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1.
Cell Rep ; 36(8): 109591, 2021 08 24.
Article in English | MEDLINE | ID: covidwho-1370154

ABSTRACT

The relationship between B cells and CD4 T cells has been carefully studied, revealing a collaborative effort in which B cells promote the activation, differentiation, and expansion of CD4 T cells while the so-called "helper" cells provide signals to B cells, influencing their class switching and fate. Interactions between B cells and CD8 T cells are not as well studied, although CD8 T cells exhibit an accelerated contraction after certain infections in B-cell-deficient mice. Here, we find that B cells significantly enhance primary CD8 T cell responses after vaccination. Moreover, memory CD8 numbers and function are impaired in B-cell-deficient animals, leading to increased susceptibility to bacterial challenge. We also show that interleukin-27 production by B cells contributes to their impact on primary, but not memory, CD8 responses. Better understanding of the interactions between CD8 T cells and B cells may aid in the design of more effective future vaccine strategies.


Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory , Interleukin-27/immunology , Interleukin-27/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Subunit/immunology , Animals , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , Humans , Lymphocyte Count , Mice , Mice, Inbred C57BL , Receptors, Virus/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
2.
Int J Mol Sci ; 21(14)2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-1934090

ABSTRACT

Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens.


Subject(s)
B-Lymphocytes/immunology , Receptors, Steroid/immunology , Animals , B-Lymphocytes/metabolism , Gene Expression Regulation , Humans , Immunity , Immunoglobulins/genetics , Immunoglobulins/immunology , Receptors, Steroid/genetics , Thyroid Hormones/genetics , Thyroid Hormones/immunology , Vitamin A/genetics , Vitamin A/immunology , Vitamin D/genetics , Vitamin D/immunology
3.
Front Immunol ; 13: 876306, 2022.
Article in English | MEDLINE | ID: covidwho-1865451

ABSTRACT

The COVID-19 pandemic shows that vaccination strategies building on an ancestral viral strain need to be optimized for the control of potentially emerging viral variants. Therefore, aiming at strong B cell somatic hypermutation to increase antibody affinity to the ancestral strain - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants since high affinity may offer some flexibility to compensate for strain-individual mutations. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529.


Subject(s)
B-Lymphocytes , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/metabolism , Humans , Pandemics , SARS-CoV-2/genetics , Vaccination/methods , mRNA Vaccines/immunology
4.
Cell ; 185(5): 896-915.e19, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1670278

ABSTRACT

The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunity, Mucosal , Administration, Intranasal , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19/virology , COVID-19 Vaccines/immunology , Cytokines/blood , Genetic Vectors/genetics , Genetic Vectors/immunology , Genetic Vectors/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neutralization Tests , Nucleocapsid/genetics , Nucleocapsid/immunology , Nucleocapsid/metabolism , Pan troglodytes , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
5.
Cell Rep ; 38(8): 110399, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1664737

ABSTRACT

Follicular helper T (Tfh) cells promote, whereas follicular regulatory T (Tfr) cells restrain, germinal center (GC) reactions. However, the precise roles of these cells in the complex GC reaction remain poorly understood. Here, we perturb Tfh or Tfr cells after SARS-CoV-2 spike protein vaccination in mice. We find that Tfh cells promote the frequency and somatic hypermutation (SHM) of Spike-specific GC B cells and regulate clonal diversity. Tfr cells similarly control SHM and clonal diversity in the GC but do so by limiting clonal competition. In addition, deletion of Tfh or Tfr cells during primary vaccination results in changes in SHM after vaccine boosting. Aged mice, which have altered Tfh and Tfr cells, have lower GC responses, presenting a bimodal distribution of SHM. Together, these data demonstrate that GC responses to SARS-CoV-2 spike protein vaccines require a fine balance of positive and negative follicular T cell help to optimize humoral immunity.


