RESUMO
Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has developed substantial antigenic variability. As the majority of the population now has pre-existing immunity due to infection or vaccination, the use of experimentally generated animal immune sera can be valuable for measuring antigenic differences between virus variants. Here, we immunized Syrian hamsters by two successive infections with one of nine SARS-CoV-2 variants. Their sera were titrated against 16 SARS-CoV-2 variants, and the resulting titers were visualized using antigenic cartography. The antigenic map shows a condensed cluster containing all pre-Omicron variants (D614G, Alpha, Delta, Beta, Mu, and an engineered B.1+E484K variant) and considerably more diversity among a selected panel of Omicron subvariants (BA.1, BA.2, BA.4/BA.5, the BA.5 descendants BF.7 and BQ.1.18, the BA.2.75 descendant BN.1.3.1, the BA.2-derived recombinants XBB.2 and EG.5.1, and the BA.2.86 descendant JN.1). Some Omicron subvariants were as antigenically distinct from each other as the wildtype is from the Omicron BA.1 variant. Compared to titers measured in human sera, titers in hamster sera are of higher magnitude, show less fold change, and result in a more compact antigenic map topology. The results highlight the potential of sera from hamsters for the continued antigenic characterization of SARS-CoV-2.
Assuntos
Variação Antigênica , COVID-19 , Mesocricetus , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , SARS-CoV-2/imunologia , SARS-CoV-2/genética , COVID-19/imunologia , COVID-19/virologia , Cricetinae , Variação Antigênica/imunologia , Variação Antigênica/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Antígenos Virais/imunologia , Antígenos Virais/genética , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Humanos , Soros Imunes/imunologiaRESUMO
Many pathogens evolve to escape immunity, yet it remains difficult to predict whether immune pressure will lead to diversification, serial replacement of one variant by another, or more complex patterns. Pathogen strain dynamics are mediated by cross-protective immunity, whereby exposure to one strain partially protects against infection by antigenically diverged strains. There is growing evidence that this protection is influenced by early exposures, a phenomenon referred to as original antigenic sin (OAS) or imprinting. In this paper, we derive constraints on the emergence of the pattern of successive strain replacements demonstrated by influenza, SARS-CoV-2, seasonal coronaviruses, and other pathogens. We find that OAS implies that the limited diversity found with successive strain replacement can only be maintained if [Formula: see text] is less than a threshold set by the characteristic antigenic distances for cross-protection and for the creation of new immune memory. This bound implies a "speed limit" on the evolution of new strains and a minimum variance of the distribution of infecting strains in antigenic space at any time. To carry out this analysis, we develop a theoretical model of pathogen evolution in antigenic space that implements OAS by decoupling the antigenic distances required for protection from infection and strain-specific memory creation. Our results demonstrate that OAS can play an integral role in the emergence of strain structure from host immune dynamics, preventing highly transmissible pathogens from maintaining serial strain replacement without diversification.
Assuntos
Antígenos Virais , SARS-CoV-2 , Humanos , Antígenos Virais/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/genética , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Variação Antigênica/imunologia , Proteção Cruzada/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Memória Imunológica/imunologiaRESUMO
Hematogenous dissemination is a critical step in the evolution of local infection to systemic disease. The Lyme disease (LD) spirochete, which efficiently disseminates to multiple tissues, has provided a model for this process, in particular for the key early event of pathogen adhesion to the host vasculature. This occurs under shear force mediated by interactions between bacterial adhesins and mammalian cell-surface proteins or extracellular matrix (ECM). Using real-time intravital imaging of the Lyme spirochete in living mice, we previously identified BBK32 as the first LD spirochetal adhesin demonstrated to mediate early vascular adhesion in a living mouse; however, deletion of bbk32 resulted in loss of only about half of the early interactions, suggesting the existence of at least one other adhesin (adhesin-X) that promotes early vascular interactions. VlsE, a surface lipoprotein, was identified long ago by its capacity to undergo rapid antigenic variation, is upregulated in the mammalian host and required for persistent infection in immunocompetent mice. In immunodeficient mice, VlsE shares functional overlap with OspC, a multi-functional protein that displays dermatan sulfate-binding activity and is required for joint invasion and colonization. In this research, using biochemical and genetic approaches as well as intravital imaging, we have identified VlsE as adhesin-X; it is a dermatan sulfate (DS) adhesin that efficiently promotes transient adhesion to the microvasculature under shear force via its DS binding pocket. Intravenous inoculation of mice with a low-passage infectious B. burgdorferi strain lacking both bbk32 and vlsE almost completely eliminated transient microvascular interactions. Comparative analysis of binding parameters of VlsE, BBK32 and OspC provides a possible explanation why these three DS adhesins display different functionality in terms of their ability to promote early microvascular interactions.
