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1.
Front Immunol ; 13: 851620, 2022.
Article in English | MEDLINE | ID: covidwho-1731787

ABSTRACT

Myocarditis and myopericarditis may occur after COVID-19 vaccination with an incidence of two to twenty cases per 100,000 individuals, but underlying mechanisms related to disease onset and progression remain unclear. Here, we report a case of myopericarditis following the first dose of the mRNA-1273 COVID-19 vaccine in a young man who had a history of mild COVID-19 three months before vaccination. The patient presented with chest pain, elevated troponin I level, and electrocardiogram abnormality. His endomyocardial biopsy revealed diffuse CD68+ cell infiltration. We characterized the immune profile of the patient using multiplex cytokine assay and flow cytometry analysis. Sex-matched vaccinated individuals and healthy individuals were used as controls. IL-18 and IL-27, Th1-type cytokines, were highly increased in the patient with COVID-19 vaccine-related myopericarditis compared with vaccinated controls who experienced no cardiac complications. In the patient, circulating NK cells and T cells showed an activated phenotype and mRNA profile, and monocytes expressed increased levels of IL-18 and its upstream NLRP3 inflammasome. We found that recombinant IL-18 administration into mice caused mild cardiac dysfunction and activation of NK cells and T cells in the hearts, similar to the findings in the patient with myopericarditis after COVID-19 mRNA vaccination. Collectively, myopericarditis following COVID-19 mRNA vaccination may be associated with increased IL-18-mediated immune responses and cardiotoxicity.


Subject(s)
/adverse effects , COVID-19/immunology , Immunity/immunology , Interleukin-18/immunology , Myocarditis/chemically induced , Vaccination/adverse effects , Adult , Animals , Humans , Killer Cells, Natural/immunology , Male , Mice , SARS-CoV-2/immunology , Young Adult
2.
PLoS One ; 17(2): e0263468, 2022.
Article in English | MEDLINE | ID: covidwho-1702396

ABSTRACT

BACKGROUND: Mass vaccination is the key element in controlling current COVID-19 pandemic. Studies comparing immunogenicity of different COVID-19 vaccines are largely lacking. We aimed at measuring anti-S antibody (Ab) levels in individuals fully vaccinated with BNT162b2, BBIBP-CorV and Gam-COVID-Vac, as well as in COVID-19 convalescents. METHODS: In this cross-sectional study, serum was collected from 400 age- and sex-matched participants, 100 fully vaccinated with BNT162b2, 100 with BBIBP-CorV and 100 with Gam-COVID-Vac on the 28th day after the second vaccine dose, and 100 recovered from COVID-19 at least 28 days after symptom(s) resolution. Sera were analyzed using the LIAISON SARS-CoV-2 S1/S2 IgG assay (DiaSorin, Saluggia, Italy). Wilcoxon rank-sum or Kruskal-Wallis tests was used for comparison of Ab levels. RESULTS: Highest mean value (210.11, SD = 100.42) was measured in the BNT162b2 group, followed by Gam-COVID-Vac (171.11, SD = 120.69) and BBIBP-CorV (68.50, SD = 72.78) AU/mL (p<0.001). Significant differences in antibody levels were found between BNT162b2 and BBIBP-CorV (p<0.001), BNT162b2 and Gam-COVID-Vac (p = 0.001), as well as BBIBP-CorV and Gam-COVID-Vac groups (p<0.001). Percentage of seropositive was 81% in the convalescent group, 83% in BBIBP-CorV vaccinated and 100% in BNT162b2 and Gam-COVID-Vac. When comparing measured antibody levels in vaccinated to those in COVID-19 recovered, significantly higher antibody levels were found for vaccinated with BNT162b2 (p<0.001), and with Gam-COVID-Vac (p<0.001), while for BBIBP-CorV there was no statistically significant difference (p = 0.641). CONCLUSIONS: All three investigated vaccines, BNT162b2, BBIBP-CorV and Gam-COVID-Vac, provide robust immune response 28 days after the second dose of vaccine, in the majority of participants. All individuals vaccinated with BNT162b2 and Gam-COVID-Vac seroconverted, while in vaccinated with BBIBP-CorV and COVID-19 recovered seroconversion rates were lower. Although less potent compared to other two vaccines, immune response after BBIBP-CorV was similar to response measured in convalescents. Challenge still remains to examine dynamics and durability of immunoprotection.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/immunology , COVID-19/therapy , Treatment Outcome , Adult , Antibodies/analysis , Antibodies/blood , Antibodies, Viral/blood , COVID-19/blood , COVID-19 Vaccines/immunology , Convalescence , Cross-Sectional Studies , Female , Humans , Immunity/immunology , Immunity, Innate/immunology , Immunogenicity, Vaccine/immunology , Immunoglobulin G/analysis , Immunoglobulin G/blood , Male , Middle Aged , SARS-CoV-2/immunology , Serbia , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Inactivated/immunology , Vaccines, Synthetic/immunology
3.
Cells ; 11(3)2022 01 30.
Article in English | MEDLINE | ID: covidwho-1667057

