RESUMO
While searching for new therapeutics against malaria, Lanzavecchia and colleagues discovered that antibodies can be diversified by DNA sequences encoded outside of antibody genes.
Assuntos
Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Variação Antigênica/imunologia , Antígenos de Protozoários/imunologia , Malária/imunologia , Mutagênese Insercional/genética , Plasmodium falciparum/imunologia , Receptores Imunológicos/imunologia , HumanosRESUMO
Natural killer (NK) cells are lymphocytes that contribute to the early immune responses to viruses. NK cells are innate immune cells that do not express rearranged antigen receptors but sense their environment via receptors for pro-inflammatory cytokines, as well as via germline-encoded activating receptors specific for danger or pathogen signals. A group of such activating receptors is stochastically expressed by certain subsets within the NK cell compartment. After engagement of the cognate viral ligand, these receptors contribute to the specific activation and 'preferential' population expansion of defined NK cell subsets, which partially recapitulate some features of adaptive lymphocytes. In this Review, we discuss the numerous modes for the specific recognition of viral antigens and peptides by NK cells and the implications of this for the composition of the NK cell repertoire as well as for the the selection of viral variants.
Assuntos
Antígenos Virais/imunologia , Células Matadoras Naturais/imunologia , Peptídeos/imunologia , Receptores de Células Matadoras Naturais/imunologia , Viroses/imunologia , Animais , Variação Antigênica , Humanos , Imunidade Inata , LigantesRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge during the global pandemic and may facilitate escape from current antibody therapies and vaccine protection. Here we showed that the South African variant B.1.351 was the most resistant to current monoclonal antibodies and convalescent plasma from coronavirus disease 2019 (COVID-19)-infected individuals, followed by the Brazilian variant P.1 and the United Kingdom variant B.1.1.7. This resistance hierarchy corresponded with Y144del and 242-244del mutations in the N-terminal domain and K417N/T, E484K, and N501Y mutations in the receptor-binding domain (RBD) of SARS-CoV-2. Crystal structure analysis of the B.1.351 triple mutant (417N-484K-501Y) RBD complexed with the monoclonal antibody P2C-1F11 revealed the molecular basis for antibody neutralization and escape. B.1.351 and P.1 also acquired the ability to use mouse and mink ACE2 receptors for entry. Our results demonstrate major antigenic shifts and potential broadening of the host range for B.1.351 and P.1 variants, which poses serious challenges to current antibody therapies and vaccine protection.
Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Neutralizantes/imunologia , Evasão da Resposta Imune , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Variação Antigênica/genética , COVID-19/imunologia , COVID-19/virologia , Especificidade de Hospedeiro , Humanos , Evasão da Resposta Imune/genética , Camundongos , Vison , Mutação , Ligação Proteica , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do VírusRESUMO
Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Reações Cruzadas , Proteína gp120 do Envelope de HIV/imunologia , Animais , Variação Antigênica , Linfócitos B/imunologia , Simulação por Computador , Proteína gp120 do Envelope de HIV/genética , HIV-1/imunologia , CamundongosRESUMO
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
The search for a vaccine against human immunodeficiency virus type 1 (HIV-1) has many hurdles to overcome. Ideally, the stimulation of both broadly neutralizing antibodies and cell-mediated immune responses remains the best option, but no candidate in clinical trials at present has elicited such antibodies, and efficacy trials have not demonstrated any benefit for vaccines designed to stimulate immune responses of CD8(+) T cells. Findings obtained with the simian immunodeficiency virus (SIV) monkey model have provided new evidence that stimulating effective CD8(+) T cell immunity could provide protection, and in this Perspective we explore the path forward for optimizing such responses in humans.
Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Variação Antigênica/imunologia , Antígenos Virais/genética , Antígenos Virais/metabolismo , Ensaios Clínicos como Assunto , Citotoxicidade Imunológica , Haplorrinos , Humanos , Imunização , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/metabolismo , Engenharia de Proteínas , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Resultado do TratamentoRESUMO
Antigenic variation is the main immune escape mechanism for RNA viruses like influenza or SARS-CoV-2. While high mutation rates promote antigenic escape, they also induce large mutational loads and reduced fitness. It remains unclear how this cost-benefit trade-off selects the mutation rate of viruses. Using a traveling wave model for the coevolution of viruses and host immune systems in a finite population, we investigate how immunity affects the evolution of the mutation rate and other nonantigenic traits, such as virulence. We first show that the nature of the wave depends on how cross-reactive immune systems are, reconciling previous approaches. The immune-virus system behaves like a Fisher wave at low cross-reactivities, and like a fitness wave at high cross-reactivities. These regimes predict different outcomes for the evolution of nonantigenic traits. At low cross-reactivities, the evolutionarily stable strategy is to maximize the speed of the wave, implying a higher mutation rate and increased virulence. At large cross-reactivities, where our estimates place H3N2 influenza, the stable strategy is to increase the basic reproductive number, keeping the mutation rate to a minimum and virulence low.
