RESUMO
Monitoring the seroprevalence of SARS-CoV-2 in children and adolescents can provide valuable information for effective SARS-CoV-2 surveillance, and thus guide vaccination strategies. In this study, we quantified antibodies against the spike S1 domains of several SARS-CoV-2 variants (wild-type, Alpha, Delta, and Omicron variants) as well as endemic human coronaviruses (HCoVs) in 1,309 children and adolescents screened between December 2020 and March 2023. Their antibody binding profiles were compared with those of 22 pre-pandemic samples from children and adolescents using an in-house Luminex®-based Corona Array (CA). The primary objectives of this study were to (i) monitor SARS-CoV-2-specific antibodies in children and adolescents, (ii) evaluate whether the S1-specific antibody response can identify the infecting variant of concern (VoC), (iii) estimate the prevalence of silent infections, and (iv) test whether vaccination or infection with SARS-CoV-2 induce HCoV cross-reactive antibodies. Both SARS-CoV-2 infection and vaccination induced a robust antibody response against the S1 domain of WT and VoCs in children and adolescents. Antibodies specific for the S1 domain were able to distinguish between SARS-CoV-2 VoCs in infected children. The serologically identified VoC was typically the predominant VoC at the time of infection. Furthermore, our highly sensitive CA identified more silent SARS-CoV-2 infections than a commercial ELISA (12.1% vs. 6.3%, respectively), and provided insights into the infecting VoC. Seroconversion to endemic HCoVs occurred in early childhood, and vaccination or infection with SARS-CoV-2 did not induce HCoV S1 cross-reactive antibodies. In conclusion, the antibody response to the S1 domain of the spike protein of SARS-CoV-2 is highly specific, providing information about the infecting VoC and revealing clinically silent infections.
Assuntos
Anticorpos Antivirais , COVID-19 , Reações Cruzadas , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , COVID-19/imunologia , COVID-19/diagnóstico , COVID-19/epidemiologia , SARS-CoV-2/imunologia , Criança , Adolescente , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Masculino , Glicoproteína da Espícula de Coronavírus/imunologia , Feminino , Pré-Escolar , Reações Cruzadas/imunologia , Estudos Soroepidemiológicos , Lactente , Vacinas contra COVID-19/imunologiaRESUMO
Multiple sclerosis (MS) is a prototypical autoimmune disease of the central nervous system (CNS). In addition to CD4+ T cells, memory B cells are now recognized as a critical cell type in the disease. This is underlined by the fact that the best-characterized environmental risk factor for MS is the Epstein-Barr virus (EBV), which can infect and persist in memory B cells throughout life. Several studies have identified changes in anti-EBV immunity in patients with MS. Examples include elevated titers of anti-EBV nuclear antigen 1 (EBNA1) antibodies, interactions of these with the MS-associated HLA-DR15 haplotype, and molecular mimicry with MS autoantigens like myelin basic protein (MBP), anoctamin-2 (ANO2), glial cell adhesion molecule (GlialCAM), and alpha-crystallin B (CRYAB). In this study, we employ a simple in vitro assay to examine the memory B cell antibody repertoire in MS patients and healthy controls. We replicate previous serological data from MS patients demonstrating an increased secretion of anti-EBNA1380-641 IgG in cell culture supernatants, as well as a positive correlation of these levels with autoantibodies against GlialCAM262-416 and ANO21-275. For EBNA1380-641 and ANO21-275, we provide additional evidence suggesting antibody cross-reactivity between the two targets. Further, we show that two efficacious MS treatments - natalizumab (NAT) and autologous hematopoietic stem cell transplantation (aHSCT) - are associated with distinct changes in the EBNA1-directed B cell response and that these alterations can be attributed to the unique mechanisms of action of these therapies. Using an in vitro system, our study confirms MS-associated changes in the anti-EBNA1 memory B cell response, EBNA1380-641 antibody cross-reactivity with ANO21-275, and reveals treatment-associated changes in the immunoglobulin repertoire in MS.