Assuntos
Adesinas Bacterianas , Variação Antigênica , Antígenos de Bactérias , Proteínas de Bactérias , Borrelia burgdorferi , Lipoproteínas , Doença de Lyme , Microvasos , Adesinas Bacterianas/genética , Adesinas Bacterianas/imunologia , Animais , Variação Antigênica/genética , Variação Antigênica/imunologia , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Aderência Bacteriana/genética , Aderência Bacteriana/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Borrelia burgdorferi/genética , Borrelia burgdorferi/imunologia , Dermatan Sulfato/imunologia , Lipoproteínas/genética , Lipoproteínas/imunologia , Doença de Lyme/genética , Doença de Lyme/imunologia , Doença de Lyme/microbiologia , Mamíferos , Camundongos , Microvasos/imunologia , Microvasos/microbiologia , Resistência ao CisalhamentoRESUMO
BACKGROUND & AIMS: Development of a prophylactic hepatitis C virus (HCV) vaccine will require accurate and reproducible measurement of neutralizing breadth of vaccine-induced antibodies. Currently available HCV panels may not adequately represent the genetic and antigenic diversity of circulating HCV strains, and the lack of standardization of these panels makes it difficult to compare neutralization results obtained in different studies. Here, we describe the selection and validation of a genetically and antigenically diverse reference panel of 15 HCV pseudoparticles (HCVpps) for neutralization assays. METHODS: We chose 75 envelope (E1E2) clones to maximize representation of natural polymorphisms observed in circulating HCV isolates, and 65 of these clones generated functional HCVpps. Neutralization sensitivity of these HCVpps varied widely. HCVpps clustered into 15 distinct groups based on patterns of relative sensitivity to 7 broadly neutralizing monoclonal antibodies. We used these data to select a final panel of 15 antigenically representative HCVpps. RESULTS: Both the 65 and 15 HCVpp panels span 4 tiers of neutralization sensitivity, and neutralizing breadth measurements for 7 broadly neutralizing monoclonal antibodies were nearly equivalent using either panel. Differences in neutralization sensitivity between HCVpps were independent of genetic distances between E1E2 clones. CONCLUSIONS: Neutralizing breadth of HCV antibodies should be defined using viruses spanning multiple tiers of neutralization sensitivity rather than panels selected solely for genetic diversity. We propose that this multitier reference panel could be adopted as a standard for the measurement of neutralizing antibody potency and breadth, facilitating meaningful comparisons of neutralization results from vaccine studies in different laboratories.
Assuntos
Variação Antigênica/imunologia , Antígenos Virais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Hepacivirus/imunologia , Testes de Neutralização/métodos , Proteínas do Envelope Viral/imunologia , Variação Antigênica/genética , Antígenos Virais/genética , Linhagem Celular Tumoral , Hepacivirus/genética , Hepatite C/prevenção & controle , Humanos , Imunogenicidade da Vacina , Reprodutibilidade dos Testes , Desenvolvimento de Vacinas , Proteínas do Envelope Viral/genética , Vacinas contra Hepatite Viral/imunologiaRESUMO
Similar to several other countries in the world, the epidemiology of hepatitis A virus changed from high to intermediate endemicity level in Tunisia, which led to the occurrence of outbreaks. This study aimed to determine the genetic and antigenic variability of HAV strains circulating in Tunisia during the last few years. Genotyping using complete VP1 gene and VP1-2A junction confirmed the predominance of genotype IA, with co-circulation of several genetic and antigenic variants. Phylogenetic analysis including Tunisian and strains from other regions of the world showed the presence of at least two IA-variants within IA subgenotype. Amino-acid analysis showed several mutations in or close to epitope regions in the VP1-region. This study provides a baseline on the genetic and antigenic variability of HAV circulating strains before the introduction of vaccination into the national immunization schedule.