Subject(s)
COVID-19/prevention & control , Germinal Center/immunology , Spike Glycoprotein, Coronavirus/administration & dosage , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Aging , Animals , Antibodies, Viral/blood , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19/virology , Germinal Center/cytology , Germinal Center/metabolism , Immunity, Humoral , Mice , Mice, Inbred C57BL , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Vaccination , Vaccines, Subunit/immunology
6.
Ann Neurol ; 91(3): 342-352, 2022 03.
Article in English | MEDLINE | ID: covidwho-1648414

ABSTRACT

OBJECTIVE: The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant. METHODS: We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant. RESULTS: SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B-cell depleted compared to nondepleted patients. INTERPRETATION: Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352.


Subject(s)
Autoimmune Diseases of the Nervous System/immunology , B-Lymphocytes/immunology , COVID-19 Vaccines/administration & dosage , Immunity, Cellular/immunology , Immunity, Humoral/immunology , SARS-CoV-2/immunology , Adult , Autoimmune Diseases of the Nervous System/blood , Autoimmune Diseases of the Nervous System/epidemiology , B-Lymphocytes/metabolism , COVID-19/epidemiology , COVID-19/prevention & control , Cohort Studies , Female , Humans , Male , Middle Aged , Neuroimmunomodulation/immunology , Prospective Studies , SARS-CoV-2/metabolism
7.
Nat Immunol ; 23(2): 210-216, 2022 02.
Article in English | MEDLINE | ID: covidwho-1625648

ABSTRACT

A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-ß) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-ß, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.


Subject(s)
B-Lymphocytes/immunology , COVID-19/complications , Immunity, Innate , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , Aged , B-Lymphocytes/metabolism , B-Lymphocytes/virology , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Cytokines/blood , Female , Host-Pathogen Interactions , Humans , Inflammation Mediators/blood , Male , Middle Aged , Prognosis , SARS-CoV-2/pathogenicity , Severity of Illness Index , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Time Factors
8.
PLoS One ; 16(12): e0261656, 2021.
Article in English | MEDLINE | ID: covidwho-1623659

ABSTRACT

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n = 8) or severe (n = 5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG+ B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG+ B cells showed increased expression of markers associated with durable B cell memory, including T-bet and FcRL5, as compared to individuals who experienced severe disease. While the frequency of T-bet+ spike-specific IgG+ B cells differed between the two groups, these cells predominantly showed an activated switched memory B cell phenotype in both groups. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet+ IgG+ memory B cells decreased to baseline levels. Collectively, our results highlight subtle differences in the B cells response after non-severe and severe COVID-19 and suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.


Subject(s)
COVID-19/immunology , Receptors, Fc/metabolism , T-Box Domain Proteins/metabolism , Adult , Aged , Antibodies, Viral/blood , B-Lymphocytes/metabolism , Biomarkers/analysis , COVID-19/metabolism , Female , Flow Cytometry/methods , Hospitalization/trends , Humans , Immunoglobulin G/blood , Immunologic Memory , Male , /metabolism , Middle Aged , Receptors, Fc/blood , Receptors, Fc/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , T-Box Domain Proteins/blood
9.
Front Immunol ; 12: 760249, 2021.
Article in English | MEDLINE | ID: covidwho-1581341

ABSTRACT

Background: The humoral and cellular immune responses to SARS-COV-2 vaccination remain to be elucidated in hemodialysis (HD) patients and kidney transplant recipients (KTRs), considering their baseline immunosuppressed status. The aim of our study was to assess the associations of vaccine-induced antibody responses with circulating lymphocytes sub-populations and their respective patterns of alterations in maintenance HD patients and KTRs. Materials and Methods: We included 34 HD patients and 54 KTRs who received two doses of the mRNA-vaccine BNT162b2. Lymphocyte subpopulations were analyzed by flow cytometry before vaccination (T0), before the second vaccine dose (T1) and 2 weeks after the second dose (T2). The anti-SARS-CoV2 antibody response was assessed at T1 and at T2. Results: 31 HD patients (91.8%) and 16 KTRs (29.6%) became seropositive at T2. HD patients who became seropositive following the first dose displayed higher CD19+ B lymphocytes compared to their seronegative HD counterparts. A positive correlation was established between CD19+ B cells counts and antibody titers at all time-points in both groups (p < 0.001). KTRs showed higher naïve CD4+CD45RA+ T helper cells compared to HD patients at baseline and T2 whereas HD patients displayed higher memory CD45RO+ T cells compared to KTRs at T2. The naïve CD4+CD45RA to memory CD4+CD45RO+ T helper cells fraction was negatively associated with antibody production in both groups. Conclusions: Our study provides a potential conceptual framework for monitoring vaccination efficacy in HD patients and KTRs considering the correlation established between CD19+ B cells, generation of memory CD4+ T helper cells and anti SARS-CoV2 antibody response to vaccination.