Assuntos
Reações Cruzadas , Antígenos Nucleares do Vírus Epstein-Barr , Células B de Memória , Esclerose Múltipla , Humanos , Esclerose Múltipla/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Reações Cruzadas/imunologia , Feminino , Masculino , Adulto , Células B de Memória/imunologia , Herpesvirus Humano 4/imunologia , Pessoa de Meia-Idade , Anticorpos Antivirais/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Linfócitos B/imunologia , Memória ImunológicaRESUMO
BACKGROUND: Hybrid immunity provides better protection against COVID-19 than vaccination or prior natural infection alone. It induces high magnitude and broadly cross-reactive neutralising anti-Spike IgG antibodies. However, it is not clear how long these potent antibodies last, especially in the context of adenovirus-based COVID-19 vaccines. METHODS: We conducted a longitudinal cohort study and enrolled 20 adults who had received an adenovirus-based COVID-19 vaccine before a laboratory-confirmed SARS-CoV-2 infection. We followed up the study participants for 390 days post the initial breakthrough infection. We assessed the longevity and cross-reactive breadth of serum antibodies against SARS-CoV-2 variants of concern (VOCs), including Omicron. RESULTS: The binding anti-Spike IgG antibodies remained within the reported putative levels for at least 360 days and were cross-neutralising against Beta, Gamma, Delta, and Omicron. During the follow up period, a median of one SARS-CoV-2 re-infection event was observed across the cohort, but none resulted in severe COVID-19. Moreover, the re-exposure events were associated with augmented anti-Spike and anti-RBD IgG antibody titres. CONCLUSIONS: This study confirms that hybrid immunity provides durable broadly cross-reactive antibody immunity against SARS-CoV-2 variants of concern for at least a year (360 days), and that it is further augment by SARS-CoV-2 re-exposure.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Reações Cruzadas , Imunoglobulina G , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Masculino , Feminino , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Adulto , Estudos Longitudinais , Pessoa de Meia-Idade , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Reações Cruzadas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adenoviridae/imunologia , Idoso , Estudos de CoortesRESUMO
Recent mumps outbreaks have been observed in vaccinated young adults due to the mumps virus (MuV) of genotype G, whereas the current vaccine is a mixture of two genotype A strains. These outbreaks could be attributed to waning vaccine immunity or the antigenic differences between the HN and F glycoproteins in the vaccine and circulating MuV. These glycoproteins are essential targets for the immune system, and antigenic variations may reduce the recognition of mumps antibodies, rendering the population susceptible to the MuV. We established stable cell lines expressing the MuV glycoproteins to study cross-reactivity between genotype A and genotype G. Cross-reactivity between the genotypes was evaluated via immunofluorescence using patient sera from vaccinated individuals, infected individuals, and vaccinated individuals infected with genotype G. Titer ratios showed that the vaccinated individuals exhibited a titer 3.68 times higher for the HN protein and 2.3 times higher for the F protein when comparing genotype A with genotype G. In contrast, the infected individuals showed a lower titer for genotype A compared with genotype G, at 0.43 and 0.33 for the HN and F proteins, respectively. No difference in titer ratio was observed for individuals vaccinated and subsequently infected with mumps. These findings suggest that antigenic variations between the two genotypes may potentially result in immune escape of the circulating strain, resulting in individuals susceptible to the MuV.
