techniques , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , COVID-19/metabolism , COVID-19/pathology , Cell Differentiation , Cell Division , Clone Cells/cytology , Clone Cells/metabolism , Clone Cells/virology , Humans , In Vitro Techniques , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N1 Subtype/physiology , Integrin alpha6/analysis , Integrin beta4/analysis , Keratin-5/analysis , Organoids/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2/growth & development , Single-Cell Analysis , TWEAK Receptor/analysis
14.
Science ; 369(6511)2020 09 25.
Article in English | MEDLINE | ID: covidwho-822138

ABSTRACT

Although the development of effective vaccines has saved countless lives from infectious diseases, the basic workings of the human immune system are complex and have required the development of animal models, such as inbred mice, to define mechanisms of immunity. More recently, new strategies and technologies have been developed to directly explore the human immune system with unprecedented precision. We discuss how these approaches are advancing our mechanistic understanding of human immunology and are facilitating the development of vaccines and therapeutics for infection, autoimmune diseases, and cancer.


Subject(s)
Immune System , Immunity , Immunogenicity, Vaccine , Vaccination , Vaccines/immunology , Vaccines/therapeutic use , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Communicable Disease Control , Disease Models, Animal , Genetic Variation , Humans , Immunity/genetics , Immunogenicity, Vaccine/genetics , Infections/immunology , Infections/therapy , Mice , Mice, Inbred Strains , Neoplasms/immunology , Neoplasms/therapy , /trends
15.
mBio ; 11(3)2020 06 23.
Article in English | MEDLINE | ID: covidwho-612678

ABSTRACT

It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.


Subject(s)
Betacoronavirus/immunology , CD47 Antigen/metabolism , Immunomodulation/immunology , Receptors, Pattern Recognition/immunology , A549 Cells , Adaptive Immunity/immunology , Animals , CD47 Antigen/genetics , Cell Line, Tumor , Cytokines/immunology , Female , Humans , Immunity, Innate/immunology , Lymphocytic choriomeningitis virus/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/immunology , SARS-CoV-2 , Up-Regulation/immunology
16.
Curr Cardiol Rep ; 22(5): 36, 2020 05 13.
Article in English | MEDLINE | ID: covidwho-309604

ABSTRACT

It has been pointed out that the second paragraph of the section "Treatments for SARS-CoV-2 Infection" contains an error. The original article has been corrected.

17.
Curr Cardiol Rep ; 22(5): 32, 2020 04 21.
Article in English | MEDLINE | ID: covidwho-100111

ABSTRACT

PURPOSE OF REVIEW: Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. RECENT FINDINGS: A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensin-converting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/immunology , Heart Diseases/complications , Heart Diseases/immunology , Heart Diseases/virology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus , COVID-19 , Coronavirus Infections/therapy , Cytokines/immunology , Humans , Hypoxia/pathology , Myocytes, Cardiac/pathology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/therapy , SARS-CoV-2
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