Assuntos
Variação Antigênica/genética , Variação Genética , Vírus da Hepatite A/classificação , Vírus da Hepatite A/genética , Hepatite A/epidemiologia , Substituição de Aminoácidos , Variação Antigênica/imunologia , Análise por Conglomerados , DNA Viral/genética , Surtos de Doenças , Genótipo , Hepatite A/prevenção & controle , Hepatite A/virologia , Vacinas contra Hepatite A/administração & dosagem , Humanos , Filogenia , Saúde Pública , RNA Viral/genética , Estudos Retrospectivos , Análise de Sequência de DNA , Tunísia/epidemiologia , Proteínas Virais/genéticaRESUMO
Avian influenza virus (AIV) H7N9 that emerged in 2013 in eastern China is a novel zoonotic agent mainly circulating in poultry without clinical signs but causing severe disease with high fatality in humans in more than 5 waves. Since the emergence of highly pathogenic (HP) H7N9 variants in 2016, it has induced heavy losses in the poultry industry leading to the implementation of an intensive nationwide vaccination program at the end of wave 5 (September 2017). To characterize the ongoing evolution of H7N9 AIV, we conducted analyses of H7N9 glycoprotein genes obtained from 2013 to 2019. Bayesian analyses revealed a decreasing population size of HP H7N9 variants post wave 5. Phylogenetic topologies revealed that two novel small subclades were formed and carried several fixed amino acid mutations that were along HA and NA phylogenetic trees since wave 5. Some of the mutations were located at antigenic sites or receptor binding sites. The antigenic analysis may reveal a significant antigenic drift evaluated by hemagglutinin inhibition (HI) assay and the antigenicity of H7N9 AIV might evolute in large leaps in wave 7. Molecular simulations found that the mutations (V135T, S145P, and L226Q) around the HA receptor pocket increased the affinity to α2,3-linked sialic acid (SIA) while decreased to α2,6-linked SIA. Altered affinity may suggest that HP H7N9 variations aggravate the pathogenicity to poultry but lessen the threat to public health. Selection analyses showed that the HP H7N9 AIV experienced an increasing selection pressure since wave 5, and the national implementation of vaccination might intensify the role of natural selection during the evolution waves 6 and 7. In summary, our data provide important insights about the genetic and antigenic diversity of circulating HP H7N9 viruses from 2017 to 2019. Enhanced surveillance is urgently warranted to understand the current situation of HP H7N9 AIV.
Assuntos
Variação Antigênica/imunologia , Aves , Variação Genética , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Aviária/virologia , Animais , China , Subtipo H7N9 do Vírus da Influenza A/imunologia , FilogeniaAssuntos
Vacinas contra COVID-19/imunologia , COVID-19/complicações , Mieloma Múltiplo/complicações , SARS-CoV-2/imunologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Variação Antigênica/genética , Variação Antigênica/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , COVID-19/prevenção & controle , Epitopos/genética , Epitopos/imunologia , Humanos , Imunidade Celular , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mutação , SARS-CoV-2/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The antigenicity of the hemagglutinin esterase (HE) glycoprotein of influenza C virus is known to be stable; however, information about residues related to antigenic changes has not yet been fully acquired. Using selection with anti-HE monoclonal antibodies, we previously obtained some escape mutants and identified four antigenic sites, namely, A-1, A-2, A-3, and Y-1. To confirm whether the residues identified as the neutralizing epitope possibly relate to the antigenic drift, we analyzed the growth kinetics of these mutants. The results showed that some viruses with mutations in antigenic site A-1 were able to replicate to titers comparable to that of the wild-type, while others showed reduced titers. The mutants possessing substitutions in the A-2 or A-3 site replicated as efficiently as the wild-type virus. Although the mutant containing a deletion at positions 192 to 195 in the Y-1 site showed lower titers than the wild-type virus, it was confirmed that this region in the 190-loop on the top side of the HE protein is not essential for viral propagation. Then, we revealed that antigenic changes due to substitutions in the A-1, A-3, and/or Y-1 site had occurred in nature in Japan for the past 30 years. These results suggest that some residues (i.e., 125, 176, 192) in the A-1 site, residue 198 in the A-3 site, and residue 190 in the Y-1 site are likely to mediate antigenic drift while maintaining replicative ability.