Assuntos
Anticorpos Antivirais , Reações Cruzadas , Genótipo , Vacina contra Caxumba , Vírus da Caxumba , Caxumba , Vírus da Caxumba/imunologia , Vírus da Caxumba/genética , Vírus da Caxumba/classificação , Humanos , Reações Cruzadas/imunologia , Caxumba/imunologia , Caxumba/virologia , Caxumba/prevenção & controle , Vacina contra Caxumba/imunologia , Vacina contra Caxumba/genética , Vacina contra Caxumba/administração & dosagem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteína HN/imunologia , Proteína HN/genética , Proteínas Virais de Fusão/imunologia , Proteínas Virais de Fusão/genética , Adulto , Linhagem CelularRESUMO
Systemic mastocytosis (SM) is a clonal mast cell disorder that can lead to potentially severe anaphylactic reactions. Hymenoptera sting is one of the most frequent triggers of anaphylaxis in these patients, and diagnosis of indolent SM (ISM) without skin involvement (ISMs) is not rare. In this subgroup of patients, venom immunotherapy (VIT) is an effective treatment decreasing subsequent systemic reactions, and lifelong administration is recommended. An individualized diagnosis is necessary to offer the most adequate VIT, and molecular diagnosis (MD) may be useful to discriminate between primary sensitization and cross-reactivity. Nevertheless, other techniques such as ImmunoCAP inhibition assays may be necessary to identify the genuine sensitization to offer the most suitable VIT. We present a male patient with an anaphylactic reaction following several wasp stings. The patient was diagnosed with ISM, and allergy to both Polistes dominula and Vespula sp venom was confirmed. In this scenario, MD did not discriminate between a genuine double sensitization and venom cross-reactivity between both vespids. Thus, CAP-inhibition assay was performed. This case indicated the importance of an accurate diagnosis of hymenoptera venom allergy (HVA). It also highlights the usefulness of CAP-inhibition assays when MD fails to distinguish between genuine double Polistes-Vespula sensitization and cross-reactivity.
Assuntos
Anafilaxia , Reações Cruzadas , Mordeduras e Picadas de Insetos , Mastocitose Sistêmica , Venenos de Vespas , Vespas , Humanos , Masculino , Venenos de Vespas/imunologia , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/imunologia , Mastocitose Sistêmica/complicações , Animais , Anafilaxia/diagnóstico , Anafilaxia/imunologia , Anafilaxia/etiologia , Mordeduras e Picadas de Insetos/imunologia , Mordeduras e Picadas de Insetos/diagnóstico , Mordeduras e Picadas de Insetos/complicações , Vespas/imunologia , Reações Cruzadas/imunologia , Dessensibilização Imunológica/métodos , Alérgenos/imunologia , Alérgenos/administração & dosagem , Triptases/sangue , Imunoglobulina E/imunologia , Imunoglobulina E/sangueRESUMO
There is a need to investigate novel strategies in order to create an effective, broadly protective vaccine for current and future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. The currently available vaccines demonstrate compromised efficacy against emerging SARS-CoV-2 variants of concern (VOCs), short-lived immunity, and susceptibility to immune imprinting due to frequent boosting practices. In this study, we examined the specificity of cross-reactive IgG antibody responses in mRNA-vaccinated, AstraZeneca-vaccinated, and unvaccinated donors to identify potentially conserved, cross-reactive epitopes to target in order to create a broadly protective SARS-CoV-2 vaccine. Our study provides evidence for cross-reactive IgG antibodies specific to eight different spike (S) variants. Furthermore, the specificities of these cross-variant IgG antibody titers were associated to some extent with spike S1- and S2-subunit-derived epitopes P1 and P2, respectively. In addition, nucleocapsid (N)- and membrane (M)-specific IgG antibody titers correlated with N- and M-derived epitopes conserved across beta-CoVs, P3-7. This study reveals conserved epitopes of viral antigens, targeted by natural and/or vaccine-induced human immunity, for future designs of next-generation COVID-19 vaccines.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Reações Cruzadas , Epitopos , Imunoglobulina G , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Vacinas contra COVID-19/imunologia , Reações Cruzadas/imunologia , Epitopos/imunologia , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Vacinação , Formação de Anticorpos/imunologia , Antígenos Virais/imunologiaRESUMO
NKG2D is an activating receptor expressed by natural killer (NK) cells and other cytotoxic lymphocytes that plays a pivotal role in the elimination of neoplastic cells through recognition of different stress-induced cell surface ligands (NKG2DL). To employ this mechanism for cancer immunotherapy, we generated NKG2D-engaging bispecific antibodies that selectively redirect immune effector cells to cancer cells expressing the tumor-associated antigen ErbB2 (HER2). NKG2D-specific single chain fragment variable (scFv) antibodies cross-reactive toward the human and murine receptors were derived by consecutive immunization of chicken with the human and murine antigens, followed by stringent screening of a yeast surface display immune library. Four distinct species cross-reactive (sc) scFv domains were selected, and reformatted into a bispecific engager format by linking them via an IgG4 Fc domain to a second scFv fragment specific for ErbB2. The resulting molecules (termed scNKAB-ErbB2) were expressed as disulfide-linked homodimers, and demonstrated efficient binding to ErbB2-positive cancer cells as well as NKG2D-expressing primary human and murine lymphocytes, and NK-92 cells engineered with chimeric antigen receptors derived from human and murine NKG2D (termed hNKAR and mNKAR). Two of the scNKAB-ErbB2 molecules were found to compete with the natural NKG2D ligand MICA, while the other two engagers interacted with an epitope outside of the ligand binding site. Nevertheless, all four tested scNKAB-ErbB2 antibodies were similarly effective in redirecting the cytotoxic activity of primary human and murine lymphocytes as well as hNKAR-NK-92 and mNKAR-NK-92 cells to ErbB2-expressing targets, suggesting that further development of these species cross-reactive engager molecules for cancer immunotherapy is warranted.