Assuntos
Influenza Humana , Vírus de RNA , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Variação Antigênica/genética , Vírus de RNA/genética , Glicoproteínas de Hemaglutininação de Vírus da InfluenzaRESUMO
RNA-DNA hybrids are epigenetic features of all genomes that intersect with many processes, including transcription, telomere homeostasis, and centromere function. Increasing evidence suggests that RNA-DNA hybrids can provide two conflicting roles in the maintenance and transmission of genomes: They can be the triggers of DNA damage, leading to genome change, or can aid the DNA repair processes needed to respond to DNA lesions. Evasion of host immunity by African trypanosomes, such as Trypanosoma brucei, relies on targeted recombination of silent Variant Surface Glycoprotein (VSG) genes into a specialized telomeric locus that directs transcription of just one VSG from thousands. How such VSG recombination is targeted and initiated is unclear. Here, we show that a key enzyme of T. brucei homologous recombination, RAD51, interacts with RNA-DNA hybrids. In addition, we show that RNA-DNA hybrids display a genome-wide colocalization with DNA breaks and that this relationship is impaired by mutation of RAD51. Finally, we show that RAD51 acts to repair highly abundant, localised DNA breaks at the single transcribed VSG and that mutation of RAD51 alters RNA-DNA hybrid abundance at 70 bp repeats both around the transcribed VSG and across the silent VSG archive. This work reveals a widespread, generalised role for RNA-DNA hybrids in directing RAD51 activity during recombination and uncovers a specialised application of this interplay during targeted DNA break repair needed for the critical T. brucei immune evasion reaction of antigenic variation.
Assuntos
Trypanosoma brucei brucei , Estruturas R-Loop , Variação Antigênica/genética , Quebras de DNA , DNA , RNA , Glicoproteínas Variantes de Superfície de Trypanosoma/genéticaRESUMO
The primary antigenic and virulence determinant of the human malaria parasite Plasmodium falciparum is a variant surface protein called PfEMP1. Different forms of PfEMP1 are encoded by a multicopy gene family called var, and switching between active genes enables the parasites to evade the antibody response of their human hosts. var gene switching is key for the maintenance of chronic infections; however, what controls switching is unknown, although it has been suggested to occur at a constant frequency with little or no environmental influence. var gene transcription is controlled epigenetically through the activity of histone methyltransferases (HMTs). Studies in model systems have shown that metabolism and epigenetic control of gene expression are linked through the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor in biological methylation modifications, which can fluctuate based on nutrient availability. To determine whether environmental conditions and changes in metabolism can influence var gene expression, P. falciparum was cultured in media with altered concentrations of nutrients involved in SAM metabolism. We found that conditions that influence lipid metabolism induce var gene switching, indicating that parasites can respond to changes in their environment by altering var gene expression patterns. Genetic modifications that directly modified expression of the enzymes that control SAM levels similarly led to profound changes in var gene expression, confirming that changes in SAM availability modulate var gene switching. These observations directly challenge the paradigm that antigenic variation in P. falciparum follows an intrinsic, programed switching rate, which operates independently of any external stimuli.