ABSTRACT

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing, as is research on the molecular mechanisms underlying cellular infection by coronaviruses, with the hope of developing therapeutic agents against this pandemic. Other important respiratory viruses such as 2009 pandemic H1N1 and H7N9 avian influenza virus (AIV), influenza A viruses, are also responsible for a possible outbreak due to their respiratory susceptibility. However, the interaction of these viruses with host cells and the regulation of post-transcriptional genes remains unclear. In this study, we detected and analyzed the comparative transcriptome profiling of SARS-CoV-2, panH1N1 (A/California/07/2009), and H7N9 (A/Shanghai/1/2013) infected cells. The results showed that the commonly upregulated genes among the three groups were mainly involved in autophagy, pertussis, and tuberculosis, which indicated that autophagy plays an important role in viral pathogenicity. There are three groups of commonly downregulated genes involved in metabolic pathways. Notably, unlike panH1N1 and H7N9, SARS-CoV-2 infection can inhibit the m-TOR pathway and activate the p53 signaling pathway, which may be responsible for unique autophagy induction and cell apoptosis. Particularly, upregulated expression of IRF1 was found in SARS-CoV-2, panH1N1, and H7N9 infection. Further analysis showed SARS-CoV-2, panH1N1, and H7N9 infection-induced upregulation of lncRNA-34087.27 could serve as a competitive endogenous RNA to stabilize IRF1 mRNA by competitively binding with miR-302b-3p. This study provides new insights into the molecular mechanisms of influenza A virus and SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Immunity/immunology , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H7N9 Subtype/immunology , Influenza, Human/immunology , RNA/immunology , Transcriptome/immunology , A549 Cells , Animals , COVID-19/genetics , COVID-19/virology , HEK293 Cells , Host-Pathogen Interactions/immunology , Humans , Immunity/genetics , Influenza A Virus, H1N1 Subtype/physiology , Influenza A Virus, H7N9 Subtype/physiology , Influenza, Human/genetics , Influenza, Human/virology , Interferon Regulatory Factor-1/genetics , Interferon Regulatory Factor-1/immunology , Interferon Regulatory Factor-1/metabolism , MicroRNAs/genetics , MicroRNAs/immunology , MicroRNAs/metabolism , Pandemics/prevention & control , RNA/genetics , RNA/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/immunology , RNA, Long Noncoding/metabolism , RNA, Messenger/genetics , RNA, Messenger/immunology , RNA, Messenger/metabolism , RNA-Seq/methods , SARS-CoV-2/physiology , Signal Transduction/genetics , Signal Transduction/immunology , Transcriptome/genetics
4.
Front Immunol ; 12: 800074, 2021.
Article in English | MEDLINE | ID: covidwho-1662584

ABSTRACT

Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein-Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS.


