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1.
Nat Commun ; 13(1): 269, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1621240

ABSTRACT

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.


Subject(s)
COVID-19/immunology , SARS-CoV-2/physiology , Aged , Autopsy , COVID-19/diagnosis , COVID-19/genetics , COVID-19/virology , China , Diagnosis , Female , Hepatitis A Virus Cellular Receptor 2/genetics , Hepatitis A Virus Cellular Receptor 2/immunology , Humans , Lymphocyte Activation , Lymphocytes/immunology , Male , Middle Aged , Myeloid Cells/immunology , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , Viral Load
3.
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
4.
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
5.
Cells ; 10(12)2021 11 25.
Article in English | MEDLINE | ID: covidwho-1542428

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a serious lung condition characterized by severe hypoxemia leading to limitations of oxygen needed for lung function. In this study, we investigated the effect of anandamide (AEA), an endogenous cannabinoid, on Staphylococcal enterotoxin B (SEB)-mediated ARDS in female mice. Single-cell RNA sequencing data showed that the lung epithelial cells from AEA-treated mice showed increased levels of antimicrobial peptides (AMPs) and tight junction proteins. MiSeq sequencing data on 16S RNA and LEfSe analysis demonstrated that SEB caused significant alterations in the microbiota, with increases in pathogenic bacteria in both the lungs and the gut, while treatment with AEA reversed this effect and induced beneficial bacteria. AEA treatment suppressed inflammation both in the lungs as well as gut-associated mesenteric lymph nodes (MLNs). AEA triggered several bacterial species that produced increased levels of short-chain fatty acids (SCFAs), including butyrate. Furthermore, administration of butyrate alone could attenuate SEB-mediated ARDS. Taken together, our data indicate that AEA treatment attenuates SEB-mediated ARDS by suppressing inflammation and preventing dysbiosis, both in the lungs and the gut, through the induction of AMPs, tight junction proteins, and SCFAs that stabilize the gut-lung microbial axis driving immune homeostasis.


Subject(s)
Arachidonic Acids/therapeutic use , Endocannabinoids/therapeutic use , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Lung/pathology , Polyunsaturated Alkamides/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/microbiology , Animals , Arachidonic Acids/pharmacology , Butyrates/metabolism , Cecum/pathology , Cell Separation , Colon/drug effects , Colon/pathology , Discriminant Analysis , Dysbiosis/complications , Dysbiosis/microbiology , Endocannabinoids/pharmacology , Enterotoxins , Female , Gastrointestinal Tract/drug effects , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphocyte Activation/drug effects , Mice, Inbred C57BL , Pneumonia/drug therapy , Pneumonia/microbiology , Polyunsaturated Alkamides/pharmacology , Respiratory Distress Syndrome/complications , T-Lymphocytes/drug effects
6.
Biomedica ; 41(Sp. 2): 86-102, 2021 10 15.
Article in English, Spanish | MEDLINE | ID: covidwho-1529016

ABSTRACT

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.


Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección. Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2. Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa. Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia. Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia.


Subject(s)
COVID-19/immunology , Killer Cells, Natural , SARS-CoV-2/immunology , T-Lymphocytes , Adult , Antibodies, Viral/analysis , CD56 Antigen/immunology , Case-Control Studies , Colombia , Family Health , Granzymes/metabolism , Humans , Interleukin-10/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , Perforin/metabolism , Phenotype , Receptors, CCR7/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/blood , Young Adult
8.
Viral Immunol ; 34(9): 639-645, 2021 11.
Article in English | MEDLINE | ID: covidwho-1517820

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may produce a systemic disease, the coronavirus disease-19 (COVID-19), with high morbidity and mortality. Even though we do not fully understand the interaction of innate and adaptive immunity in the control and complications of the viral infection, it is well recognized that SARS-CoV-2 induces an immunodepression that impairs the elimination of the virus and favors its rapid dissemination in the organism. Even less is known about the possible participation of inhibitory cells of the innate immune system, such as the myeloid-derived suppressor cells (MDSCs), or the adaptive immune system, such as the T regulatory cells (Tregs). That is why we aimed to study blood levels of MDSCs, as well as lymphocyte subpopulations, including Tregs, and activated (OX-40+) and inhibited (PD-1) T lymphocytes in patients with mild COVID-19 in comparison with data obtained from control donors. We have found that 20 hospitalized patients with COVID-19 and no health history of immunosuppression had a significant increase in the number of peripheral monocytic MDSCs (M-MDSC), but a decrease in Tregs, as well as an increase in the number of inhibited or exhausted T cells, whereas the number of activated T cells was significantly decreased compared with that from 20 healthy controls. Moreover, there was a significant negative correlation (r = 0.496) between the number of M-MDSC and the number of activated T cells. Therefore, M-MDSC rather than Tregs may contribute to the immunosuppression observed in patients with COVID-19.