Assuntos
Malária Falciparum , Parasitos , Animais , Humanos , Plasmodium falciparum/metabolismo , Parasitos/metabolismo , Regulação da Expressão Gênica , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Malária Falciparum/parasitologia , Variação Antigênica/genéticaRESUMO
BACKGROUND: The TprK protein of the syphilis agent, Treponema pallidum subsp. pallidum (T. pallidum), undergoes antigenic variation in seven discrete variable (V) regions via non-reciprocal segmental gene conversion. These recombination events transfer information from a repertoire of 53 silent chromosomal donor cassettes (DCs) into the single tprK expression site to continually generate TprK variants. Several lines of research developed over the last two decades support the theory that this mechanism is central to T. pallidum's ability for immune avoidance and persistence in the host. Structural and modeling data, for example, identify TprK as an integral outer membrane porin with the V regions exposed on the pathogen's surface. Furthermore, infection-induced antibodies preferentially target the V regions rather than the predicted ß-barrel scaffolding, and sequence variation abrogates the binding of antibodies elicited by antigenically different V regions. Here, we engineered a T. pallidum strain to impair its ability to vary TprK and assessed its virulence in the rabbit model of syphilis. PRINCIPAL FINDINGS: A suicide vector was transformed into the wild-type (WT) SS14 T. pallidum isolate to eliminate 96% of its tprK DCs. The resulting SS14-DCKO strain exhibited an in vitro growth rate identical to the untransformed strain, supporting that the elimination of the DCs did not affect strain viability in absence of immune pressure. In rabbits injected intradermally with the SS14-DCKO strain, generation of new TprK sequences was impaired, and the animals developed attenuated lesions with a significantly reduced treponemal burden compared to control animals. During infection, clearance of V region variants originally in the inoculum mirrored the generation of antibodies to these variants, although no new variants were generated in the SS14-DCKO strain to overcome immune pressure. Naïve rabbits that received lymph node extracts from animals infected with the SS14-DCKO strain remained uninfected. CONCLUSION: These data further support the critical role of TprK in T. pallidum virulence and persistence during infection.
Assuntos
Sífilis , Animais , Coelhos , Treponema pallidum , Treponema , Variação Antigênica/genética , AnticorposRESUMO
Several persistent pathogens employ antigenic variation to continually evade mammalian host adaptive immune responses. African trypanosomes use variant surface glycoproteins (VSGs) for this purpose, transcribing one telomeric VSG expression-site at a time, and exploiting a reservoir of (sub)telomeric VSG templates to switch the active VSG. It has been known for over fifty years that new VSGs emerge in a predictable order in Trypanosoma brucei, and differential activation frequencies are now known to contribute to the hierarchy. Switching of approximately 0.01% of dividing cells to many new VSGs, in the absence of post-switching competition, suggests that VSGs are deployed in a highly profligate manner, however. Here, we report that switched trypanosomes do indeed compete, in a highly predictable manner that is dependent upon the activated VSG. We induced VSG gene recombination and switching in in vitro culture using CRISPR-Cas9 nuclease to target the active VSG. VSG dynamics, that were independent of host immune selection, were subsequently assessed using RNA-seq. Although trypanosomes activated VSGs from repressed expression-sites at relatively higher frequencies, the population of cells that activated minichromosomal VSGs subsequently displayed a competitive advantage and came to dominate. Furthermore, the advantage appeared to be more pronounced for longer VSGs. Differential growth of switched clones was also associated with wider differences, affecting transcripts involved in nucleolar function, translation, and energy metabolism. We conclude that antigenic variants compete, and that the population of cells that activates minichromosome derived VSGs displays a competitive advantage. Thus, competition among variants impacts antigenic variation dynamics in African trypanosomes and likely prolongs immune evasion with a limited set of antigens.
Assuntos
Trypanosoma brucei brucei , Trypanosoma , Animais , Glicoproteínas Variantes de Superfície de Trypanosoma/genética , Trypanosoma brucei brucei/metabolismo , Variação Antigênica/genética , Evasão da Resposta Imune/genética , Glicoproteínas de Membrana/metabolismo , MamíferosRESUMO
RNA-DNA hybrids are epigenetic features of genomes that provide a diverse and growing range of activities. Understanding of these functions has been informed by characterising the proteins that interact with the hybrids, but all such analyses have so far focused on mammals, meaning it is unclear if a similar spectrum of RNA-DNA hybrid interactors is found in other eukaryotes. The African trypanosome is a single-cell eukaryotic parasite of the Discoba grouping and displays substantial divergence in several aspects of core biology from its mammalian host. Here, we show that DNA-RNA hybrid immunoprecipitation coupled with mass spectrometry recovers 602 putative interactors in T. brucei mammal- and insect-infective cells, some providing activities also found in mammals and some lineage-specific. We demonstrate that loss of three factors, two putative helicases and a RAD51 paralogue, alters T. brucei nuclear RNA-DNA hybrid and DNA damage levels. Moreover, loss of each factor affects the operation of the parasite immune survival mechanism of antigenic variation. Thus, our work reveals the broad range of activities contributed by RNA-DNA hybrids to T. brucei biology, including new functions in host immune evasion as well as activities likely fundamental to eukaryotic genome function.
