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2.
Nat Commun ; 13(1): 153, 2022 01 10.
Article in English | MEDLINE | ID: covidwho-1616980

ABSTRACT

Anti-viral immunity continuously declines over time after SARS-CoV-2 infection. Here, we characterize the dynamics of anti-viral immunity during long-term follow-up and after BNT162b2 mRNA-vaccination in convalescents after asymptomatic or mild SARS-CoV-2 infection. Virus-specific and virus-neutralizing antibody titers rapidly declined in convalescents over 9 months after infection, whereas virus-specific cytokine-producing polyfunctional T cells persisted, among which IL-2-producing T cells correlated with virus-neutralizing antibody titers. Among convalescents, 5% of individuals failed to mount long-lasting immunity after infection and showed a delayed response to vaccination compared to 1% of naïve vaccinees, but successfully responded to prime/boost vaccination. During the follow-up period, 8% of convalescents showed a selective increase in virus-neutralizing antibody titers without accompanying increased frequencies of circulating SARS-CoV-2-specific T cells. The same convalescents, however, responded to vaccination with simultaneous increase in antibody and T cell immunity revealing the strength of mRNA-vaccination to increase virus-specific immunity in convalescents.


Subject(s)
/immunology , COVID-19/immunology , Convalescence , Nucleocapsid/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Flow Cytometry/methods , Follow-Up Studies , Humans , Immunoglobulin G/immunology , Interleukin-2/immunology , Interleukin-2/metabolism , Kinetics , SARS-CoV-2/physiology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Time Factors , Vaccination/methods
5.
Curr Opin Immunol ; 72: 286-297, 2021 10.
Article in English | MEDLINE | ID: covidwho-1606955

ABSTRACT

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune Regulator (AIRE) gene, which impair the thymic negative selection of self-reactive T-cells and underlie the development of autoimmunity that targets multiple endocrine and non-endocrine tissues. Beyond autoimmunity, APECED features heightened susceptibility to certain specific infections, which is mediated by anti-cytokine autoantibodies and/or T-cell driven autoimmune tissue injury. These include the 'signature' APECED infection chronic mucocutaneous candidiasis (CMC), but also life-threatening coronavirus disease 2019 (COVID-19) pneumonia, bronchiectasis-associated bacterial pneumonia, and sepsis by encapsulated bacteria. Here we discuss the expanding understanding of the immunological mechanisms that contribute to infection susceptibility in this prototypic syndrome of impaired central tolerance, which provide the foundation for devising improved diagnostic and therapeutic strategies for affected patients.


Subject(s)
COVID-19/immunology , Candidiasis, Cutaneous/immunology , Polyendocrinopathies, Autoimmune/immunology , T-Lymphocytes/immunology , Transcription Factors/genetics , Animals , Autoimmunity , Bronchiectasis , COVID-19/epidemiology , COVID-19/genetics , Candidiasis, Cutaneous/epidemiology , Candidiasis, Cutaneous/genetics , Clonal Selection, Antigen-Mediated/genetics , Disease Susceptibility , Humans , Immune Tolerance/genetics , Polyendocrinopathies, Autoimmune/epidemiology , Polyendocrinopathies, Autoimmune/genetics
6.
Curr Opin Immunol ; 72: 126-134, 2021 10.
Article in English | MEDLINE | ID: covidwho-1606183

ABSTRACT

Membrane cofactor protein (MCP; CD46), a ubiquitously expressed complement regulatory protein, serves as a cofactor for serine protease factor I to cleave and inactivate C3b and C4b deposited on host cells. However, CD46 also plays roles in human reproduction, autophagy, modulating T cell activation and effector functions and is a member of the newly identified intracellular complement system (complosome). CD46 also is a receptor for 11 pathogens ('pathogen magnet'). While CD46 deficiencies contribute to inflammatory disorders, its overexpression in cancers and role as a receptor for some adenoviruses has led to its targeting by oncolytic agents and adenoviral-based therapeutic vectors, including coronavirus disease of 2019 (COVID-19) vaccines. This review focuses on recent advances in identifying disease-causing CD46 variants and its pathogen connections.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Membrane Cofactor Protein/metabolism , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Animals , Autophagy , Complement Activation , Host-Pathogen Interactions , Humans , Lymphocyte Activation , Membrane Cofactor Protein/genetics , Oncolytic Virotherapy , Polymorphism, Genetic , Reproduction
7.
PLoS Pathog ; 17(12): e1010211, 2021 12.
Article in English | MEDLINE | ID: covidwho-1591125

ABSTRACT

The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Vaccination , Adult , Aged , Antibodies, Neutralizing/blood , Female , Humans , Immunoglobulin G/blood , Longitudinal Studies , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology
9.
PLoS Pathog ; 17(12): e1010162, 2021 12.
Article in English | MEDLINE | ID: covidwho-1595940

ABSTRACT

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over five million people worldwide as of December 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.


