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1.
Front Immunol ; 12: 738073, 2021.
Article in English | MEDLINE | ID: covidwho-1497076

ABSTRACT

The mechanisms underlying the immune remodeling and severity response in coronavirus disease 2019 (COVID-19) are yet to be fully elucidated. Our comprehensive integrative analyses of single-cell RNA sequencing (scRNAseq) data from four published studies, in patients with mild/moderate and severe infections, indicate a robust expansion and mobilization of the innate immune response and highlight mechanisms by which low-density neutrophils and megakaryocytes play a crucial role in the cross talk between lymphoid and myeloid lineages. We also document a marked reduction of several lymphoid cell types, particularly natural killer cells, mucosal-associated invariant T (MAIT) cells, and gamma-delta T (γδT) cells, and a robust expansion and extensive heterogeneity within plasmablasts, especially in severe COVID-19 patients. We confirm the changes in cellular abundances for certain immune cell types within a new patient cohort. While the cellular heterogeneity in COVID-19 extends across cells in both lineages, we consistently observe certain subsets respond more potently to interferon type I (IFN-I) and display increased cellular abundances across the spectrum of severity, as compared with healthy subjects. However, we identify these expanded subsets to have a more muted response to IFN-I within severe disease compared to non-severe disease. Our analyses further highlight an increased aggregation potential of the myeloid subsets, particularly monocytes, in COVID-19. Finally, we provide detailed mechanistic insights into the interaction between lymphoid and myeloid lineages, which contributes to the multisystemic phenotype of COVID-19, distinguishing severe from non-severe responses.


Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , Mucosal-Associated Invariant T Cells/immunology , Neutrophils/immunology , SARS-CoV-2/physiology , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , COVID-19/diagnosis , Cell Differentiation , Cell Proliferation , Humans , Immunity, Innate , Interferon Type I/metabolism , Lymphopoiesis , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Sequence Analysis, RNA , Single-Cell Analysis , Systemic Inflammatory Response Syndrome/diagnosis , T-Lymphocytes/metabolism , Thrombopoiesis
2.
Front Endocrinol (Lausanne) ; 12: 731974, 2021.
Article in English | MEDLINE | ID: covidwho-1485049

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a worldwide epidemic. It spreads very fast and hits people of all ages, especially patients with underlying diseases such as diabetes. In this review, we focus on the influences of diabetes on the outcome of SARS-CoV-2 infection and the involved mechanisms including lung dysfunction, immune disorder, abnormal expression of angiotensin-converting enzyme 2 (ACE2), overactivation of mechanistic target of rapamycin (mTOR) signaling pathway, and increased furin level. On the other hand, SARS-CoV-2 may trigger the development of diabetes. It causes the damage of pancreatic ß cells, which is probably mediated by ACE2 protein in the islets. Furthermore, SARS-CoV-2 may aggravate insulin resistance through attacking other metabolic organs. Of note, certain anti-diabetic drugs (OADs), such as peroxisome proliferator-activated receptor γ (PPARγ) activator and glucagon-like peptide 1 receptor (GLP-1R) agonist, have been shown to upregulate ACE2 in animal models, which may increase the risk of SARS-CoV-2 infection. However, Metformin, as a first-line medicine for the treatment of type 2 diabetes mellitus (T2DM), may be a potential drug benefiting diabetic patients with SARS-CoV-2 infection, probably via a suppression of mTOR signaling together with its anti-inflammatory and anti-fibrosis function in lung. Remarkably, another kind of OADs, dipeptidyl Peptidase 4 (DPP4) inhibitor, may also exert beneficial effects in this respect, probably via a prevention of SARS-CoV-2 binding to cells. Thus, it is of significant to identify appropriate OADs for the treatment of diabetes in the context of SARS-CoV-2 infections.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Lung/drug effects , Lung/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
3.
J Immunol ; 207(10): 2405-2410, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1471046

ABSTRACT

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) causes severe acute respiratory syndrome. mRNA vaccines directed at the SARS-CoV-2 spike protein resulted in development of Abs and protective immunity. To determine the mechanism, we analyzed the kinetics of induction of circulating exosomes with SARS-CoV-2 spike protein and Ab following vaccination of healthy individuals. Results demonstrated induction of circulating exosomes expressing spike protein on day 14 after vaccination followed by Abs 14 d after the second dose. Exosomes with spike protein, Abs to SARS-CoV-2 spike, and T cells secreting IFN-γ and TNF-α increased following the booster dose. Transmission electron microscopy of exosomes also demonstrated spike protein Ags on their surface. Exosomes with spike protein and Abs decreased in parallel after four months. These results demonstrate an important role of circulating exosomes with spike protein for effective immunization following mRNA-based vaccination. This is further documented by induction of humoral and cellular immune responses in mice immunized with exosomes carrying spike protein.