Assuntos
Anticorpos Biespecíficos , Reações Cruzadas , Células Matadoras Naturais , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptor ErbB-2 , Animais , Humanos , Receptor ErbB-2/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Camundongos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Reações Cruzadas/imunologia , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/genética , Linhagem Celular Tumoral , Neoplasias/imunologia , Neoplasias/terapia , Imunoterapia/métodosRESUMO
Breast milk is a vital source of nutrients, prebiotics, probiotics, and protective factors, including antibodies, immune cells and antimicrobial proteins. Using bacterial lipopolysaccharide arrays, we investigated the reactivity and specificity of breast milk antibodies towards microbial antigens, comparing samples from rural Kenya and urban Switzerland. Results showed considerable variability in antibody reactivity both within and between these locations. Kenyan breast milk demonstrated broad reactivity to bacterial lipopolysaccharides, likely due to increased microbial exposure. Antibodies primarily recognized the O-antigens of lipopolysaccharides and showed strong binding to specific carbohydrate motifs. Notably, antibodies against specific Escherichia coli O-antigens showed cross-reactivity with parasitic pathogens like Leishmania major and Plasmodium falciparum, thus showing that antibodies reacting against lipopolysaccharide O-antigens can recognize a wide range of antigens beyond bacteria. The observed diversity in antigen recognition highlights the significance of breast milk in safeguarding infants from infections, particularly those prevalent in specific geographic regions. The findings also offer insights for potential immunobiotic strategies to augment natural antibody-mediated defense against diverse pathogens.
Assuntos
Lipopolissacarídeos , Leite Humano , Leite Humano/imunologia , Leite Humano/química , Humanos , Quênia , Lipopolissacarídeos/imunologia , Feminino , Reações Cruzadas/imunologia , Suíça , Anticorpos Antibacterianos/imunologia , Antígenos O/imunologia , Adulto , Escherichia coli/imunologiaRESUMO
Influenza neuraminidase (NA) is a promising target for a broadly protective vaccine. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to develop N2 NA vaccine candidates. The unique wild type (WT) N2 sequences of human and swine influenza strains isolated between 1957 and 2019 were used to design the COBRA N2-A NA vaccine, while the unique WT N2 sequences of human influenza strains isolated between 2000 and 2019 were used to design the COBRA N2-B NA vaccine. Sera collected from COBRA N2 NA vaccinated mice showed more broadly reactive antibody responses against a broad panel of H×N2 influenza virus strains than sera collected from mice vaccinated with WT N2 NA vaccines. Antibodies elicited by COBRA or WT N2 NA antigens cross react with recent human H3N2 influenza viruses from different clades, while the antibodies elicited by A/Switzerland/9715293/2013 hemagglutinin (HA) reacted with viruses from the same clade. Furthermore, mice vaccinated with COBRA N2-B NA vaccine had lower viral lung titers compared to mock vaccinated mice when challenged with human H3N2 influenza viruses. Thus, the COBRA N2 NA vaccines elicit broadly protective murine anti-NA antibodies against multiple strains across subtypes and the viral loads were significantly decreased in the lungs of the mice in the COBRA N2 NA vaccine groups, compared to the mice in the mock vaccinated group, indicating that the COBRA-based N2 subtype NA vaccines have a potential to be a component in a universal influenza vaccine.