Subject(s)
COVID-19/complications , Glomerulosclerosis, Focal Segmental/etiology , Kidney Glomerulus/virology , Animals , COVID-19/immunology , COVID-19/virology , Epithelial Cells/immunology , Epithelial Cells/virology , Glomerulosclerosis, Focal Segmental/immunology , Glomerulosclerosis, Focal Segmental/virology , Humans , Immunity/immunology , Kidney Glomerulus/immunology , Podocytes/immunology , Podocytes/virology , Proteinuria/etiology , Proteinuria/immunology , Proteinuria/virology , SARS-CoV-2/immunology
5.
Front Immunol ; 12: 729990, 2021.
Article in English | MEDLINE | ID: covidwho-1662578

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19) pandemic, represents a global crisis. Most patients developed mild/moderate symptoms, and the status of immune system varied in acute and regulatory stages. The crosstalk between immune cells and the dynamic changes of immune cell contact is rarely described. Here, we analyzed the features of immune response of paired peripheral blood mononuclear cell (PBMC) samples from the same patients during acute and regulatory stages. Consistent with previous reports, both myeloid and T cells turned less inflammatory and less activated at recovery phase. Additionally, the communication patterns of myeloid-T cell and T-B cell are obviously changed. The crosstalk analysis reveals that typical inflammatory cytokines and several chemokines are tightly correlated with the recovery of COVID-19. Intriguingly, the signal transduction of metabolic factor insulin-like growth factor 1 (IGF1) is altered at recovery phase. Furthermore, we confirmed that the serum levels of IGF1 and several inflammatory cytokines are apparently dampened after the negative conversion of SARS-CoV-2 RNA. Thus, these results reveal several potential detection and therapeutic targets that might be used for COVID-19 recovery.


Subject(s)
COVID-19/immunology , Cell Communication/immunology , Immunity/immunology , Insulin-Like Growth Factor I/immunology , B-Lymphocytes/immunology , Cytokines/immunology , Disease Progression , Humans , Leukocytes, Mononuclear/immunology , Myeloid Cells/immunology , SARS-CoV-2/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology
6.
Int J Mol Sci ; 22(16)2021 Aug 23.
Article in English | MEDLINE | ID: covidwho-1662694

ABSTRACT

Polyethyleneimine (PEI) induced immune responses were investigated in human bronchial epithelial (hBE) cells and mice. PEI rapidly induced ATP release from hBE cells and pretreatment with glutathione (GSH) blocked the response. PEI activated two conductive pathways, VDAC-1 and pannexin 1, which completely accounted for ATP efflux across the plasma membrane. Moreover, PEI increased intracellular Ca2+ concentration ([Ca2+]i), which was reduced by the pannexin 1 inhibitor, 10Panx (50 µM), the VDAC-1 inhibitor, DIDS (100 µM), and was nearly abolished by pretreatment with GSH (5 mM). The increase in [Ca2+]i involved Ca2+ uptake through two pathways, one blocked by oxidized ATP (oATP, 300 µM) and another that was blocked by the TRPV-1 antagonist A784168 (100 nM). PEI stimulation also increased IL-33 mRNA expression and protein secretion. In vivo experiments showed that acute (4.5 h) PEI exposure stimulated secretion of Th2 cytokines (IL-5 and IL-13) into bronchoalveolar lavage (BAL) fluid. Conjugation of PEI with ovalbumin also induced eosinophil recruitment and secretion of IL-5 and IL-13 into BAL fluid, which was inhibited in IL-33 receptor (ST2) deficient mice. In conclusion, PEI-induced oxidative stress stimulated type 2 immune responses by activating ATP-dependent Ca2+ uptake leading to IL-33 secretion, similar to allergens derived from Alternaria.