Subject(s)
COVID-19/immunology , Myeloid-Derived Suppressor Cells/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/immunology , Aged , COVID-19/blood , COVID-19/classification , Female , Humans , Lymphocyte Activation , Lymphocyte Count/methods , Lymphocyte Subsets , Male , Middle Aged , SARS-CoV-2/pathogenicity
9.
Elife ; 102021 07 22.
Article in English | MEDLINE | ID: covidwho-1513065

ABSTRACT

Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HLA-DR Antigens/immunology , Monocytes/immunology , Myocardial Infarction/immunology , Neprilysin/immunology , Neutrophils/immunology , Aged , Animals , Biomarkers , Cell Differentiation , Cell Proliferation , Cytokines , Female , Humans , Inflammation , Lymphocyte Activation , Male , Mice , Middle Aged , Myocardial Infarction/pathology , T-Lymphocytes/immunology
10.
Cell Transplant ; 30: 9636897211054481, 2021.
Article in English | MEDLINE | ID: covidwho-1511642

ABSTRACT

Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Interleukin-6/biosynthesis , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/immunology , Cells, Cultured , Coculture Techniques , Combined Modality Therapy , DNA, Complementary/genetics , Gene Expression Regulation/drug effects , Humans , Inflammation , Interleukin-6/genetics , Interleukin-6/pharmacology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation/drug effects , Phytohemagglutinins/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/biosynthesis , Receptors, Interleukin-6/genetics , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Umbilical Cord/cytology
11.
J Clin Invest ; 131(20)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1501861

ABSTRACT

The mRNA-1273 vaccine is effective against SARS-CoV-2 and was granted emergency use authorization by the FDA. Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibits severe SARS-CoV-2 disease similar to that in hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and nonhuman primates, low-level virus replication in mRNA-1273-vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high-resolution analysis that is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a 2-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.


Subject(s)
COVID-19 Vaccines/pharmacology , COVID-19/immunology , COVID-19/prevention & control , Lung/immunology , SARS-CoV-2 , Animals , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Disease Models, Animal , Female , Humans , Immunization, Secondary , Lung/pathology , Lung/virology , Lymphocyte Activation , Mesocricetus , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Single-Cell Analysis , Virus Replication
13.
Front Immunol ; 12: 748097, 2021.
Article in English | MEDLINE | ID: covidwho-1477829

ABSTRACT

The SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)] is associated with severe lymphopenia and impaired immune response, including expansion of myeloid cells with regulatory functions, e.g., so-called low-density neutrophils, containing granulocytic myeloid-derived suppressor cells (LDNs/PMN-MDSCs). These cells have been described in both infections and cancer and are known for their immunosuppressive activity. In the case of COVID-19, long-term complications have been frequently observed (long-COVID). In this context, we aimed to investigate the immune response of COVID-19 convalescents after a mild or asymptomatic course of disease. We enrolled 13 convalescents who underwent a mild or asymptomatic infection with SARS-CoV-2, confirmed by a positive result of the PCR test, and 13 healthy donors without SARS-CoV-2 infection in the past. Whole blood was used for T-cell subpopulation and LDNs/PMN-MDSCs analysis. LDNs/PMN-MDSCs and normal density neutrophils (NDNs) were sorted out by FACS and used for T-cell proliferation assay with autologous T cells activated with anti-CD3 mAb. Serum samples were used for the detection of anti-SARS-CoV-2 neutralizing IgG and GM-CSF concentration. Our results showed that in convalescents, even 3 months after infection, an elevated level of LDNs/PMN-MDSCs is still maintained in the blood, which correlates negatively with the level of CD8+ and double-negative T cells. Moreover, LDNs/PMN-MDSCs and NDNs showed a tendency for affecting the production of anti-SARS-CoV-2 S1 neutralizing antibodies. Surprisingly, our data showed that in addition to LDNs/PMN-MDSCs, NDNs from convalescents also inhibit proliferation of autologous T cells. Additionally, in the convalescent sera, we detected significantly higher concentrations of GM-CSF, indicating the role of emergency granulopoiesis. We conclude that in mild or asymptomatic COVID-19 convalescents, the neutrophil dysfunction, including propagation of PD-L1-positive LDNs/PMN-MDSCs and NDNs, is responsible for long-term endotype of immunosuppression.