Assuntos
Variação Antigênica/imunologia , Antígenos Virais , Gammainfluenzavirus , Animais , Antígenos Virais/genética , Antígenos Virais/imunologia , Cães , Gammainfluenzavirus/genética , Gammainfluenzavirus/imunologia , Células Madin Darby de Rim CaninoRESUMO
The antigenic diversity of influenza A viruses (IAV) circulating in swine challenges the development of effective vaccines, increasing zoonotic threat and pandemic potential. High-throughput sequencing technologies can quantify IAV genetic diversity, but there are no accurate approaches to adequately describe antigenic phenotypes. This study evaluated an ensemble of nonlinear regression models to estimate virus phenotype from genotype. Regression models were trained with a phenotypic data set of pairwise hemagglutination inhibition (HI) assays, using genetic sequence identity and pairwise amino acid mutations as predictor features. The model identified amino acid identity, ranked the relative importance of mutations in the hemagglutinin (HA) protein, and demonstrated good prediction accuracy. Four previously untested IAV strains were selected to experimentally validate model predictions by HI assays. Errors between predicted and measured distances of uncharacterized strains were 0.35, 0.61, 1.69, and 0.13 antigenic units. These empirically trained regression models can be used to estimate antigenic distances between different strains of IAV in swine by using sequence data. By ranking the importance of mutations in the HA, we provide criteria for identifying antigenically advanced IAV strains that may not be controlled by existing vaccines and can inform strain updates to vaccines to better control this pathogen.IMPORTANCE Influenza A viruses (IAV) in swine constitute a major economic burden to an important global agricultural sector, impact food security, and are a public health threat. Despite significant improvement in surveillance for IAV in swine over the past 10 years, sequence data have not been integrated into a systematic vaccine strain selection process for predicting antigenic phenotype and identifying determinants of antigenic drift. To overcome this, we developed nonlinear regression models that predict antigenic phenotype from genetic sequence data by training the model on hemagglutination inhibition assay results. We used these models to predict antigenic phenotype for previously uncharacterized IAV, ranked the importance of genetic features for antigenic phenotype, and experimentally validated our predictions. Our model predicted virus antigenic characteristics from genetic sequence data and provides a rapid and accurate method linking genetic sequence data to antigenic characteristics. This approach also provides support for public health by identifying viruses that are antigenically advanced from strains used as pandemic preparedness candidate vaccine viruses.
Assuntos
Variação Antigênica/genética , Genótipo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/genética , Aprendizado de Máquina , Infecções por Orthomyxoviridae/veterinária , Infecções por Orthomyxoviridae/virologia , Fenótipo , Substituição de Aminoácidos , Animais , Variação Antigênica/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/classificação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H3N2/classificação , Vírus da Influenza A Subtipo H3N2/imunologia , Infecções por Orthomyxoviridae/imunologia , Análise de Regressão , Suínos , Doenças dos Suínos/virologiaRESUMO
Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly 100 yr. Recent studies revealed that trypanosome strains that express the variant surface glycoprotein (VSG) VSGsur possess heightened resistance to suramin. Here, we show that VSGsur binds tightly to suramin but other VSGs do not. By solving high-resolution crystal structures of VSGsur and VSG13, we also demonstrate that these VSGs define a structurally divergent subgroup of the coat proteins. The co-crystal structure of VSGsur with suramin reveals that the chemically symmetric drug binds within a large cavity in the VSG homodimer asymmetrically, primarily through contacts of its central benzene rings. Structure-based, loss-of-contact mutations in VSGsur significantly decrease the affinity to suramin and lead to a loss of the resistance phenotype. Altogether, these data show that the resistance phenotype is dependent on the binding of suramin to VSGsur, establishing that the VSG proteins can possess functionality beyond their role in antigenic variation.