Subject(s)
Antibodies, Viral/metabolism , COVID-19 Vaccines/immunology , COVID-19/immunology , Exosomes/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/metabolism , Animals , Blood Circulation , Cells, Cultured , Exosomes/immunology , Healthy Volunteers , Humans , Immunization , Interferon-gamma/metabolism , Mice , Mice, Inbred C57BL , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/metabolism , Vaccination
4.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1470893

ABSTRACT

SputnikV is a vaccine against SARS-CoV-2 developed by the Gamaleya National Research Centre for Epidemiology and Microbiology. The vaccine has been shown to induce both humoral and cellular immune responses, yet the mechanisms remain largely unknown. Forty SputnikV vaccinated individuals were included in this study which aimed to demonstrate the location of immunogenic domains of the SARS-CoV-2 S protein using an overlapping peptide library. Additionally, cytokines in the serum of vaccinated and convalescent COVID-19 patients were analyzed. We have found antibodies from both vaccinated and convalescent sera bind to immunogenic regions located in multiple domains of SARS-CoV-2 S protein, including Receptor Binding Domain (RBD), N-terminal Domain (NTD), Fusion Protein (FP) and Heptad Repeats (HRs). Interestingly, many peptides were recognized by immunized and convalescent serum antibodies and correspond to conserved regions in circulating variants of SARS-CoV-2. This breadth of reactivity was still evident 90 days after the first dose of the vaccine, showing that the vaccine has induced a prolonged response. As evidenced by the activation of T cells, cellular immunity strongly suggests the high potency of the SputnikV vaccine against SARS-CoV-2 infection.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunity, Cellular , Immunity, Humoral , Adult , Amino Acid Sequence , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Cytokines/metabolism , Female , Humans , Male , Peptides/chemistry , Peptides/immunology , Principal Component Analysis , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vaccination
5.
J Clin Invest ; 131(17)2021 09 01.
Article in English | MEDLINE | ID: covidwho-1463086

ABSTRACT

Defining the correlates of protection necessary to manage the COVID-19 pandemic requires the analysis of both antibody and T cell parameters, but the complexity of traditional tests limits virus-specific T cell measurements. We tested the sensitivity and performance of a simple and rapid SARS-CoV-2 spike protein-specific T cell test based on the stimulation of whole blood with peptides covering the SARS-CoV-2 spike protein, followed by cytokine (IFN-γ, IL-2) measurement in different cohorts including BNT162b2-vaccinated individuals (n = 112), convalescent asymptomatic and symptomatic COVID-19 patients (n = 130), and SARS-CoV-1-convalescent individuals (n = 12). The sensitivity of this rapid test is comparable to that of traditional methods of T cell analysis (ELISPOT, activation-induced marker). Using this test, we observed a similar mean magnitude of T cell responses between the vaccinees and SARS-CoV-2 convalescents 3 months after vaccination or virus priming. However, a wide heterogeneity of the magnitude of spike-specific T cell responses characterized the individual responses, irrespective of the time of analysis. The magnitude of these spike-specific T cell responses cannot be predicted from the neutralizing antibody levels. Hence, both humoral and cellular spike-specific immunity should be tested after vaccination to define the correlates of protection necessary to evaluate current vaccine strategies.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 , Immunity, Cellular/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes , Adult , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
7.
Viruses ; 13(10)2021 09 30.
Article in English | MEDLINE | ID: covidwho-1444330