Subject(s)
Antibodies, Neutralizing/blood , COVID-19/complications , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Viral/blood , Asymptomatic Infections , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Female , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Humans , Immunocompromised Host/immunology , Immunoglobulin G/blood , Lymphocyte Activation/immunology , Male , Middle Aged
14.
Life Sci ; 286: 120063, 2021 Dec 01.
Article in English | MEDLINE | ID: covidwho-1472089

ABSTRACT

COVID-19 is a multi-faceted disease ranging from asymptomatic to severely ill condition that primarily affects the lungs and could advance to other organs as well. It's causing factor, SARS-CoV-2 is recognized to develop robust cell-mediated immunity that responsible to either control or exaggerate the infection. As an important cell subset that control immune responses and are significantly dysregulated in COVID-19, Tregs is proposed to be considered for COVID-19 management. Among its hallmark, TNFR2 is recently recognized to play important role in the function and survival of Tregs. This review gathers available TNFR2 agonists to directly target Tregs as a potential approach to overcome immune dysregulation that affect the severity in COVID-19. Furthermore, this review performs a rigid body docking of TNF-TNFR2 interaction and such interaction with TNFR2 agonist to predict the optimal targeting approach.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Receptors, Tumor Necrosis Factor, Type II/physiology , T-Lymphocytes, Regulatory/immunology , COVID-19/virology , Humans , Lymphocyte Activation , SARS-CoV-2/isolation & purification
15.
Cell Rep ; 37(5): 109942, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1471904

ABSTRACT

Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.


Subject(s)
Antibodies, Monoclonal/therapeutic use , COVID-19/prevention & control , SARS-CoV-2/immunology , Aging/immunology , Animals , COVID-19/cerebrospinal fluid , COVID-19/complications , COVID-19/immunology , Diabetes Complications/immunology , Diabetes Complications/virology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/immunology , Female , Humans , Lymphocyte Activation , Macaca mulatta , Male , Neuritis/immunology , Neuritis/prevention & control , Pre-Exposure Prophylaxis , T-Lymphocytes/immunology , Virus Replication/immunology
16.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1470894

ABSTRACT

Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as "cytokine storm", which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation. Peptides from the N-terminal fragment of Tag7 bind only to TREM-1, while peptides from the C-terminal fragment interact solely with TNFR1. Selected peptides are capable of inhibiting the production of proinflammatory cytokines both in peripheral blood mononuclear cells (PBMCs) from healthy donors and in vivo in the mouse model of acute lung injury (ALI) by diffuse alveolar damage (DAD). Treatment with peptides significantly decreases the infiltration of mononuclear cells to lungs in animals with DAD. Our findings suggest that Tag7-derived peptides might be beneficial in terms of the therapy or prevention of acute lung injury, e.g., for treating COVID-19 patients with severe pulmonary lesions.


Subject(s)
Acute Lung Injury/pathology , Cytokines/chemistry , Peptides/metabolism , Receptors, Tumor Necrosis Factor, Type I/metabolism , Triggering Receptor Expressed on Myeloid Cells-1/metabolism , Acute Lung Injury/metabolism , Animals , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism , Lung/pathology , Lymphocyte Activation/drug effects , Male , Mice , Mice, Inbred ICR , Peptides/chemistry , Peptides/pharmacology , Protein Binding , Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors , Triggering Receptor Expressed on Myeloid Cells-1/antagonists & inhibitors
17.
Crit Rev Immunol ; 41(2): 1-19, 2021.
Article in English | MEDLINE | ID: covidwho-1468219