Assuntos
Resistência a Medicamentos/imunologia , Suramina/metabolismo , Trypanosoma brucei rhodesiense/imunologia , Glicoproteínas Variantes de Superfície de Trypanosoma/química , Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo , Variação Antigênica/efeitos dos fármacos , Variação Antigênica/imunologia , Sítios de Ligação , Cristalografia por Raios X , Resistência a Medicamentos/genética , Endocitose/genética , Evasão da Resposta Imune , Mutação , Ligação Proteica , Conformação Proteica , Suramina/toxicidade , Tripanossomicidas/metabolismo , Tripanossomicidas/toxicidade , Trypanosoma brucei rhodesiense/química , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/metabolismo , Tripanossomíase Africana/parasitologia , Glicoproteínas Variantes de Superfície de Trypanosoma/genéticaRESUMO
HIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128-135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01+ individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.
Assuntos
Variação Antigênica/imunologia , Infecções por HIV , HIV-1 , Evasão da Resposta Imune/genética , Linfócitos T Citotóxicos/imunologia , Células Cultivadas , Evolução Clonal/imunologia , Epitopos de Linfócito T/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , Soropositividade para HIV , HIV-1/classificação , HIV-1/genética , HIV-1/imunologia , Células HeLa , Adaptação ao Hospedeiro/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Tipagem Molecular , Mutação , Linfócitos T Citotóxicos/metabolismo , Carga Viral/imunologia , Replicação Viral/genética , Replicação Viral/imunologiaRESUMO
A zoonotic A/sw/H1avN1 1C.2.2 influenza virus infection was detected in a German child that presented with influenza-like illness, including high fever. There was a history of close contact with pigs 3 days before symptom onset. The child recovered within 3 days. No other transmissions were observed. Serological investigations of the virus isolate revealed cross-reactions with ferret antisera against influenza A(H1N1)pdm09 virus, indicating a closer antigenic relationship with A(H1N1)pdm09 than with the former seasonal H1N1 viruses.
Assuntos
Variação Antigênica/genética , Furões/virologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/diagnóstico , Infecções por Orthomyxoviridae/diagnóstico , Doenças dos Suínos/transmissão , Zoonoses/virologia , Animais , Anticorpos Antivirais/sangue , Variação Antigênica/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/transmissão , Influenza Humana/virologia , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/veterinária , Infecções por Orthomyxoviridae/virologia , Reação em Cadeia da Polimerase , Análise de Sequência , Suínos , Doenças dos Suínos/virologia , Zoonoses/transmissãoRESUMO
Understanding the dynamics of the selection of influenza A immune escape variants by serum antibody is critical for designing effective vaccination programs for animals, especially poultry where large populations have a short generation time and may be vaccinated with high frequency. In this report, immune-escape mutants of A/turkey/New York/4450/1994 H7N2 low pathogenic avian influenza virus, were selected by serially passaging the virus in the presence of continuously increasing concentrations of homologous chicken polyclonal sera. Amino acid mutations were identified by sequencing the parental hemagglutinin (HA) gene and every 10 passages by both Sanger and deep sequencing, and the antigenic distance of the mutants to the parent strain was determined. Progressively, a total of five amino acid mutations were observed over the course of 30 passages. Based on their absence from the parental virus with deep sequencing, the mutations appear to have developed de novo. The antigenic distance between the selected mutants and the parent strain increased as the number of amino acid mutations accumulated and the concentration of antibodies had to be periodically increased to maintain the same reduction in virus titer during selection. This selection system demonstrates how H7 avian influenza viruses behave under selection with homologous sera, and provides a glimpse of their evolutionary dynamics, which can be applied to developing vaccination programs that maximize the effectiveness of a vaccine over time.