ABSTRACT

BACKGROUND: The immunological changes associated with COVID-19 are largely unknown. METHODS: Patients with COVID-19 showing moderate (n = 18; SpO2 > 93%, respiratory rate > 22 per minute, CRP > 10 mg/L) and severe (n = 23; SpO2 < 93%, respiratory rate >30 per minute, PaO2/FiO2 ≤ 300 mmHg, permanent oxygen therapy, qSOFA > 2) infection, and 37 healthy donors (HD) were enrolled. Circulating T- and B-cell subsets were analyzed by flow cytometry. RESULTS: CD4+Th cells were skewed toward Th2-like phenotypes within CD45RA+CD62L- (CM) and CD45RA-CD62L- (EM) cells in patients with severe COVID-19, while CM CCR6+ Th17-like cells were decreased if compared with HD. Within CM Th17-like cells "classical" Th17-like cells were increased and Th17.1-like cells were decreased in severe COVID-19 cases. Circulating CM follicular Th-like (Tfh) cells were decreased in all COVID-19 patients, and Tfh17-like cells represented the most predominant subset in severe COVID-19 cases. Both groups of patients showed increased levels of IgD-CD38++ B cells, while the levels of IgD+CD38- and IgD-CD38- were decreased. The frequency of IgD+CD27+ and IgD-CD27+ B cells was significantly reduced in severe COVID-19 cases. CONCLUSIONS: We showed an imbalance within almost all circulating memory Th subsets during acute COVID-19 and showed that altered Tfh polarization led to a dysregulated humoral immune response.


Subject(s)
B-Lymphocyte Subsets/immunology , COVID-19/immunology , Immunity , SARS-CoV-2 , ADP-ribosyl Cyclase 1 , Adult , Aged , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Female , Flow Cytometry , Humans , Immunoglobulin D , Male , Middle Aged , Oxygen , Receptors, CCR6 , T-Lymphocytes/metabolism , Th17 Cells/immunology
9.
Nat Commun ; 12(1): 2790, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1387341

ABSTRACT

SARS-CoV-2 is of zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction of the spike protein. Here, we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in Vero E6 cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no obvious pathological changes and does not induce elevation of proinflammatory cytokines, but still triggers a strong neutralizing antibody and T cell response in hamsters and mice. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, with little sign of virus replication in the upper or lower respiratory tract, demonstrating sterilizing immunity.


Subject(s)
COVID-19/diagnosis , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Virus Replication/genetics , Animals , COVID-19/immunology , COVID-19/virology , Cell Line, Tumor , Chlorocebus aethiops , Cricetinae , Cytokines/immunology , Cytokines/metabolism , Female , Host-Pathogen Interactions , Humans , Male , Mesocricetus , Mice, Inbred BALB C , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vero Cells , Virulence/genetics , Virulence/immunology
10.
Front Immunol ; 12: 635942, 2021.
Article in English | MEDLINE | ID: covidwho-1389176

ABSTRACT

SARS-CoV-2 infection takes a mild or clinically inapparent course in the majority of humans who contract this virus. After such individuals have cleared the virus, only the detection of SARS-CoV-2-specific immunological memory can reveal the exposure, and hopefully the establishment of immune protection. With most viral infections, the presence of specific serum antibodies has provided a reliable biomarker for the exposure to the virus of interest. SARS-CoV-2 infection, however, does not reliably induce a durable antibody response, especially in sub-clinically infected individuals. Consequently, it is plausible for a recently infected individual to yield a false negative result within only a few months after exposure. Immunodiagnostic attention has therefore shifted to studies of specific T cell memory to SARS-CoV-2. Most reports published so far agree that a T cell response is engaged during SARS-CoV-2 infection, but they also state that in 20-81% of SARS-CoV-2-unexposed individuals, T cells respond to SARS-CoV-2 antigens (mega peptide pools), allegedly due to T cell cross-reactivity with Common Cold coronaviruses (CCC), or other antigens. Here we show that, by introducing irrelevant mega peptide pools as negative controls to account for chance cross-reactivity, and by establishing the antigen dose-response characteristic of the T cells, one can clearly discern between cognate T cell memory induced by SARS-CoV-2 infection vs. cross-reactive T cell responses in individuals who have not been infected with SARS-CoV-2.


Subject(s)
COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Antigens, Viral/immunology , Biomarkers , COVID-19/metabolism , Cross Reactions/immunology , Cytokines/metabolism , Epitopes, T-Lymphocyte/immunology , Humans , Immunodominant Epitopes/immunology , Immunologic Memory , Peptides/immunology , Protein Binding , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/metabolism
11.
Biomolecules ; 11(8)2021 08 16.
Article in English | MEDLINE | ID: covidwho-1360720