Assuntos
Anticorpos Antivirais , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza , Neuraminidase , Infecções por Orthomyxoviridae , Animais , Feminino , Humanos , Camundongos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Reações Cruzadas/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Influenza Humana/imunologia , Pulmão/virologia , Pulmão/imunologia , Camundongos Endogâmicos BALB C , Neuraminidase/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/imunologia , Carga Viral , Proteínas Virais/imunologiaRESUMO
Many archetypal and emerging classes of small-molecule therapeutics form covalent protein adducts. In vivo, both the resulting conjugates and their off-target side-conjugates have the potential to elicit antibodies, with implications for allergy and drug sequestration. Although ß-lactam antibiotics are a drug class long associated with these immunological phenomena, the molecular underpinnings of off-target drug-protein conjugation and consequent drug-specific immune responses remain incomplete. Here, using the classical ß-lactam penicillin G (PenG), we probe the B and T cell determinants of drug-specific IgG responses to such conjugates in mice. Deep B cell clonotyping reveals a dominant murine clonal antibody class encompassing phylogenetically-related IGHV1, IGHV5 and IGHV10 subgroup gene segments. Protein NMR and x-ray structural analyses reveal that these drive structurally convergent binding modes in adduct-specific antibody clones. Their common primary recognition mechanisms of the penicillin side-chain moiety (phenylacetamide in PenG)-regardless of CDRH3 length-limits cross-reactivity against other ß-lactam antibiotics. This immunogenetics-guided discovery of the limited binding solutions available to antibodies against side products of an archetypal covalent inhibitor now suggests future potential strategies for the 'germline-guided reverse engineering' of such drugs away from unwanted immune responses.
Assuntos
Antibacterianos , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/imunologia , Imunoglobulina G/imunologia , Penicilina G/imunologia , Penicilina G/química , Linfócitos B/imunologia , Penicilinas/imunologia , Penicilinas/química , Feminino , Reações Cruzadas/imunologia , Cristalografia por Raios XRESUMO
OBJECTIVE: To investigate the effects of repeated vaccination with ancestral SARS-CoV-2 (Wuhan-hu-1)-based inactivated, recombinant protein subunit or vector-based vaccines on the neutralizing antibody response to Omicron subvariants. METHODS: Individuals who received four-dose vaccinations with the Wuhan-hu-1 strain, individuals who were infected with the BA.5 variant alone without prior vaccination, and individuals who experienced a BA.5 breakthrough infection (BTI) following receiving 2-4 doses of the Wuhan-hu-1 vaccine were enrolled. Neutralizing antibodies against D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 were detected using a pseudovirus-based neutralization assay. Antigenic cartography was used to analyze cross-reactivity patterns among D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 and sera from individuals. RESULTS: The highest neutralizing antibody titers against D614G were observed in individuals who only received four-dose vaccination and those who experienced BA.5 BTI, which was also significantly higher than the antibody titers against XBB.1.5, EG.5.1, and BA.2.86. In contrast, only BA.5 infection elicited comparable neutralizing antibody titers against the tested variants. While neutralizing antibody titers against D614G or BA.5 were similar across the cohorts, the neutralizing capacity of antibodies against XBB.1.5, EG.5.1, and BA.2.86 was significantly reduced. BA.5 BTI following heterologous booster induced significantly higher neutralizing antibody titers against the variants, particularly against XBB.1.5 and EG.5.1, than uninfected vaccinated individuals, only BA.5 infected individuals, or those with BA.5 BTI after primary vaccination. CONCLUSIONS: Our findings suggest that repeated vaccination with the Wuhan-hu-1 strain imprinted a neutralizing antibody response toward the Wuhan-hu-1 strain with limited effects on the antibody response to the Omicron subvariants.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/imunologia , COVID-19/prevenção & controle , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Vacinação , Glicoproteína da Espícula de Coronavírus/imunologia , Imunização Secundária , Reações Cruzadas/imunologia , Testes de NeutralizaçãoRESUMO