Assuntos
Variação Antigênica/genética , Evasão da Resposta Imune , Soros Imunes , Vírus da Influenza A Subtipo H7N2/genética , Vírus da Influenza A Subtipo H7N2/imunologia , Influenza Aviária/virologia , Mutação , Aves Domésticas/virologia , Aminoácidos/genética , Animais , Anticorpos Antivirais/sangue , Variação Antigênica/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H7N2/patogenicidade , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Aves Domésticas/imunologia , Organismos Livres de Patógenos Específicos , VacinaçãoRESUMO
Borrelia burgdorferi, the Lyme disease pathogen causes persistent infection by evading the host immune response. Differential expression of the surface-exposed lipoprotein VlsE that undergoes antigenic variation is a key immune evasion strategy employed by B. burgdorferi. Most studies focused on the mechanism of VlsE antigen variation, but little is known about VlsE regulation and factor(s) that regulates differential vlsE expression. In this study, we investigated BB0025, a putative YebC family transcriptional regulator (and hence designated BB0025 as YebC of B. burgdorferi herein). We constructed yebC mutant and complemented strain in an infectious strain of B. burgdorferi. The yebC mutant could infect immunocompromised SCID mice but not immunocompetent mice, suggesting that YebC plays an important role in evading host adaptive immunity. RNA-seq analyses identified vlsE as one of the genes whose expression was most affected by YebC. Quantitative RT-PCR and Western blot analyses confirmed that vlsE expression was dependent on YebC. In vitro, YebC and VlsE were co-regulated in response to growth temperature. In mice, both yebC and vlsE were inversely expressed with ospC in response to the host adaptive immune response. Furthermore, EMSA proved that YebC directly binds to the vlsE promoter, suggesting a direct transcriptional control. These data demonstrate that YebC is a new regulator that modulates expression of vlsE and other genes important for spirochetal infection and immune evasion in the mammalian host.
Assuntos
Variação Antigênica/imunologia , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Borrelia burgdorferi/imunologia , Evasão da Resposta Imune/imunologia , Lipoproteínas/metabolismo , Doença de Lyme/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Lipoproteínas/genética , Lipoproteínas/imunologia , Doença de Lyme/metabolismo , Doença de Lyme/microbiologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos SCID , Mutação , Conformação Proteica , Homologia de SequênciaRESUMO
Protective vaccines for hypervariable pathogens are urgently needed. It has been proposed that amputating highly variable epitopes from vaccine antigens would induce the production of broadly protective antibodies targeting conserved epitopes. However, so far, these approaches have failed, partially because conserved epitopes are occluded in vivo and partially because co-localizing patterns of immunodominance and antigenic variability render variable epitopes the primary target for antibodies in natural infection. In this Perspective, to recast the challenge of vaccine development for hypervariable pathogens, I evaluate convergent mechanisms of adaptive variation, such as intrahost immune-mediated diversification, spatiotemporally defined antigenic space, and infection-enhancing cross-immunoreactivity. The requirements of broadly protective immune responses targeting variable pathogens are formulated in terms of cross-immunoreactivity, stoichiometric thresholds for neutralization, and the elicitation of antibodies targeting physicochemically conserved signatures within sequence variable domains.
Assuntos
Variação Antigênica/imunologia , Epitopos Imunodominantes/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/imunologia , Viroses/imunologia , Animais , Anticorpos Neutralizantes , Variação Antigênica/genética , Humanos , Epitopos Imunodominantes/genética , Mutação/genética , Vacinação , Proteínas do Envelope Viral/genéticaRESUMO
The ubiquitously expressed, monomorphic MHC class Ib molecule MHC class I-related protein 1 (MR1) presents microbial metabolites to mucosal-associated invariant T (MAIT) cells. However, recent work demonstrates that both the ligands bound by MR1 and the T cells restricted by it are more diverse than originally thought. It is becoming increasingly clear that MR1 is capable of presenting a remarkable variety of both microbial and non-microbial small molecule antigens to a diverse group of MR1-restricted T cells (MR1Ts) and that the antigen presentation pathway differs between exogenously delivered antigen and intracellular microbial infection. These distinct antigen presentation pathways suggest that MR1 shares features of both MHC class I and MHC class II antigen presentation, enabling it to sample diverse intracellular compartments and capture antigen of both intracellular and extracellular origin. Here, we review recent developments and new insights into the cellular mechanisms of MR1-dependent antigen presentation with a focus on microbial MR1T cell antigens.