Subject(s)
COVID-19 , Disease Models, Animal , Macaca nemestrina , Monkey Diseases/virology , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/physiopathology , COVID-19/virology , Humans , Immunity, Humoral , Lung/immunology , Lung/virology , Male , Monkey Diseases/immunology , Monkey Diseases/pathology , Monkey Diseases/physiopathology , T-Lymphocytes/immunology
10.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1594167

ABSTRACT

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Subject(s)
COVID-19/complications , Hepatitis A Virus Cellular Receptor 2/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Monocytes/metabolism , Receptors, IgG/metabolism , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Alveolar Epithelial Cells/pathology , B-Lymphocytes/immunology , Blood Vessels/pathology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Child , Cohort Studies , Complement Activation , Cytokines/metabolism , Enterocytes/pathology , Female , Humans , Immunity, Humoral , Inflammation/pathology , Interferon Type I/metabolism , Interleukin-15/metabolism , Lymphocyte Activation/immunology , Male , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2/immunology , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/pathology
11.
Lancet Oncol ; 23(1): 16-18, 2022 01.
Article in English | MEDLINE | ID: covidwho-1586208
13.
Front Immunol ; 12: 763098, 2021.
Article in English | MEDLINE | ID: covidwho-1581339

ABSTRACT

Although initial immunophenotypical studies on peripheral blood and bronchoalveolar lavage samples have provided a glimpse into the immunopathology of COVID-19, analyses of pulmonary draining lymph nodes are currently scarce. 22 lethal COVID-19 cases and 28 controls were enrolled in this study. Pulmonary draining lymph nodes (mediastinal, tracheal, peribronchial) were collected at autopsy. Control lymph nodes were selected from a range of histomorphological sequelae [unremarkable histology, infectious mononucleosis, follicular hyperplasia, non-SARS related HLH, extrafollicular plasmablast activation, non-SARS related diffuse alveolar damage (DAD), pneumonia]. Samples were mounted on a tissue microarray and underwent immunohistochemical staining for a selection of immunological markers and in-situ hybridization for Epstein Barr Virus (EBV) and SARS-CoV-2. Gene expression profiling was performed using the HTG EdgeSeq Immune Response Panel. Characteristic patterns of a dysregulated immune response were detected in COVID-19: 1. An accumulation of extrafollicular plasmablasts with a relative paucity or depletion of germinal centers. 2. Evidence of T-cell dysregulation demonstrated by immunohistochemical paucity of FOXP3+, Tbet+ and LEF1+ positive T-cells and a downregulation of key genes responsible for T-cell crosstalk, maturation and migration as well as a reactivation of herpes viruses in 6 COVID-19 lymph nodes (EBV, HSV). 3. Macrophage activation by a M2-polarized, CD163+ phenotype and increased incidence of hemophagocytic activity. 4. Microvascular dysfunction, evidenced by an upregulation of hemostatic (CD36, PROCR, VWF) and proangiogenic (FLT1, TEK) genes and an increase of fibrin microthrombi and CD105+ microvessels. Taken together, these findings imply widespread dysregulation of both innate and adoptive pathways with concordant microvascular dysfunction in severe COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Lymph Nodes/immunology , Lymph Nodes/pathology , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Lung , Macrophage Activation/immunology , Male , Middle Aged , SARS-CoV-2 , T-Lymphocytes/immunology , T-Lymphocytes/pathology , /pathology , /virology
14.
Front Immunol ; 12: 779026, 2021.
Article in English | MEDLINE | ID: covidwho-1581330

ABSTRACT

A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.


Subject(s)
COVID-19/complications , Myocarditis/pathology , Myocarditis/virology , Systemic Inflammatory Response Syndrome/pathology , T-Lymphocytes/immunology , Adult , COVID-19/immunology , COVID-19/pathology , Humans , Male , Myocarditis/immunology , RNA, Viral/analysis , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology
15.
Cells ; 11(1)2021 12 27.
Article in English | MEDLINE | ID: covidwho-1580992