Subject(s)
Adenosine Triphosphate/immunology , Epithelial Cells/drug effects , Epithelial Cells/immunology , Immunity/drug effects , Nanoparticles/administration & dosage , Oxidative Stress/drug effects , Polyethyleneimine/pharmacology , Allergens/immunology , Animals , Calcium/immunology , Cells, Cultured , Cytokines/immunology , Female , Humans , Immunity/immunology , Mice , Mice, Inbred BALB C , Oxidative Stress/immunology , RNA, Messenger/immunology , Respiratory Mucosa/drug effects , Respiratory Mucosa/immunology
7.
Cell Rep ; 38(6): 110345, 2022 02 08.
Article in English | MEDLINE | ID: covidwho-1654153

ABSTRACT

Understanding the long-term maintenance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity is critical for predicting protection against reinfection. In an age- and gender-matched cohort of 24 participants, the association of disease severity and early immune responses on the maintenance of humoral immunity 12 months post-infection is examined. All severely affected participants maintain a stable subset of SARS-CoV-2 receptor-binding domain (RBD)-specific memory B cells (MBCs) and good neutralizing antibody breadth against the majority of the variants of concern, including the Delta variant. Modeling these immune responses against vaccine efficacy data indicate a 45%-76% protection against symptomatic infection (variant dependent). Overall, these findings indicate durable humoral responses in most participants after infection, reasonable protection against reinfection, and implicate baseline antigen-specific CD4+ T cell responses as a predictor of maintenance of antibody neutralization breadth and RBD-specific MBC levels at 12 months post-infection.


Subject(s)
Broadly Neutralizing Antibodies/metabolism , SARS-CoV-2/immunology , Adult , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Australia , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , COVID-19/immunology , Cohort Studies , Female , Humans , Immunity/immunology , Immunity, Humoral/immunology , Male , SARS-CoV-2/pathogenicity , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology
9.
Nat Commun ; 13(1): 320, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1632529

ABSTRACT

Pregnant women represent a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Here we show that SARS-CoV-2 infection during pregnancy primarily induces unique inflammatory responses at the maternal-fetal interface, which are largely governed by maternal T cells and fetal stromal cells. SARS-CoV-2 infection during pregnancy is also associated with humoral and cellular immune responses in the maternal blood, as well as with a mild cytokine response in the neonatal circulation (i.e., umbilical cord blood), without compromising the T-cell repertoire or initiating IgM responses. Importantly, SARS-CoV-2 is not detected in the placental tissues, nor is the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and emphasizes the rarity of placental infection.


Subject(s)
COVID-19/immunology , Immunity/immunology , Infectious Disease Transmission, Vertical , Placenta/immunology , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , Adult , COVID-19/blood , COVID-19/virology , Cytokines/blood , Cytokines/immunology , Cytokines/metabolism , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Infant, Newborn , Placenta/virology , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/virology , RNA, Viral/genetics , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Young Adult
10.
PLoS One ; 17(1): e0262311, 2022.
Article in English | MEDLINE | ID: covidwho-1622358

ABSTRACT

In the fight against SARS-COV-2, the development of serological assays based on different antigenic domains represent a versatile tool to get a comprehensive picture of the immune response or differentiate infection from vaccination beyond simple diagnosis. Here we use a combination of the Nucleoprotein (NP), the Spike 1 (S1) and Spike 2 (S2) subunits, and the receptor binding domain (RBD) and N-terminal domain (NTD) of the Spike antigens from the CoViDiag® multiplex IgG assay, to follow the immune response to SARS-CoV-2 infection over a long time period and depending on disease severity. Using a panel of 209 sera collected from 61 patients up to eight months after infection, we observed that most patients develop an immune response against multiple viral epitope, but anti-S2 antibodies seemed to last longer. For all the tested IgGs, we have found higher responses for hospitalized patients than for non-hospitalized ones. Moreover the combination of the five different IgG responses increased the correlation to the neutralizing antibody titers than if considered individually. Multiplex immunoassays have the potential to improve diagnostic performances, especially for ancient infection or mild form of the disease presenting weaker antibody responses. Also the combined detection of anti-NP and anti-Spike-derived domains can be useful to differentiate vaccination from viral infection and accurately assess the antibody potential to neutralize the virus.