Assuntos
Apresentação de Antígeno/imunologia , Variação Antigênica/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Proteínas de Transporte/metabolismo , Metabolismo Energético , Humanos , Espaço Intracelular/imunologia , Espaço Intracelular/metabolismo , Ligantes , Ligação ProteicaRESUMO
Influenza A subtypes are categorized into group 1 and group 2 based on the hemagglutinin (HA) sequence. Owing to the phylogenetic distance of HAs in different groups, antibodies that bind multiple HA subtypes across different groups are extremely rare. In this study, we demonstrated that an immunization with acid-treated HA antigen elicits germinal center (GC) B cells that bind multiple HA subtypes in both group 1 and group 2. The cross-group GC B cells utilized mostly one VH gene (1S56) and exhibited a sign of clonal evolution within GCs. The 1S56-lineage IgGs derived from GC B cells were able to bind to HA protein on the infected cell surface but not to the native form of HA protein, suggesting the cryptic nature of the 1S56 epitope and its exposure in infected cells. Finally, the 1S56-lineage IgGs provided protection against lethal infection in an Fc-dependent manner, independent of the virus-neutralizing activity. Thus, we identified 1S56-lineage antibodies as a unique stereotype for achieving cross-group influenza specificity. The antigens exposing the 1S56 epitope may be good candidates for broadly protective immunogens.
Assuntos
Linfócitos B/imunologia , Vacinas contra Influenza/imunologia , Animais , Variação Antigênica/genética , Variação Antigênica/imunologia , Galinhas , Vacinas contra Influenza/genética , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos B/imunologiaRESUMO
Seasonal influenza vaccines prevent influenza-related illnesses, hospitalizations, and deaths. However, these vaccines are not as effective as other viral vaccines, and there is clearly room for improvement. Here, we review the history of seasonal influenza vaccines, describe challenges associated with producing influenza vaccine antigens, and discuss the inherent difficulties of updating influenza vaccine strains each influenza season. We argue that seasonal influenza vaccines can be dramatically improved by modernizing antigen production processes and developing models that are better at predicting viral evolution. Resources should be specifically dedicated to improving seasonal influenza vaccines while developing entirely new vaccine platforms.
Assuntos
Variação Antigênica/imunologia , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/normas , Influenza Humana/prevenção & controle , Orthomyxoviridae/imunologia , Variação Antigênica/genética , Evolução Molecular , História do Século XX , Humanos , Imunogenicidade da Vacina , Vacinas contra Influenza/história , Influenza Humana/imunologia , Influenza Humana/virologia , Orthomyxoviridae/classificação , Orthomyxoviridae/genéticaRESUMO
The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.
Assuntos
Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Proteínas com Domínio T/imunologia , Animais , Variação Antigênica/imunologia , Sobrevivência Celular/imunologia , Células Cultivadas , Seleção Clonal Mediada por Antígeno/genética , Seleção Clonal Mediada por Antígeno/imunologia , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária , Camundongos , Células Precursoras de Linfócitos T/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Proteínas com Domínio T/genéticaRESUMO
In the endemic settings of India, high CFR (3.6-7.02%) was observed in the consecutive 2009, 2015 and 2017 A/H1N1pdm09 outbreaks, though in eastern India CFR varied between 0 and 5.5% during same period. Recurrent outbreaks of pandemic Influenza A/H1N1pdm09, fragmented nationwide incidence data, lack of national policy for Influenza vaccination in India underscores the necessity for generating regional level data. Thus, during 2017-19, 4106 referred samples from patients hospitalized with severe acute respiratory illness (SARI) in eastern India were tested for A/H1N1pdm09 infection. Among which 16.5% (n = 677/4106) were found A/H1N1pdm09 positive. Individuals <20 years and middle-aged persons (40-60 years) were most susceptible to A/H1N1pdm09 infection. The vaccine strain (A/human/California/07/2009) which was globally used before 2017, clustered in a different lineage away from the representative eastern Indian strains in the phylogenetic dendrogram. The vaccine strain (A/human/Michigan/45/2015) used in India during the study period and the WHO recommended strain (A/human/Brisbane/02/2018) for 2019-20 flu season for the northern hemisphere, clustered with the circulating isolates in the same lineage-6b. Dissimilarities in the amino acids encompassing the antigenic epitopes were seen to be highest with the vaccine strain- A/human/California/07/2009. The significant amino acid variations in the circulating strains with the current WHO recommended vaccine strain, implies the exigency of continuous pandemic A/H1N1pdm09 surveillance studies in this epidemiological setting. The absence of any Oseltamivir resistant mutation (H275Y) in the neuraminidase gene of the current isolates suggests continuing use of Tamiflu® as an antiviral therapy in suspected subjects in this region.