Apical membrane antigen-1 (AMA1) is a conserved malarial vaccine candidate essential for the formation of tight junctions with the rhoptry neck protein (RON) complex, enabling Plasmodium parasites to invade human erythrocytes, hepatocytes, and mosquito salivary glands. Despite its critical role, extensive surface polymorphisms in AMA1 have led to strain-specific protection, limiting the success of AMA1-based interventions beyond initial clinical trials. Here, we identify an i-body, a humanised single-domain antibody-like molecule that recognises a conserved pan-species conformational epitope in AMA1 with low nanomolar affinity and inhibits the binding of the RON2 ligand to AMA1. Structural characterisation indicates that the WD34 i-body epitope spans the centre of the conserved hydrophobic cleft in AMA1, where interacting residues are highly conserved among all Plasmodium species. Furthermore, we show that WD34 inhibits merozoite invasion of erythrocytes by multiple Plasmodium species and hepatocyte invasion by P. falciparum sporozoites. Despite a short half-life in mouse serum, we demonstrate that WD34 transiently suppressed P. berghei infections in female BALB/c mice. Our work describes the first pan-species AMA1 biologic with inhibitory activity against multiple life-cycle stages of Plasmodium. With improved pharmacokinetic characteristics, WD34 could be a potential immunotherapy against multiple species of Plasmodium.
Assuntos
Antígenos de Protozoários , Eritrócitos , Fígado , Proteínas de Membrana , Camundongos Endogâmicos BALB C , Proteínas de Protozoários , Animais , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/metabolismo , Feminino , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Humanos , Eritrócitos/parasitologia , Eritrócitos/imunologia , Fígado/parasitologia , Fígado/imunologia , Fígado/metabolismo , Vacinas Antimaláricas/imunologia , Malária/imunologia , Malária/parasitologia , Malária/prevenção & controle , Reações Cruzadas/imunologia , Plasmodium falciparum/imunologia , Plasmodium berghei/imunologia , Epitopos/imunologia , Hepatócitos/parasitologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Plasmodium/imunologia , Merozoítos/imunologia , Merozoítos/metabolismoRESUMO
Despite successful vaccination efforts, the emergence of new SARS-CoV-2 variants poses ongoing challenges to control COVID-19. Understanding humoral responses regarding SARS-CoV-2 infections and their impact is crucial for developing future vaccines that are effective worldwide. Here, we identified 41 immunodominant linear B-cell epitopes in its spike glycoprotein with an SPOT synthesis peptide array probed with a pool of serum from hospitalized COVID-19 patients. The bioinformatics showed a restricted set of epitopes unique to SARS-CoV-2 compared to other coronavirus family members. Potential crosstalk was also detected with Dengue virus (DENV), which was confirmed by screening individuals infected with DENV before the COVID-19 pandemic in a commercial ELISA for anti-SARS-CoV-2 antibodies. A high-resolution evaluation of antibody reactivity against peptides representing epitopes in the spike protein identified ten sequences in the NTD, RBD, and S2 domains. Functionally, antibody-dependent enhancement (ADE) in SARS-CoV-2 infections of monocytes was observed in vitro with pre-pandemic Dengue-positive sera. A significant increase in viral load was measured compared to that of the controls, with no detectable neutralization or considerable cell death, suggesting its role in viral entry. Cross-reactivity against peptides from spike proteins was observed for the pre-pandemic sera. This study highlights the importance of identifying specific epitopes generated during the humoral response to a pathogenic infection to understand the potential interplay of previous and future infections on diseases and their impact on vaccinations and immunodiagnostics.