ABSTRACT

The SARS-CoV-2 pandemic has completely disrupted the health systems of the entire planet. From the earliest months, it became increasingly clear that in addition to affecting the upper airways and lungs, there were other organs that could be affected. Among these, the skin became a real "sentinel signal" to be able to even suspect COVID-19. Background: this study deals with a little-explored issue for now: the study of skin immunopathology in SARS-CoV-2 positive subjects ascertained using the most reliable methods available. Methods: we used skin biopsy samples from SARS-CoV-2 positive and negative patients, studying morphology (Hematoxylin-Eosin), T lymphocyte population (CD4 and CD8), three markers such as HMGB-1, TIM-3 and HO-1 by immunohistochemistry. Results: although the presence of the CD4 and CD8 T population did not differ statistically significantly, we found greater activation and release of HMGB-1 in skin samples from SARS-CoV-2 positive patients, greater immunolabeling for TIM-3 at the level of CD4 and CD8 and a reduced expression of Heme oxygenase 1. Conclusions: these results support the possibility that there is immune deregulation in SARS-CoV-2 positive patients who develop skin manifestations of various kinds.


Subject(s)
COVID-19/complications , HMGB1 Protein/metabolism , Heme Oxygenase (Decyclizing)/metabolism , Hepatitis A Virus Cellular Receptor 2/metabolism , Skin Diseases/metabolism , Skin/metabolism , Adult , Aged , Female , Humans , Male , Middle Aged , Skin/pathology , Skin Diseases/etiology , Skin Diseases/pathology , T-Lymphocytes/metabolism
12.
Cell Rep ; 36(8): 109570, 2021 08 24.
Article in English | MEDLINE | ID: covidwho-1356159

ABSTRACT

The rapid development of mRNA-based vaccines against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to the design of accelerated vaccination schedules that have been extremely effective in naive individuals. While a two-dose immunization regimen with the BNT162b2 vaccine has been demonstrated to provide a 95% efficacy in naive individuals, the effects of the second vaccine dose in individuals who have previously recovered from natural SARS-CoV-2 infection has not been investigated in detail. In this study, we characterize SARS-CoV-2 spike-specific humoral and cellular immunity in naive and previously infected individuals during and after two doses of BNT162b2 vaccination. Our results demonstrate that, while the second dose increases both the humoral and cellular immunity in naive individuals, COVID-19 recovered individuals reach their peak of immunity after the first dose. These results suggests that a second dose, according to the current standard regimen of vaccination, may be not necessary in individuals previously infected with SARS-CoV-2.


Subject(s)
COVID-19/prevention & control , T-Lymphocytes/immunology , Vaccines, Synthetic/administration & dosage , Antibodies, Viral/blood , CD40 Ligand/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Immunoglobulin G/blood , Interferon-gamma/metabolism , Interleukin-2/metabolism , Peptides/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Vaccination , Vaccines, Synthetic/immunology
13.
Blood Cancer J ; 11(8): 142, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1351934

ABSTRACT

This study evaluated the safety and immunogenicity of BNT162b2 vaccine in patients with hematological malignancies. Antibodies blocking spike binding to immobilized ACE-2 (NAb) correlated with anti-Spike (S) IgG d42 titers (Spearman r = 0.865, p < 0.0001), and an anti-S IgG d42 level ≥3100 UA/mL was predictive of NAb ≥ 30%, the positivity cutoff for NAb (p < 0.0001). Only 47% of the patients achieved an anti-S IgG d42 level ≥3100 UA/mL after the two BNT162b2 inocula, compared to 87% of healthy controls. In multivariable analysis, male patients, use of B-cell targeting treatment within the last 12 months prior to vaccination, and CD19+ B-cell level <120/uL, were associated with a significantly decreased probability of achieving a protective anti-S IgG level after the second BNT162b2 inoculum. Finally, using the IFN-γ ELISPOT assay, we found a significant increase in T-cell response against the S protein, with 53% of patients having an anti-S IgG-positive ELISPOT after the second BNT162b2 inoculum. There was a correlation between the anti-S ELISPOT response and IgG d42 level (Spearman r = 0.3026, p = 0.012). These findings suggest that vaccination with two BNT162b2 inocula translates into a significant increase in humoral and cellular response in patients with hematological malignancies, but only around half of the patients can likely achieve effective immune protection against COVID-19.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/complications , COVID-19/immunology , Hematologic Neoplasms/complications , Hematologic Neoplasms/immunology , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Adaptive Immunity , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/administration & dosage , Comorbidity , Female , Host-Pathogen Interactions/immunology , Humans , Immunoglobulin G/immunology , Male , Middle Aged , Risk Factors , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Young Adult
14.
Nat Commun ; 12(1): 4636, 2021 07 30.
Article in English | MEDLINE | ID: covidwho-1347938