Subject(s)
COVID-19/immunology , Immunity/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Female , Humans , Immunoassay/methods , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology
11.
Nutrients ; 14(1)2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1613923

ABSTRACT

Elderly people are particularly vulnerable to COVID-19, with a high risk of developing severe disease and a reduced immune response to the COVID-19 vaccine. A randomized, placebo-controlled, double-blind trial to assess the effect of the consumption of the probiotic Loigolactobacillus coryniformis K8 CECT 5711 on the immune response generated by the COVID-19 vaccine in an elderly population was performed. Two hundred nursing home residents >60 yrs that had not COVID-19 were randomized to receive L. coryniformis K8 or a placebo daily for 3 months. All volunteers received a complete vaccination schedule of a mRNA vaccine, starting the intervention ten days after the first dose. Specific IgG and IgA antibody levels were analyzed 56 days after the end of the immunization process. No differences between the groups were observed in the antibody levels. During the intervention, 19 subjects had COVID-19 (11 receiving K8 vs. 8 receiving placebo, p = 0.457). Subgroup analysis in these patients showed that levels of IgG were significantly higher in those receiving K8 compared to placebo (p = 0.038). Among subjects >85 yrs that did not get COVID-19, administration of K8 tended to increase the IgA levels (p = 0.082). The administration of K8 may enhance the specific immune response against COVID-19 and may improve the COVID-19 vaccine-specific responses in elderly populations.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Geriatric Assessment/methods , Immunity/immunology , Lactobacillus/immunology , Probiotics/administration & dosage , Aged , Aged, 80 and over , COVID-19/immunology , Double-Blind Method , Female , Humans , Male , SARS-CoV-2
12.
Front Immunol ; 12: 807134, 2021.
Article in English | MEDLINE | ID: covidwho-1604257

ABSTRACT

ORF8 is a viral immunoglobulin-like (Ig-like) domain protein encoded by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome. It tends to evolve rapidly and interfere with immune responses. However, the structural characteristics of various coronavirus ORF8 proteins and their subsequent effects on biological functions remain unclear. Herein, we determined the crystal structures of SARS-CoV-2 ORF8 (S84) (one of the epidemic isoforms) and the bat coronavirus RaTG13 ORF8 variant at 1.62 Å and 1.76 Å resolution, respectively. Comparison of these ORF8 proteins demonstrates that the 62-77 residues in Ig-like domain of coronavirus ORF8 adopt different conformations. Combined with mutagenesis assays, the residue Cys20 of ORF8 is responsible for forming the covalent disulfide-linked dimer in crystal packing and in vitro biochemical conditions. Furthermore, immune cell-binding assays indicate that various ORF8 (SARS-CoV-2 ORF8 (L84), ORF8 (S84), and RaTG13 ORF8) proteins have different interaction capabilities with human CD14+ monocytes in human peripheral blood. These results provide new insights into the specific characteristics of various coronavirus ORF8 and suggest that ORF8 variants may influence disease-related immune responses.


Subject(s)
COVID-19/immunology , Chiroptera/immunology , Immunity/immunology , Immunoglobulin Domains/immunology , Viral Proteins/immunology , Animals , Binding Sites/genetics , COVID-19/virology , Cells, Cultured , Chiroptera/genetics , Chiroptera/metabolism , Crystallography, X-Ray , Humans , Immunity/genetics , Immunoglobulin Domains/genetics , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Models, Molecular , Monocytes/immunology , Monocytes/metabolism , Mutation , Protein Binding , Species Specificity , Viral Proteins/classification , Viral Proteins/genetics
13.
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
14.
Cell ; 185(4): 603-613.e15, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1588149