Subject(s)
Antibody Formation/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Immunity, Humoral , Immunocompromised Host , Immunologic Memory , B-Lymphocytes/metabolism , Biomarkers , CD4-Positive T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Female , Humans , Immunophenotyping , Kidney Transplantation , Lymphocyte Count , Male , Renal Dialysis , SARS-CoV-2/immunology
10.
Front Immunol ; 12: 776933, 2021.
Article in English | MEDLINE | ID: covidwho-1581333

ABSTRACT

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.


Subject(s)
B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Clonal Selection, Antigen-Mediated/immunology , Germinal Center/immunology , Host-Pathogen Interactions/immunology , SARS-CoV-2/immunology , Antigens/immunology , B-Lymphocytes/metabolism , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Dose-Response Relationship, Immunologic , Germinal Center/metabolism , Humans , Immunization, Secondary , Models, Theoretical , Vaccination
11.
Molecules ; 26(23)2021 Dec 06.
Article in English | MEDLINE | ID: covidwho-1559466

ABSTRACT

Bruton's tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "BTK" and "BTK inhibitors" as keywords.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Autoimmune Diseases/drug therapy , Autoimmune Diseases/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Kinase Inhibitors/therapeutic use , Agammaglobulinaemia Tyrosine Kinase/chemistry , Agammaglobulinaemia Tyrosine Kinase/classification , Animals , B-Lymphocytes/metabolism , Humans , Inhibitory Concentration 50 , Treatment Outcome
12.
J Virol ; 96(3): e0150421, 2022 02 09.
Article in English | MEDLINE | ID: covidwho-1546442

ABSTRACT

In the age of COVID, nucleic acid vaccines have garnered much attention, at least in part, because of the simplicity of construction, production, and flexibility to adjust and adapt to an evolving outbreak. Orthopoxviruses remain a threat on multiple fronts, especially as emerging zoonoses. In response, we developed a DNA vaccine, termed 4pox, that protected nonhuman primates against monkeypox virus (MPXV)-induced severe disease. Here, we examined the protective efficacy of the 4pox DNA vaccine delivered by intramuscular (i.m.) electroporation (EP) in rabbits challenged with aerosolized rabbitpox virus (RPXV), a model that recapitulates the respiratory route of exposure and low dose associated with natural smallpox exposure in humans. We found that 4pox-vaccinated rabbits developed immunogen-specific antibodies, including neutralizing antibodies, and did not develop any clinical disease, indicating protection against aerosolized RPXV. In contrast, unvaccinated animals developed significant signs of disease, including lesions, and were euthanized. These findings demonstrate that an unformulated, nonadjuvanted DNA vaccine delivered i.m. can protect against an aerosol exposure. IMPORTANCE The eradication of smallpox and subsequent cessation of vaccination have left a majority of the population susceptible to variola virus or other emerging poxviruses. This is exemplified by human monkeypox, as evidenced by the increase in reported endemic and imported cases over the past decades. Therefore, a malleable vaccine technology that can be mass produced and does not require complex conditions for distribution and storage is sought. Herein, we show that a DNA vaccine, in the absence of a specialized formulation or adjuvant, can protect against a lethal aerosol insult of rabbitpox virus.


