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Nature Nov 2018Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic...
Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses-Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing-that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation.
Topics: Antigenic Variation; Chromatin; DNA, Protozoan; Genome; Haplotypes; Histones; Multigene Family; Protein Isoforms; Trypanosoma brucei brucei; Variant Surface Glycoproteins, Trypanosoma
PubMed: 30333624
DOI: 10.1038/s41586-018-0619-8 -
Philosophical Transactions of the Royal... Aug 2015African trypanosomes are single-celled protozoan parasites that are capable of long-term survival while living extracellularly in the bloodstream and tissues of... (Review)
Review
African trypanosomes are single-celled protozoan parasites that are capable of long-term survival while living extracellularly in the bloodstream and tissues of mammalian hosts. Prolonged infections are possible because trypanosomes undergo antigenic variation-the expression of a large repertoire of antigenically distinct surface coats, which allows the parasite population to evade antibody-mediated elimination. The mechanisms by which antigen genes become activated influence their order of expression, most likely by influencing the frequency of productive antigen switching, which in turn is likely to contribute to infection chronicity. Superimposed upon antigen switching as a contributor to trypanosome infection dynamics is the density-dependent production of cell-cycle arrested parasite transmission stages, which limit the infection while ensuring parasite spread to new hosts via the bite of blood-feeding tsetse flies. Neither antigen switching nor developmental progression to transmission stages is driven by the host. However, the host can contribute to the infection dynamic through the selection of distinct antigen types, the influence of genetic susceptibility or trypanotolerance and the potential influence of host-dependent effects on parasite virulence, development of transmission stages and pathogenicity. In a zoonotic infection cycle where trypanosomes circulate within a range of host animal populations, and in some cases humans, there is considerable scope for a complex interplay between parasite immune evasion, transmission potential and host factors to govern the profile and outcome of infection.
Topics: Animals; Antigenic Variation; Antigens, Protozoan; Coinfection; Gene Conversion; Genes, Protozoan; Genetic Predisposition to Disease; Host-Parasite Interactions; Humans; Immune Evasion; Trypanosoma; Trypanosomiasis, African; Variant Surface Glycoproteins, Trypanosoma; Virulence; Zoonoses
PubMed: 26150654
DOI: 10.1098/rstb.2014.0288 -
Microbiology Spectrum Feb 2022The H9N2 subtype avian influenza virus (AIV) has become endemic in poultry globally; however due to its low pathogenicity, it is not under primary surveillance and...
The H9N2 subtype avian influenza virus (AIV) has become endemic in poultry globally; however due to its low pathogenicity, it is not under primary surveillance and control in many countries. Recent reports of human infection caused by H9N2 AIV has increased public concern. This study investigated the genetic and antigenic characteristics of H9N2 AIV isolated from local markets in nine provinces in Southern China from 2013 to 2018. We detected an increasing annual isolation rate of H9N2 AIV. Phylogenetic analyses of hemagglutinin (HA) genes suggests that isolated strains were rooted in BJ94 lineage but have evolved into new subgroups (II and III), which derived from subgroup I. The estimated substitution rate of the subgroup III strains was 6.23 × 10 substitutions/site/year, which was 1.5-fold faster than that of the average H9N2 HA rate (3.95 × 10 substitutions/site/year). Based on the antigenic distances, subgroup II and III strains resulted in two clear antigenic clusters 2 and 3, separated from the vaccine strain F98, cluster 1. New antigenic properties of subgroup III viruses were associated with 11 amino acid changes in the HA protein, suggesting antigenic drift in H9N2 viruses. Our phylogenetic and antigenic analyses of the H9N2 strains circulating in local markets in Southern China provide new insights on the antigenic diversification of H9N2 viruses. The H9N2 low pathogenicity avian influenza (LPAI) virus has become endemic in poultry globally. In several Asian countries, vaccination against H9N2 avian influenza virus (AIV) was approved to reduce economic losses in the poultry industry. However, surveillance programs initiated after the introduction of vaccination identified the persistence of H9N2 AIV in poultry (especially in chicken in South Korea and China). Recent reports of human infection caused by H9N2 AIV has increased public concern. Surveillance of H9N2 circulating in poultry in the fields or markets was essential to update the vaccination strategies. This study investigated the genetic and antigenic characteristics of H9N2 AIVs isolated from local markets in nine provinces in Southern China from 2013 to 2018. The discovery of mutations in the hemagglutinin (HA) gene that result in antigenic changes provides a baseline reference for evolutionary studies of H9N2 viruses and vaccination strategies in poultry.
Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Antigenic Drift and Shift; Antigenic Variation; Chickens; China; Evolution, Molecular; Hemagglutinins, Viral; Influenza A Virus, H9N2 Subtype; Influenza in Birds; Phylogeny; Poultry Diseases
PubMed: 35019707
DOI: 10.1128/spectrum.00822-21 -
Nature Ecology & Evolution Jan 2022Despite the propensity for complex and non-equilibrium dynamics in nature, eco-evolutionary analytical theory typically assumes that populations are at equilibria. In...
Despite the propensity for complex and non-equilibrium dynamics in nature, eco-evolutionary analytical theory typically assumes that populations are at equilibria. In particular, pathogens often show antigenic escape from host immune defences, leading to repeated epidemics, fluctuating selection and diversification, but we do not understand how this impacts the evolution of virulence. We model the impact of antigenic drift and escape on the evolution of virulence in a generalized pathogen and apply a recently introduced oligomorphic methodology that captures the dynamics of the mean and variance of traits, to show analytically that these non-equilibrium dynamics select for the long-term persistence of more acute pathogens with higher virulence. Our analysis predicts both the timings and outcomes of antigenic shifts leading to repeated epidemics and predicts the increase in variation in both antigenicity and virulence before antigenic escape. There is considerable variation in the degree of antigenic escape that occurs across pathogens and our results may help to explain the difference in virulence between related pathogens including, potentially, human influenzas. Furthermore, it follows that these pathogens will have a lower R, with clear implications for epidemic behaviour, endemic behaviour and control. More generally, our results show the importance of examining the evolutionary consequences of non-equilibrium dynamics.
Topics: Antigenic Drift and Shift; Biological Evolution; Epidemics; Humans; Phenotype; Virulence
PubMed: 34949816
DOI: 10.1038/s41559-021-01603-z -
Microbiology Spectrum Feb 2016Antigenic variation is a strategy used by a broad diversity of microbial pathogens to persist within the mammalian host. Whereas viruses make use of a minimal...
Antigenic variation is a strategy used by a broad diversity of microbial pathogens to persist within the mammalian host. Whereas viruses make use of a minimal proofreading capacity combined with large amounts of progeny to use random mutation for variant generation, antigenically variant bacteria have evolved mechanisms which use a stable genome, which aids in protecting the fitness of the progeny. Here, three well-characterized and highly antigenically variant bacterial pathogens are discussed: Anaplasma, Borrelia, and Neisseria. These three pathogens display a variety of mechanisms used to create the structural and antigenic variation needed for immune escape and long-term persistence. Intrahost antigenic variation is the focus; however, the role of these immune escape mechanisms at the population level is also presented.
Topics: Anaplasma marginale; Animals; Antigenic Variation; Antigens, Bacterial; Bacteria; Genome, Bacterial; Humans
PubMed: 26999387
DOI: 10.1128/microbiolspec.VMBF-0005-2015 -
Blood Cancer Discovery Mar 2022In this issue of Blood Cancer Discovery, Zheng and colleagues identify that alternative RNA splicing of CD22 within B-cell acute lymphoblastic leukemia can result in...
In this issue of Blood Cancer Discovery, Zheng and colleagues identify that alternative RNA splicing of CD22 within B-cell acute lymphoblastic leukemia can result in antigen escape from CD22-targeted immunotherapies. Drug-resistant isoforms of CD22 exist within leukemic cells pretreatment and can influence response to the CD22-directed antibody-drug conjugate inotuzumab ozogamicin, the immunotoxin moxetumomab pasudotox, as well as anti-CD22 chimeric antigen receptor T cells. See related article by Zheng et al., p. 103 (7).
Topics: Antigenic Drift and Shift; Humans; Immunotherapy; Immunotoxins; Inotuzumab Ozogamicin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sialic Acid Binding Ig-like Lectin 2
PubMed: 35015686
DOI: 10.1158/2643-3230.BCD-21-0200 -
Immunological Reviews Jan 2017A key unresolved challenge for developing an effective HIV-1 vaccine is the discovery of strategies to elicit immune responses that are able to cross-protect against a... (Review)
Review
A key unresolved challenge for developing an effective HIV-1 vaccine is the discovery of strategies to elicit immune responses that are able to cross-protect against a significant fraction of the diverse viruses that are circulating worldwide. Here, we summarize some of the immunological implications of HIV-1 diversity, and outline the rationale behind several polyvalent vaccine design strategies that are currently under evaluation. Vaccine-elicited T-cell responses, which contribute to the control of HIV-1 in natural infections, are currently being considered in both prevention and treatment settings. Approaches now in preclinical and human trials include full proteins in novel vectors, concatenated conserved protein regions, and polyvalent strategies that improve coverage of epitope diversity and enhance the cross-reactivity of responses. While many barriers to vaccine induction of broadly neutralizing antibody (bNAb) responses remain, epitope diversification has emerged as both a challenge and an opportunity. Recent longitudinal studies have traced the emergence of bNAbs in HIV-1 infection, inspiring novel approaches to recapitulate and accelerate the events that give rise to potent bNAb in vivo. In this review, we have selected two such lineage-based design strategies to illustrate how such in-depth analysis can offer conceptual improvements that may bring us closer to an effective vaccine.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Antigenic Variation; Cross Reactions; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 28133800
DOI: 10.1111/imr.12516 -
Phase and antigenic variation govern competition dynamics through positioning in bacterial colonies.Scientific Reports Sep 2017Cellular positioning towards the surface of bacterial colonies and biofilms can enhance dispersal, provide a selective advantage due to increased nutrient and space...