ABSTRACT

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunity/immunology , SARS-CoV-2/immunology , T Follicular Helper Cells/immunology , Vaccination , Vaccines, Synthetic/immunology , /immunology , Adult , B-Lymphocytes/immunology , COVID-19/blood , Clone Cells , Cohort Studies , Cytokines/metabolism , Female , Germinal Center/immunology , HLA-DP beta-Chains/immunology , Humans , Immunodominant Epitopes/immunology , Jurkat Cells , Lymph Nodes/metabolism , Male , Middle Aged , Peptides/chemistry , Peptides/metabolism , Protein Multimerization , Receptors, Antigen, T-Cell/metabolism
15.
Cell Rep ; 38(2): 110218, 2022 01 11.
Article in English | MEDLINE | ID: covidwho-1588140

ABSTRACT

SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unclear. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America.


Subject(s)
COVID-19/immunology , Immunity/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Cell Line , Female , Glycosylation , HEK293 Cells , Humans , Male , Middle Aged , Mutation/immunology , Spike Glycoprotein, Coronavirus/immunology
16.
Cell Rep ; 37(11): 110112, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1530687

ABSTRACT

An ideal vaccine against SARS-CoV-2 is expected to elicit broad immunity to prevent viral infection and disease, with efficient viral clearance in the upper respiratory tract (URT). Here, the N protein and prefusion-full S protein (SFLmut) are combined with flagellin (KF) and cyclic GMP-AMP (cGAMP) to generate a candidate vaccine, and this vaccine elicits stronger systemic and mucosal humoral immunity than vaccines containing other forms of the S protein. Furthermore, the candidate vaccine administered via intranasal route can enhance local immune responses in the respiratory tract. Importantly, human ACE2 transgenic mice given the candidate vaccine are protected against lethal SARS-CoV-2 challenge, with superior protection in the URT compared with that in mice immunized with an inactivated vaccine. In summary, the developed vaccine can elicit a multifaceted immune response and induce robust viral clearance in the URT, which makes it a potential vaccine for preventing disease and infection of SARS-CoV-2.


Subject(s)
COVID-19 Vaccines/immunology , Combined Modality Therapy/methods , SARS-CoV-2/immunology , Administration, Intranasal , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Viral/immunology , Antigens/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/genetics , Chlorocebus aethiops , Coronavirus Nucleocapsid Proteins/immunology , Female , Flagellin/immunology , HEK293 Cells , Humans , Immunity/immunology , Immunity/physiology , Immunity, Humoral/immunology , Immunization , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nucleotides, Cyclic/immunology , Phosphoproteins/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Vero Cells
17.
Front Immunol ; 12: 750448, 2021.
Article in English | MEDLINE | ID: covidwho-1526769

ABSTRACT

Background: The risk of SARS-CoV-2 infection among health care workers (HCWs) is a concern, but studies that conclusively determine whether HCWs are over-represented remain limited. Furthermore, methods used to confirm past infection vary and the immunological response after mild COVID-19 is still not well defined. Method: 314 HCWs were recruited from a Swedish Infectious Diseases clinic caring for COVID-19 patients. IgG antibodies were measured using two commercial assays (Abbot Architect nucleocapsid (N)-assay and YHLO iFlash-1800 N and spike (S)-assays) at five time-points, from March 2020 to January 2021, covering two pandemic waves. Seroprevalence was assessed in matched blood donors at three time-points. More extensive analyses were performed in 190 HCWs in September/October 2020, including two additional IgG-assays (DiaSorin LiaisonXL S1/S2 and Abbot Architect receptor-binding domain (RBD)-assays), neutralizing antibodies (NAbs), and CD4+ T-cell reactivity using an in-house developed in vitro whole-blood assay based on flow cytometric detection of activated cells after stimulation with Spike S1-subunit or Spike, Membrane and Nucleocapsid (SMN) overlapping peptide pools. Findings: Seroprevalence was higher among HCWs compared to sex and age-matched blood donors at all time-points. Seropositivity increased from 6.4% to 16.3% among HCWs between May 2020 and January 2021, compared to 3.6% to 11.9% among blood donors. We found significant correlations and high levels of agreement between NAbs and all four commercial IgG-assays. At 200-300 days post PCR-verified infection, there was a wide variation in sensitivity between the commercial IgG-assays, ranging from <30% in the N-assay to >90% in the RBD-assay. There was only moderate agreement between NAbs and CD4+ T-cell reactivity to S1 or SMN. Pre-existing CD4+ T-cell reactivity was present in similar proportions among HCW who subsequently became infected and those that did not. Conclusions: HCWs in COVID-19 patient care in Sweden have been infected with SARS-CoV-2 at a higher rate compared to blood donors. We demonstrate substantial variation between different IgG-assays and propose that multiple serological targets should be used to verify past infection. Our data suggest that CD4+ T-cell reactivity is not a suitable measure of past infection and does not reliably indicate protection from infection in naive individuals.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunity/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Adult , Aged , Female , Follow-Up Studies , Health Personnel , Humans , Male , Middle Aged , Pandemics/prevention & control , Seroepidemiologic Studies , Sweden , Young Adult
18.
Cell Immunol ; 371: 104451, 2022 01.
Article in English | MEDLINE | ID: covidwho-1499702