Subject(s)
Nucleic Acid-Based Vaccines/immunology , Orthopoxvirus/immunology , Poxviridae Infections/prevention & control , Vaccinia virus/immunology , Vaccinia/prevention & control , Viral Proteins/immunology , Viral Vaccines/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Dose-Response Relationship, Immunologic , Electroporation , Female , Immunization/methods , Immunogenicity, Vaccine , Lymphocyte Activation/immunology , Nucleic Acid-Based Vaccines/administration & dosage , Oligodeoxyribonucleotides/administration & dosage , Oligodeoxyribonucleotides/immunology , Rabbits , Vaccines, DNA/immunology , Vaccinia virus/genetics , Viral Vaccines/administration & dosage
15.
Int J Mol Sci ; 22(22)2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1524027

ABSTRACT

Severe outcomes of COVID-19 are associated with pathological response of the immune system to the SARS-CoV-2 infection. Emerging evidence suggests that an interaction may exist between COVID-19 pathogenesis and a broad range of xenobiotics, resulting in significant increases in death rates in highly exposed populations. Therefore, a better understanding of the molecular basis of the interaction between SARS-CoV-2 infection and chemical exposures may open opportunities for better preventive and therapeutic interventions. We attempted to gain mechanistic knowledge on the interaction between SARS-CoV-2 infection and chemical exposures using an in silico approach, where we identified genes and molecular pathways affected by both chemical exposures and SARS-CoV-2 in human immune cells (T-cells, B-cells, NK-cells, dendritic, and monocyte cells). Our findings demonstrate for the first time that overlapping molecular mechanisms affected by a broad range of chemical exposures and COVID-19 are linked to IFN type I/II signaling pathways and the process of antigen presentation. Based on our data, we also predict that exposures to various chemical compounds will predominantly impact the population of monocytes during the response against COVID-19.


Subject(s)
COVID-19/immunology , Immunity, Innate/drug effects , Xenobiotics/pharmacology , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Humans , Interferons/metabolism , SARS-CoV-2/isolation & purification , Signal Transduction/drug effects , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
16.
Int J Mol Sci ; 22(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1470890

ABSTRACT

Individuals with pre-existing chronic systemic low-grade inflammation are prone to develop severe COVID-19 and stronger anti-SARS-CoV-2 antibody responses. Whether this phenomenon reflects a differential expansion of antiviral B cells or a failure to regulate antibody synthesis remains unknown. Here, we compared the antiviral B cell repertoire of convalescent healthcare personnel to that of hospitalized patients with pre-existing comorbidities. Out of 277,500 immortalized B cell clones, antiviral B cell frequencies were determined by indirect immunofluorescence screening on SARS-CoV-2 infected cells. Surprisingly, frequencies of SARS-CoV-2 specific clones from the two groups were not statistically different, despite higher antibody levels in hospitalized patients. Moreover, functional analyses revealed that several B cell clones from healthcare personnel with low antibody levels had neutralizing properties. This study reveals for the first time a key qualitative defect of antibody synthesis in severe patients and calls for caution regarding estimated protective immunity based only on circulating antiviral antibodies.


Subject(s)
Antibodies, Viral/blood , B-Lymphocytes/immunology , COVID-19/pathology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Viral/immunology , Antibody Formation , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/virology , Comorbidity , Female , Health Personnel , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness Index , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
17.
Sci Immunol ; 6(66): eabl5842, 2021 Dec 10.
Article in English | MEDLINE | ID: covidwho-1467664

ABSTRACT

Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat. Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Here, we isolated naive B cells from eight seronegative human donors targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD). Single-cell B cell receptor (BCR) sequencing identified diverse gene usage and no restriction on complementarity determining region length. A subset of recombinant antibodies produced by naive B cell precursors bound to SARS-CoV-2 RBD and engaged circulating variants including B.1.1.7, B.1.351, and B.1.617.2, as well as preemergent bat-derived coronaviruses RaTG13, SHC104, and WIV1. By structural characterization of a naive antibody in complex with SARS-CoV-2 spike, we identified a conserved mode of recognition shared with infection-induced antibodies. We found that representative naive antibodies could signal in a B cell activation assay, and by using directed evolution, we could select for a higher-affinity RBD interaction, conferred by a single amino acid change. The minimally mutated, affinity-matured antibodies also potently neutralized SARS-CoV-2. Understanding the SARS-CoV-2 RBD­specific naive repertoire may inform potential responses capable of recognizing future SARS-CoV-2 variants or emerging coronaviruses, enabling the development of pan-coronavirus vaccines aimed at engaging protective germline responses.