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by the SARS-CoV-2 coronavirus. T cells play an essential role in the body's fighting against the virus invasion, and the T cell receptor (TCR) is crucial in T cell-mediated virus recognition and clearance. However, little has been known about the features of T cell response in convalescent COVID-19 patients. In this study, using 5'RACE technology and PacBio sequencing, we analyzed the TCR repertoire of COVID-19 patients after recovery for 2 weeks and 6 months compared with the healthy donors. The TCR clustering and CDR3 annotation were exploited to discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. We first identified CD4+ and CD8+ T cell clones with certain clonal expansion after infection, and then observed the preferential recombination usage of V(D) J gene segments in CD4+ and CD8+ T cells of COVID-19 patients with different convalescent stages. More important, the TRBV6-5-TRBD2-TRBJ2-7 combination with high frequency was shared between CD4+ T and CD8+ T cells of different COVID-19 patients. Finally, we found the dominant characteristic motifs of the CDR3 sequence between recovered COVID-19 and healthy control. Our study provides novel insights on TCR in COVID-19 with different convalescent phases, contributing to our understanding of the immune response induced by SARS-CoV-2.


Subject(s)
COVID-19/immunology , High-Throughput Nucleotide Sequencing/methods , Immunity/immunology , Receptors, Antigen, T-Cell/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Aged , Amino Acid Sequence , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Complementarity Determining Regions/genetics , Complementarity Determining Regions/immunology , Convalescence , Female , Humans , Male , Middle Aged , Patient Acuity , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/immunology , Receptors, Antigen, T-Cell, alpha-beta/metabolism , SARS-CoV-2/physiology , T-Lymphocytes/metabolism , T-Lymphocytes/virology
16.
Front Immunol ; 12: 719077, 2021.
Article in English | MEDLINE | ID: covidwho-1575525

ABSTRACT

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world's population at record speeds. However, there is still a demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (αOX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T-cell response in mice. Protein binding, immunohistochemical, and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles, and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response, which can be used as a new candidate to combat SARS-CoV-2. Given the T-cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.


Subject(s)
Antigens, Differentiation/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Sindbis Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Cricetinae , Female , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Sindbis Virus/genetics , T-Lymphocytes/immunology , Vaccination
19.
Front Immunol ; 12: 733539, 2021.
Article in English | MEDLINE | ID: covidwho-1572288

ABSTRACT

The response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely impacted by the level of virus exposure and status of the host immunity. The nature of protection shown by direct asymptomatic contacts of coronavirus disease 2019 (COVID-19)-positive patients is quite intriguing. In this study, we have characterized the antibody titer, SARS-CoV-2 surrogate virus neutralization, cytokine levels, single-cell T-cell receptor (TCR), and B-cell receptor (BCR) profiling in asymptomatic direct contacts, infected cases, and controls. We observed significant increase in antibodies with neutralizing amplitude in asymptomatic contacts along with cytokines such as Eotaxin, granulocyte-colony stimulating factor (G-CSF), interleukin 7 (IL-7), migration inhibitory factor (MIF), and macrophage inflammatory protein-1α (MIP-1α). Upon single-cell RNA (scRNA) sequencing, we explored the dynamics of the adaptive immune response in few representative asymptomatic close contacts and COVID-19-infected patients. We reported direct asymptomatic contacts to have decreased CD4+ naive T cells with concomitant increase in CD4+ memory and CD8+ Temra cells along with expanded clonotypes compared to infected patients. Noticeable proportions of class switched memory B cells were also observed in them. Overall, these findings gave an insight into the nature of protection in asymptomatic contacts.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Genomics/methods , SARS-CoV-2/immunology , Single-Cell Analysis/methods , Adaptive Immunity/genetics , Adult , Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Female , Gene Expression Profiling/methods , Humans , Male , /metabolism , Middle Aged , SARS-CoV-2/physiology , Sequence Analysis, RNA/methods , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Young Adult
20.
J Steroid Biochem Mol Biol ; 213: 105957, 2021 10.
Article in English | MEDLINE | ID: covidwho-1561628

ABSTRACT

This review examines the beneficial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-inflammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultraviolet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ultraviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non-Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Therefore, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -independent pathways is necessary to understand how they influence the course of many human diseases.


Subject(s)
COVID-19/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Diabetes Mellitus, Type 2/prevention & control , Multiple Sclerosis/prevention & control , Neoplasms/prevention & control , Sunlight , Vitamin D/metabolism , Alcohol Drinking/adverse effects , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Dendritic Cells/immunology , Dendritic Cells/radiation effects , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/pathology , Disease Progression , Disease Susceptibility , Heme Oxygenase (Decyclizing)/genetics , Heme Oxygenase (Decyclizing)/immunology , Humans , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Neoplasms/immunology , Neoplasms/pathology , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/radiation effects , Sedentary Behavior , T-Lymphocytes/immunology , T-Lymphocytes/radiation effects , Vitamin D/immunology
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