ABSTRACT

Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18-50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and T-cell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT50 seroconversion after a single dose.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Chikungunya Fever/immunology , Chikungunya virus/immunology , Viral Vaccines/immunology , Adolescent , Adult , Chikungunya Fever/prevention & control , Chikungunya Fever/virology , Chikungunya virus/classification , Chikungunya virus/physiology , Cytokines/immunology , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Fatigue/chemically induced , Female , Headache/chemically induced , Humans , Immunoglobulin G/immunology , Injections, Intramuscular , Male , Middle Aged , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vaccination/methods , Viral Vaccines/administration & dosage , Viral Vaccines/adverse effects , Young Adult
15.
Sci Rep ; 11(1): 15927, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1345584

ABSTRACT

Previous studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range. We applied single-cell RNA-sequencing and measured the cellular composition and transcriptional profile of the nasal mucosa in 35 SARS-CoV-2 negative children and adults, ranging in age from 4 months to 65 years. We analyzed in total of ~ 30,000 immune and epithelial cells and found that age and immune cell proportion in the nasal mucosa are inversely correlated, with little evidence for structural changes in the transcriptional state of a given cell type across the age range. Orthogonal validation by epigenome sequencing indicate that it is especially cells of the innate immune system that underlie the age-association. Additionally, we characterize the predominate immune cell type in the nasal mucosa: a resident T cell like population with potent antiviral properties. These results demonstrate fundamental changes in the immune cell makeup of the uninfected nasal mucosa over the lifespan. The resource we generate here is an asset for future studies focusing on respiratory infection and immunization strategies.


Subject(s)
COVID-19/immunology , Nasal Mucosa/immunology , SARS-CoV-2/immunology , Adolescent , Adult , COVID-19/genetics , Child , Child, Preschool , Female , Humans , Immunity, Cellular , Immunity, Innate , Infant , Male , Middle Aged , Nasal Mucosa/cytology , Nasal Mucosa/metabolism , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transcriptome , Young Adult
16.
Nat Commun ; 12(1): 4515, 2021 07 26.
Article in English | MEDLINE | ID: covidwho-1327196

ABSTRACT

The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for 'reverse phenotyping'. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.


Subject(s)
COVID-19/immunology , Gene Expression Profiling/methods , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , T-Lymphocytes/metabolism , Aged , Aged, 80 and over , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/virology , COVID-19/epidemiology , COVID-19/virology , Cells, Cultured , Cohort Studies , Female , Humans , Male , Middle Aged , Pandemics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2/physiology , T-Lymphocytes/virology
17.
Emerg Microbes Infect ; 10(1): 1598-1608, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1316786

ABSTRACT

Since the outbreak of COVID-19, a variety of vaccine platforms have been developed. Amongst these, inactivated vaccines have been authorized for emergency use or conditional marketing in many countries. To further enhance the protective immune responses in populations that have completed vaccination regimen, we investigated the immunogenic characteristics of different vaccine platforms and tried homologous or heterologous boost strategy post two doses of inactivated vaccines in a mouse model. Our results showed that the humoral and cellular immune responses induced by different vaccines when administered individually differ significantly. In particular, inactivated vaccines showed relatively lower level of neutralizing antibody and T cell responses, but a higher IgG2a/IgG1 ratio compared with other vaccines. Boosting with either recombinant subunit, adenovirus vectored or mRNA vaccine after two-doses of inactivated vaccine further improved both neutralizing antibody and Spike-specific Th1-type T cell responses compared to boosting with a third dose of inactivated vaccine. Our results provide new ideas for prophylactic inoculation strategy of SARS-CoV-2 vaccines.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Immunization, Secondary , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Vaccines, Inactivated/immunology , Animals , Antibodies, Viral/immunology , COVID-19 Vaccines/administration & dosage , Cytokines , Disease Models, Animal , Female , Humans , Immunoglobulin G/immunology , Mice , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vaccines, Inactivated/administration & dosage
20.
Nat Rev Immunol ; 21(8): 475-484, 2021 08.
Article in English | MEDLINE | ID: covidwho-1294475

ABSTRACT

Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein. Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries. The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs. After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses. These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms. Identifying the mechanisms of protection as well as correlates of protection is crucially important to inform further vaccine development and guide the use of licensed COVID-19 vaccines worldwide.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Humans , Immunity/drug effects , Immunity/immunology , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Treatment Outcome
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