Assuntos
Anticorpos Antivirais , COVID-19 , Reações Cruzadas , Vírus da Dengue , Epitopos de Linfócito B , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Glicoproteína da Espícula de Coronavírus/imunologia , Humanos , Reações Cruzadas/imunologia , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/virologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Epitopos de Linfócito B/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Dengue/virologia , Anticorpos Facilitadores/imunologia , Pandemias , Epitopos Imunodominantes/imunologiaRESUMO
Public health systems reported low mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in East Asia, in low-income countries, and for children during the first year of the SARS-CoV-2 pandemic. These reports led commentators to suggest that cross-reactive immunity from prior exposure to other pathogens reduced fatality risk. Resolution of initial infection waves also contributed to speculation that herd immunity prevented further waves prior to vaccination. Serology instead implied that immunity was too limited to achieve herd immunity and that there was little impact from cross-reactive protection. Paediatric deaths exceeded those from influenza, with higher age-specific fatality risk in lower-income nations and similar fatality risk in East Asia compared with demographically similar regions. Neither pre-outbreak exposure to related pathogens nor immunity induced by initial infection waves are necessarily a reliable response to future pathogen outbreaks. Preparedness for future pathogen outbreaks should instead focus on strategies such as voluntary behavioural changes, nonpharmaceutical interventions, and vaccination.
Assuntos
COVID-19 , Reações Cruzadas , Imunidade Coletiva , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Reações Cruzadas/imunologia , SARS-CoV-2/imunologia , Pandemias , Criança , Índice de Gravidade de Doença , Anticorpos Antivirais/sangue , VacinaçãoRESUMO
PURPOSE OF REVIEW: Cephalosporins are one of the most prescribed antibiotics worldwide and are implicated in a wide range of hypersensitivity reactions (HSR). This review summarizes recent updates in cephalosporin hypersensitivity with a focus on diagnostic testing. RECENT FINDINGS: Reported testing strategies to evaluate different immediate and delayed cephalosporin HSR have included skin testing, in vitro testing, and diagnostic drug challenges. However, the diagnostic performance of in vivo and in vitro tests remains unclear across different hypersensitivity endotypes; adequately powered studies investigating the true positive and negative predictive value of these diagnostic modalities are needed using the reference standard of drug challenges to define cephalosporin hypersensitivity. Refinement of diagnostic testing should be guided by growth in our understanding of cephalosporin antigenic determinants. This growth will be crucial in driving further clarification of cross-reactivity between cephalosporins, and potentially delineating streamlined evaluation processes resulting in reduced unnecessary antibiotic avoidance.
Assuntos
Antibacterianos , Cefalosporinas , Hipersensibilidade a Drogas , Testes Cutâneos , Humanos , Cefalosporinas/efeitos adversos , Cefalosporinas/imunologia , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Antibacterianos/efeitos adversos , Antibacterianos/imunologia , Reações Cruzadas/imunologia , Testes Diagnósticos de RotinaRESUMO
Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.
Assuntos
Anticorpos Antivirais , Autoanticorpos , COVID-19 , Reações Cruzadas , Epitopos , Mimetismo Molecular , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Criança , Humanos , Anticorpos Antivirais/imunologia , Autoanticorpos/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/química , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , COVID-19/imunologia , COVID-19/virologia , COVID-19/complicações , Reações Cruzadas/imunologia , Epitopos/imunologia , Epitopos/química , Mimetismo Molecular/imunologia , Fosfoproteínas/química , Fosfoproteínas/imunologia , SARS-CoV-2/química , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Nexinas de Classificação/química , Nexinas de Classificação/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Linfócitos T/imunologiaRESUMO
PURPOSE OF REVIEW: There is growing evidence that enolase is involved in allergy. This manuscript reviews the impact of enolase in allergic disease and describes several sources of this allergen including molds, plants, animals, and pollens, among others. IgE epitopes are carefully analyzed as they may account for cross-reactivity. RECENT FINDINGS: Enolase has been previously associated to food allergy and contact dermatitis. However, other groups and we have identified recently novel enolases derived from diverse pollens in patients suffering asthma and allergic rhinitis. Exposure to outdoor enolases may cause respiratory disease. Enolase has been identified across various species and its amino acid sequence is highly conserved among different sources of this allergen. The demonstration that enolase is involved in many allergic diseases including respiratory allergies, is of clinic relevance. Thus, the development of novel molecular-based diagnostic and therapeutic strategies may pave the way for improved diagnosis and therapeutics.