Cellular positioning towards the surface of bacterial colonies and biofilms can enhance dispersal, provide a selective advantage due to increased nutrient and space availability, or shield interior cells from external stresses. Little is known about the molecular mechanisms that govern bacterial positioning. Using the type IV pilus (T4P) of Neisseria gonorrhoeae, we tested the hypothesis that the processes of phase and antigenic variation govern positioning and thus enhance bacterial fitness in expanding gonococcal colonies. By independently tuning growth rate and T4P-mediated interaction forces, we show that the loss of T4P and the subsequent segregation to the front confers a strong selective advantage. Sequencing of the major pilin gene of the spatially segregated sub-populations and an investigation of the spatio-temporal population dynamics was carried out. Our findings indicate that pilin phase and antigenic variation generate a standing variation of pilin sequences within the inoculation zone, while variants associated with a non-piliated phenotype segregate to the front of the growing colony. We conclude that tuning of attractive forces by phase and antigenic variation is a powerful mechanism for governing the dynamics of bacterial colonies.
Topics: Antigenic Variation; Biofilms; Fimbriae Proteins; Gonorrhea; Humans; Mutation; Neisseria gonorrhoeae
PubMed: 28939833
DOI: 10.1038/s41598-017-12472-7 -
Journal of Immunology (Baltimore, Md. :... Jan 2019Protection from yearly recurring, highly acute infections with a pathogen that rapidly and continuously evades previously induced protective neutralizing Abs, as seen... (Review)
Review
Protection from yearly recurring, highly acute infections with a pathogen that rapidly and continuously evades previously induced protective neutralizing Abs, as seen during seasonal influenza virus infections, can be expected to require a B cell response that is too highly variable, able to adapt rapidly, and able to reduce morbidity and death when sterile immunity cannot be garnered quickly enough. As we outline in this , the influenza-specific B cell response is exactly that: it is multifaceted, involves both innate-like and conventional B cells, provides early and later immune protection, employs B cells with distinct BCR repertoires and distinct modes of activation, and continuously adapts to the ever-changing virus while enhancing overall protection. A formidable response to a formidable pathogen.
Topics: Animals; Antibodies, Viral; Antigenic Variation; Antigens, Viral; B-Lymphocytes; Cross Protection; Humans; Immunity, Heterologous; Immunity, Humoral; Immunity, Innate; Influenza A virus; Influenza Vaccines; Influenza, Human; Orthomyxoviridae Infections
PubMed: 30617116
DOI: 10.4049/jimmunol.1801208 -
Viruses Apr 2019Influenza A virions possess two surface glycoproteins-the hemagglutinin (HA) and neuraminidase (NA)-which exert opposite functions. HA attaches virions to cells by... (Review)
Review
Influenza A virions possess two surface glycoproteins-the hemagglutinin (HA) and neuraminidase (NA)-which exert opposite functions. HA attaches virions to cells by binding to terminal sialic acid residues on glycoproteins/glycolipids to initiate the infectious cycle, while NA cleaves terminal sialic acids, releasing virions to complete the infectious cycle. Antibodies specific for HA or NA can protect experimental animals from IAV pathogenesis and drive antigenic variation in their target epitopes that impairs vaccine effectiveness in humans. Here, we review progress in understanding HA/NA co-evolution as each acquires epistatic mutations to restore viral fitness to mutants selected in the other protein by host innate or adaptive immune pressure. We also discuss recent exciting findings that antibodies to HA can function in vivo by blocking NA enzyme activity to prevent nascent virion release and enhance Fc receptor-based activation of innate immune cells.
Topics: Adaptive Immunity; Animals; Antibodies, Viral; Antigenic Variation; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunity, Innate; Influenza A virus; Influenza, Human; Neuraminidase; Viral Proteins
PubMed: 31014029
DOI: 10.3390/v11040346