ABSTRACT

The COVID-19 pandemic has once again brought to the forefront the existence of a tight link between the coagulation/fibrinolytic system and the immunologic processes. Tissue-type plasminogen activator (tPA) is a serine protease with a key role in fibrinolysis by converting plasminogen into plasmin that can finally degrade fibrin clots. tPA is released in the blood by endothelial cells and hepatocytes but is also produced by various types of immune cells including T cells and monocytes. Beyond its role on hemostasis, tPA is also a potent modulator of inflammation and is involved in the regulation of several inflammatory diseases. Here, after a brief description of tPA structure, we review its new functions in adaptive immunity focusing on T cells and antigen presenting cells. We intend to synthesize the recent knowledge on proteolysis- and receptor-mediated effects of tPA on immune response in physiological and pathological context.


Subject(s)
Blood Coagulation/immunology , COVID-19/immunology , Fibrinolysis/immunology , Immunity/immunology , SARS-CoV-2/immunology , Tissue Plasminogen Activator/immunology , Antigen-Presenting Cells/immunology , COVID-19/epidemiology , COVID-19/virology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Models, Immunological , Pandemics , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Tissue Plasminogen Activator/metabolism
19.
Dokl Biochem Biophys ; 496(1): 44-47, 2021 May.
Article in English | MEDLINE | ID: covidwho-1495017

ABSTRACT

The high efficiency of using thermoheliox (inhalation with a high-temperature mixture of helium and oxygen) in the treatment of patients affected by COVID-19 was shown. The dynamics of accumulation of IgG, IgM, and C-reactive protein (CRP) in patients with coronavirus infection in the "working" and control groups was studied experimentally. It was shown that thermoheliox intensifies the synthesis of IgG, IgM, and CRP antibodies, while eliminating the induction period on the kinetic curves of the synthesis of specific antibodies in the IgG form and transfers the synthesis of CRP to a fast phase. The results of experiments confirm the previously obtained data based on the analysis of the kinetic model of the development of coronaviral infection in the human body.


Subject(s)
Antibodies, Viral/immunology , C-Reactive Protein/biosynthesis , COVID-19/metabolism , COVID-19/prevention & control , Immunity/immunology , Vaccination/methods , COVID-19/immunology , Humans , Kinetics , Spike Glycoprotein, Coronavirus/immunology
20.
Cell Rep ; 36(6): 109504, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1491797

ABSTRACT

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Chemokine CXCL10/immunology , Interferon-gamma/immunology , Interleukin-15/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral/immunology , COVID-19/metabolism , COVID-19 Vaccines/administration & dosage , Female , Humans , Immunity/immunology , Male , Middle Aged , RNA, Messenger/immunology
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