Subject(s)
B-Lymphocytes/cytology , B-Lymphocytes/immunology , Coronavirus/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antigens, Viral/immunology , B-Lymphocytes/metabolism , COVID-19/immunology , COVID-19 Vaccines/immunology , Epitopes , Humans , Lymphocyte Activation , SARS-CoV-2/classification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
18.
Int J Mol Sci ; 22(20)2021 Oct 10.
Article in English | MEDLINE | ID: covidwho-1463713

ABSTRACT

We report a lymphoma patient with profound B-cell deficiency after chemotherapy combined with anti-CD20 antibody successfully treated with remdesivir and convalescent plasma for prolonged SARS-CoV-2 infection. Viral clearance was likely attributed to the robust expansion and activation of TCR Vß2 CD8+ cytotoxic T cells and CD16 + CD56- NK cells. This is the first presentation of TCR-specific T cell oligoclonal response in COVID-19. Our study suggests that B-cell depleted patients may effectively respond to anti-SARS-CoV-2 treatment when NK and antigen-specific Tc cell response is induced.


Subject(s)
COVID-19/therapy , Killer Cells, Natural/immunology , T-Lymphocytes, Cytotoxic/immunology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , B-Lymphocytes/metabolism , COVID-19/virology , Humans , Immunization, Passive , SARS-CoV-2/isolation & purification
19.
Sci Rep ; 11(1): 19817, 2021 10 06.
Article in English | MEDLINE | ID: covidwho-1454815

ABSTRACT

Recent studies have focused their attention on conjunctivitis as one of the symptoms of coronavirus disease 2019 (COVID-19). Therefore, tear samples were taken from COVID-19 patients and the presence of SARS-CoV-2 was evidenced using Real Time reverse transcription polymerase chain reaction. The main aim of this study was to analyze mRNA expression in the tears of patients with COVID-19 compared with healthy subjects using Next Generation Sequencing (NGS). The functional evaluation of the transcriptome highlighted 25 genes that differ statistically between healthy individuals and patients affected by COVID-19. In particular, the NGS analysis identified the presence of several genes involved in B cell signaling and keratinization. In particular, the genes involved in B cell signaling were downregulated in the tears of COVID-19 patients, while those involved in keratinization were upregulated. The results indicated that SARS-CoV-2 may induce a process of ocular keratinization and a defective B cell response.


Subject(s)
COVID-19/genetics , Eye Diseases/virology , Tears/metabolism , Transcriptome , Aged , B-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Eye Diseases/genetics , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Keratins/metabolism , Male , SARS-CoV-2/isolation & purification , Sequence Analysis, RNA/methods , Skin/metabolism , Skin/pathology , Skin/virology , Tears/virology
20.
Cell Rep ; 37(1): 109773, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1442298

ABSTRACT

SARS-CoV-2 infection in children is less severe than it is in adults. We perform a longitudinal analysis of the early innate responses in children and adults with mild infection within household clusters. Children display fewer symptoms than adults do, despite similar initial viral load, and mount a robust anti-viral immune signature typical of the SARS-CoV-2 infection and characterized by early interferon gene responses; increases in cytokines, such as CXCL10 and GM-CSF; and changes in blood cell numbers. When compared with adults, the antiviral response resolves faster (within a week of symptoms), monocytes and dendritic cells are more transiently activated, and genes associated with B cell activation appear earlier in children. Nonetheless, these differences do not have major effects on the quality of SARS-CoV-2-specific antibody responses. Our findings reveal that better early control of inflammation as observed in children may be key for rapidly controlling infection and limiting the disease course.


Subject(s)
Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/immunology , Cytokines/metabolism , Immunity, Innate , SARS-CoV-2/immunology , Transcriptome , Adaptive Immunity , Adolescent , Adult , B-Lymphocytes/metabolism , COVID-19/virology , Chemokine CXCL10/metabolism , Child , Child, Preschool , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Infant , Inflammation/virology , Interferons/metabolism , Longitudinal Studies , Middle Aged , Monocytes/metabolism , Sequence Analysis, RNA , Viral Load , Young Adult
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