Assuntos
Trypanosoma brucei brucei , Animais , Trypanosoma brucei brucei/metabolismo , Evasão da Resposta Imune/genética , RNA/genética , Antígenos de Superfície , Variação Antigênica/genética , DNA/genética , Mamíferos/genética , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismoRESUMO
Universal Minicircle Sequence binding proteins (UMSBPs) are CCHC-type zinc-finger proteins that bind the single-stranded G-rich UMS sequence, conserved at the replication origins of minicircles in the kinetoplast DNA, the mitochondrial genome of kinetoplastids. Trypanosoma brucei UMSBP2 has been recently shown to colocalize with telomeres and to play an essential role in chromosome end protection. Here we report that TbUMSBP2 decondenses in vitro DNA molecules, which were condensed by core histones H2B, H4 or linker histone H1. DNA decondensation is mediated via protein-protein interactions between TbUMSBP2 and these histones, independently of its previously described DNA binding activity. Silencing of the TbUMSBP2 gene resulted in a significant decrease in the disassembly of nucleosomes in T. brucei chromatin, a phenotype that could be reverted, by supplementing the knockdown cells with TbUMSBP2. Transcriptome analysis revealed that silencing of TbUMSBP2 affects the expression of multiple genes in T. brucei, with a most significant effect on the upregulation of the subtelomeric variant surface glycoproteins (VSG) genes, which mediate the antigenic variation in African trypanosomes. These observations suggest that UMSBP2 is a chromatin remodeling protein that functions in the regulation of gene expression and plays a role in the control of antigenic variation in T. brucei.
Assuntos
Proteínas de Protozoários , Trypanosoma brucei brucei , Variação Antigênica/genética , Cromatina/genética , Cromatina/metabolismo , Regulação da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Telômero/genética , Telômero/metabolismo , Trypanosoma brucei brucei/metabolismo , Glicoproteínas Variantes de Superfície de Trypanosoma/genética , Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo , Proteínas de Protozoários/metabolismo , Montagem e Desmontagem da CromatinaRESUMO
Influenza B virus primarily infects humans, causing seasonal epidemics globally. Two antigenic variants-Victoria-like and Yamagata-like-were detected in the 1980s, of which the molecular basis of emergence is still incompletely understood. Here, the antigenic properties of a unique collection of historical virus isolates, sampled from 1962 to 2000 and passaged exclusively in mammalian cells to preserve antigenic properties, were determined with the hemagglutination inhibition assay and an antigenic map was built to quantify and visualize the divergence of the lineages. The antigenic map revealed only three distinct antigenic clusters-Early, Victoria, and Yamagata-with relatively little antigenic diversity in each cluster until 2000. Viruses with Victoria-like antigenic properties emerged around 1972 and diversified subsequently into two genetic lineages. Viruses with Yamagata-like antigenic properties evolved from one lineage and became clearly antigenically distinct from the Victoria-like viruses around 1988. Recombinant mutant viruses were tested to show that insertions and deletions (indels), as observed frequently in influenza B virus hemagglutinin, had little effect on antigenic properties. In contrast, amino-acid substitutions at positions 148, 149, 150, and 203, adjacent to the hemagglutinin receptor binding site, determined the main antigenic differences between the Early, Victoria-like, and Yamagata-like viruses. Surprisingly, substitutions at two of the four positions reverted in recent viruses of the Victoria lineage, resulting in antigenic properties similar to viruses circulating â¼50 y earlier. These data shed light on the antigenic diversification of influenza viruses and suggest there may be limits to the antigenic evolution of influenza B virus.