Assuntos
Alérgenos , Hipersensibilidade , Fosfopiruvato Hidratase , Humanos , Fosfopiruvato Hidratase/imunologia , Animais , Alérgenos/imunologia , Hipersensibilidade/imunologia , Reações Cruzadas/imunologia , Imunoglobulina E/imunologia , Pólen/imunologiaRESUMO
Vaccines containing tetanus-diphtheria antigens have been postulated to induce cross-reactive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which could protect against coronavirus disease (COVID-19). In this work, we investigated the capacity of Tetanus-diphtheria (Td) vaccine to prime existing T cell immunity to SARS-CoV-2. To that end, we first collected known SARS-CoV-2 specific CD8+ T cell epitopes targeted during the course of SARS-CoV-2 infection in humans and identified as potentially cross-reactive with Td vaccine those sharing similarity with tetanus-diphtheria vaccine antigens, as judged by Levenshtein edit distances (≤ 20% edits per epitope sequence). As a result, we selected 25 potentially cross-reactive SARS-CoV-2 specific CD8+ T cell epitopes with high population coverage that were assembled into a synthetic peptide pool (TDX pool). Using peripheral blood mononuclear cells, we first determined by intracellular IFNγ staining assays existing CD8+ T cell recall responses to the TDX pool and to other peptide pools, including overlapping peptide pools covering SARS-CoV-2 Spike protein and Nucleocapsid phosphoprotein (NP). In the studied subjects, CD8+ T cell recall responses to Spike and TDX peptide pools were dominant and comparable, while recall responses to NP peptide pool were less frequent and weaker. Subsequently, we studied responses to the same peptides using antigen-inexperienced naive T cells primed/stimulated in vitro with Td vaccine. Priming stimulations were carried out by co-culturing naive T cells with autologous irradiated peripheral mononuclear cells in the presence of Td vaccine, IL-2, IL-7 and IL-15. Interestingly, naive CD8+ T cells stimulated/primed with Td vaccine responded strongly and specifically to the TDX pool, not to other SARS-CoV-2 peptide pools. Finally, we show that Td-immunization of C57BL/6J mice elicited T cells cross-reactive with the TDX pool. Collectively, our findings support that tetanus-diphtheria vaccines can prime SARS-CoV-2 cross-reactive T cells and likely contribute to shape the T cell responses to the virus.
Assuntos
Linfócitos T CD8-Positivos , COVID-19 , Reações Cruzadas , Epitopos de Linfócito T , SARS-CoV-2 , Humanos , Reações Cruzadas/imunologia , SARS-CoV-2/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Toxoide Tetânico/imunologia , Animais , Camundongos , Feminino , Vacinas contra COVID-19/imunologia , Masculino , Adulto , Glicoproteína da Espícula de Coronavírus/imunologia , Pessoa de Meia-IdadeRESUMO
Introduction: Fibroblast activation protein (FAP) overexpression on cancer-associated fibroblasts (CAFs) is associated with poor prognosis and worse clinical outcomes. Selective ablation of pro-tumorgenic FAP+ stromal cells with CAR-T cells may be a new therapeutic strategy. However, the clinical use of FAP-CAR T cells is suggested to proceed with caution for occasional poor efficacy and induction of on-target off-tumor toxicity (OTOT), including lethal osteotoxicity and cachexia. Hence, more investigations and preclinical trials are required to optimize the FAP-CAR T cells and to approve their safety and efficacy. Methods: In this study, we designed second-generation CAR T cells targeting FAP with 4-1BB as a co-stimulatory molecule, and tested their cytotoxicity against FAP-positive cells (hFAP-HT1080 cells and a variety of primary CAFs) in vitro and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model. Results: Results showed that our FAP-CAR T cells were powerfully potent in killing human and murine FAP-positive tumor cells and CAFs in multiple types of tumors in BALB/c and C57BL/6 mice and in patient-derived xenografts (PDX) model. And they were proved to be biologically safe and exhibit low-level OTOT. Discussion: Taken together, the human/murine cross-reactive FAP-CAR T cells were powerfully potent in killing human and murine FAP positive tumor cells and CAFs. They were biologically safe and exhibit low-level OTOT, warranting further clinical investigation into our FAP-CAR T cells.