ABSTRACT

Elucidating the role of probiotic bacteria in health and disease perhaps constitutes one of the most exciting and fastest growing fields in medicine as we uncover the beneficial roles of these bacteria in many disease processes including cancer. We and others have reported previously that probiotic bacteria play a significant role in the activation of many cells including the cancer fighting natural killer (NK) cells. NK cells are the key immune effectors which control tumor growth and metastasis due to their ability to mediate direct cytotoxicity and/or differentiation of cancer stem cells/undifferentiated tumors through secreted and membrane bound interferon-gamma and tumor necrosis factor-alpha. In this review, we present an overview of recent studies from our laboratory and those of the others on their beneficial effects on immune cell function in particular on NK cells. In addition, we also highlight the current understanding of the role of probiotics in enhancement of the effectiveness of cancer therapeutics. Moreover, we discuss the functional impairment of cancer patients' NK cells and the role of probiotics in reversal of such functional impairment. NK cell-based immuno-therapies in combination with well-selected strains of probiotic bacteria may probably represent one of the best adjunct therapeutic approaches to prevent and treat cancer in the future.


Subject(s)
Killer Cells, Natural/cytology , Lymphocyte Activation , Neoplasms , Probiotics , Humans , Neoplasms/therapy , Probiotics/therapeutic use
18.
JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: covidwho-1467778

ABSTRACT

The importance of the adaptive T cell response in the control and resolution of viral infection has been well established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of patients with COVID-19 in intensive care as a result of phenotypic and functional profiling by mass cytometry. Increased frequencies of circulating, polyfunctional CD4+CXCR5+HLA-DR+ stem cell memory T cells (Tscms) and decreased proportions of granzyme B-expressing and perforin-expressing effector memory T cells were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional PD-L1+CXCR3+CD8+ effector T cells (Teffs), CXCR5+HLA-DR+ Tscms, and anti-nucleocapsid (anti-NC) cytokine-producing T cells permitted us to differentiate between recovered and deceased patients. The results from a principal component analysis show an imbalance in the T cell compartment that allowed for the separation of recovered and deceased patients. The paucity of circulating PD-L1+CXCR3+CD8+ Teffs and NC-specific CD8+ T cells accurately forecasts fatal disease outcome. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefore might impact T cell-based vaccine designs for this infectious disease.


Subject(s)
B7-H1 Antigen/immunology , CD4-Positive T-Lymphocytes/immunology , CD8 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunity, Cellular , Receptors, CXCR3/immunology , Adult , COVID-19/mortality , COVID-19/pathology , Epitopes, T-Lymphocyte/immunology , Female , France/epidemiology , Humans , Immunologic Memory , Lymphocyte Activation , Male , SARS-CoV-2 , Survival Rate/trends
19.
J Exp Med ; 218(12)2021 12 06.
Article in English | MEDLINE | ID: covidwho-1467277

ABSTRACT

Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864-882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2-specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.


Subject(s)
COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adult , Antibodies, Viral/immunology , Female , HLA Antigens/immunology , Humans , Lymphocyte Activation , Male
20.
Int J Mol Sci ; 22(19)2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1463712

ABSTRACT

Nanomaterials have found extensive interest in the development of novel vaccines, as adjuvants and/or carriers in vaccination platforms. Conjugation of protein antigens at the particle surface by non-covalent adsorption is the most widely used approach in licensed particulate vaccines. Hence, it is essential to understand proteins' structural integrity at the material interface in order to develop safe-by-design nanovaccines. In this study, we utilized two model proteins, the wild-type allergen Bet v 1 and its hypoallergenic fold variant (BM4), to compare SiO2 nanoparticles with Alhydrogel® as particulate systems. A set of biophysical and functional assays including circular dichroism spectroscopy and proteolytic degradation was used to examine the antigens' structural integrity at the material interface. Conjugation of both biomolecules to the particulate systems decreased their proteolytic stability. However, we observed qualitative and quantitative differences in antigen processing concomitant with differences in their fold stability. These changes further led to an alteration in IgE epitope recognition. Here, we propose a toolbox of biophysical and functional in vitro assays for the suitability assessment of nanomaterials in the early stages of vaccine development. These tools will aid in safe-by-design innovations and allow fine-tuning the properties of nanoparticle candidates to shape a specific immune response.


Subject(s)
Allergens/immunology , Antigens, Plant/immunology , Epitopes/immunology , Lymphocyte Activation/immunology , Nanoparticles/chemistry , Silicon Dioxide/chemistry , Vaccines/immunology , Allergens/chemistry , Humans , Hydrogels , Immunoglobulin E/immunology , Respiratory Hypersensitivity/immunology , T-Lymphocytes/immunology
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