Assuntos
Influenza Humana , Animais , Variação Antigênica/genética , Sítios de Ligação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Hemaglutininas , Humanos , Vírus da Influenza B/genética , Mamíferos , FilogeniaRESUMO
BACKGROUND: The incidence of syphilis continues to increase in the United States, yet little is known about Treponema pallidum genomic epidemiology within American metropolitan areas. METHODS: We performed whole-genome sequencing and tprK deep sequencing of 28 T. pallidum-containing specimens, collected mostly from remnant Aptima swab specimens from 24 individuals from Seattle Sexual Health Clinic during 2021-2022. RESULTS: All 12 individuals infected with Nichols-lineage strains were men who have sex with men, while a specific SS14 cluster (mean, 0.33 single-nucleotide variant) included 1 man who has sex with women and 5 women. All T. pallidum strains sequenced were azithromycin resistant via 23S ribosomal RNA A2058G mutation. Identical T. pallidum genomic sequences were found in pharyngeal and rectal swab specimens taken concurrently from the same individuals. The tprK sequences were less variable between patient-matched specimens and between epidemiologically linked clusters. We detected a 528-base pair deletion in the tprK donor site locus, eliminating 9 donor sites, in T. pallidum genomes of 3 individuals with secondary syphilis, associated with diminution of TprK diversity. CONCLUSIONS: We developed an end-to-end workflow for public health genomic surveillance of T. pallidum from remnant Aptima swab specimens. tprK sequencing may assist in linking cases beyond routine T. pallidum genome sequencing. T. pallidum strains with deletions in tprK donor sites currently circulate and are associated with diminished TprK antigenic diversity.
Assuntos
Minorias Sexuais e de Gênero , Sífilis , Masculino , Feminino , Humanos , Treponema pallidum/genética , Homossexualidade Masculina , Sequência de Aminoácidos , Sífilis/epidemiologia , Variação Antigênica , GenômicaRESUMO
We characterized the evolution and molecular characteristics of avian influenza A(H7N9) viruses isolated in China during 2021-2023. We systematically analyzed the 10-year evolution of the hemagglutinin gene to determine the evolutionary branch. Our results showed recent antigenic drift, providing crucial clues for updating the H7N9 vaccine and disease prevention and control.
Assuntos
Antígenos Virais , Evolução Molecular , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Subtipo H7N9 do Vírus da Influenza A , Influenza Aviária , Influenza Humana , Filogenia , Subtipo H7N9 do Vírus da Influenza A/genética , Subtipo H7N9 do Vírus da Influenza A/imunologia , China/epidemiologia , Animais , Influenza Aviária/virologia , Influenza Aviária/epidemiologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Influenza Humana/epidemiologia , Influenza Humana/virologia , Influenza Humana/imunologia , Antígenos Virais/imunologia , Antígenos Virais/genética , Aves/virologia , Variação AntigênicaRESUMO
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
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus is continuously evolving, and this poses a major threat to antibody therapies and currently authorized Coronavirus Disease 2019 (COVID-19) vaccines. It is therefore of utmost importance to investigate and predict the putative mutations on the spike protein that confer immune evasion. Antibodies are key components of the human immune system's response to SARS-CoV-2, and the spike protein is a prime target of neutralizing antibodies (nAbs) as it plays critical roles in host cell recognition, fusion, and virus entry. The potency of therapeutic antibodies and vaccines partly depends on how readily the virus can escape neutralization. Recent structural and functional studies have mapped the epitope landscape of nAbs on the spike protein, which illustrates the footprints of several nAbs and the site of escape mutations. In this review, we discuss (1) the emerging SARS-CoV-2 variants; (2) the structural basis for antibody-mediated neutralization of SARS-CoV-2 and nAb classification; and (3) identification of the RBD escape mutations for several antibodies that resist antibody binding and neutralization. These escape maps are a valuable tool to predict SARS-CoV-2 fitness, and in conjunction with the structures of the spike-nAb complex, they can be utilized to facilitate the rational design of escape-resistant antibody therapeutics and vaccines.
Assuntos
Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Neutralizantes/imunologia , Variação Antigênica , COVID-19/virologia , Epitopos/imunologia , Humanos , Evasão da Resposta Imune , Modelos Estruturais , Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
It has long been thought that clonal deletion efficiently removes almost all self-specific T cells from the peripheral repertoire. We found that self-peptide MHC-specific CD8(+) T cells in the blood of healthy humans were present in frequencies similar to those specific for non-self antigens. For the Y chromosome-encoded SMCY antigen, self-specific T cells exhibited only a 3-fold lower average frequency in males versus females and were anergic with respect to peptide activation, although this inhibition could be overcome by a stronger stimulus. We conclude that clonal deletion prunes but does not eliminate self-specific T cells and suggest that to do so would create holes in the repertoire that pathogens could readily exploit. In support of this hypothesis, we detected T cells specific for all 20 amino acid variants at the p5 position of a hepatitis C virus epitope in a random group of blood donors.