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Nature Communications May 2023The genomes of most protozoa encode families of variant surface antigens. In some parasitic microorganisms, it has been demonstrated that mutually exclusive changes in...
The genomes of most protozoa encode families of variant surface antigens. In some parasitic microorganisms, it has been demonstrated that mutually exclusive changes in the expression of these antigens allow parasites to evade the host's immune response. It is widely assumed that antigenic variation in protozoan parasites is accomplished by the spontaneous appearance within the population of cells expressing antigenic variants that escape antibody-mediated cytotoxicity. Here we show, both in vitro and in animal infections, that antibodies to Variant-specific Surface Proteins (VSPs) of the intestinal parasite Giardia lamblia are not cytotoxic, inducing instead VSP clustering into liquid-ordered phase membrane microdomains that trigger a massive release of microvesicles carrying the original VSP and switch in expression to different VSPs by a calcium-dependent mechanism. This novel mechanism of surface antigen clearance throughout its release into microvesicles coupled to the stochastic induction of new phenotypic variants not only changes current paradigms of antigenic switching but also provides a new framework for understanding the course of protozoan infections as a host/parasite adaptive process.
Topics: Animals; Giardia lamblia; Giardiasis; Parasites; Antigens, Surface; Antigens, Protozoan; Intestinal Diseases, Parasitic; Antibodies; Antigenic Variation; Protozoan Proteins
PubMed: 37137944
DOI: 10.1038/s41467-023-38317-8 -
Frontiers in Cell and Developmental... 2021How does the information in the genome program the functions of the wide variety of cells in the body? While the development of biological organisms appears to follow an... (Review)
Review
How does the information in the genome program the functions of the wide variety of cells in the body? While the development of biological organisms appears to follow an explicit set of genomic instructions to generate the same outcome each time, many biological mechanisms harness molecular noise to produce variable outcomes. Non-deterministic variation is frequently observed in the diversification of cell surface molecules that give cells their functional properties, and is observed across eukaryotic clades, from single-celled protozoans to mammals. This is particularly evident in immune systems, where random recombination produces millions of antibodies from only a few genes; in nervous systems, where stochastic mechanisms vary the sensory receptors and synaptic matching molecules produced by different neurons; and in microbial antigenic variation. These systems employ overlapping molecular strategies including allelic exclusion, gene silencing by constitutive heterochromatin, targeted double-strand breaks, and competition for limiting enhancers. Here, we describe and compare five stochastic molecular mechanisms that produce variety in pathogen coat proteins and in the cell surface receptors of animal immune and neuronal cells, with an emphasis on the utility of non-deterministic variation.
PubMed: 35087825
DOI: 10.3389/fcell.2021.720798 -
Nature Communications Nov 2023Surface antigenic variation is crucial for major pathogens that infect humans. To escape the immune system, they exploit various mechanisms. Understanding these...
Surface antigenic variation is crucial for major pathogens that infect humans. To escape the immune system, they exploit various mechanisms. Understanding these mechanisms is important to better prevent and fight the deadly diseases caused. Those used by the fungus Pneumocystis jirovecii that causes life-threatening pneumonia in immunocompromised individuals remain poorly understood. Here, though this fungus is currently not cultivable, our detailed analysis of the subtelomeric sequence motifs and genes encoding surface proteins suggests that the system involves the reassortment of the repertoire of ca. 80 non-expressed genes present in each strain, from which single genes are retrieved for mutually exclusive expression. Dispersion of the new repertoires, supposedly by healthy carrier individuals, appears very efficient because identical alleles are observed in patients from different countries. Our observations reveal a unique strategy of antigenic variation. They also highlight the possible role in genome rearrangements of small imperfect mirror sequences forming DNA triplexes.
Topics: Humans; Mosaicism; Pneumocystis carinii; Antigenic Variation; DNA, Fungal
PubMed: 37919276
DOI: 10.1038/s41467-023-42685-6 -
Scientific Reports Sep 2022Seasonal influenza epidemics circulate globally every year with varying levels of severity. One of the major drivers of this seasonal variation is thought to be the...
Seasonal influenza epidemics circulate globally every year with varying levels of severity. One of the major drivers of this seasonal variation is thought to be the antigenic drift of influenza viruses, resulting from the accumulation of mutations in viral surface proteins. In this study, we aimed to investigate the association between the genetic drift of seasonal influenza viruses (A/H1N1, A/H3N2 and B) and the epidemiological severity of seasonal epidemics within a Canadian context. We obtained hemagglutinin protein sequences collected in Canada between the 2006/2007 and 2019/2020 flu seasons from GISAID and calculated Hamming distances in a sequence-based approach to estimating inter-seasonal antigenic differences. We also gathered epidemiological data on cases, hospitalizations and deaths from national surveillance systems and other official sources, as well as vaccine effectiveness estimates to address potential effect modification. These aggregate measures of disease severity were integrated into a single seasonal severity index. We performed linear regressions of our severity index with respect to the inter-seasonal antigenic distances, controlling for vaccine effectiveness. We did not find any evidence of a statistical relationship between antigenic distance and seasonal influenza severity in Canada. Future studies may need to account for additional factors, such as co-circulation of other respiratory pathogens, population imprinting, cohort effects and environmental parameters, which may drive seasonal influenza severity.
Topics: Antigenic Drift and Shift; Antigens; Canada; Hemagglutinins; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza Vaccines; Influenza, Human; Membrane Proteins; Seasons
PubMed: 36115880
DOI: 10.1038/s41598-022-19996-7 -
PLoS Pathogens Feb 2022The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus is continuously evolving, and this poses a major threat to antibody therapies and currently... (Review)
Review
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.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Antigenic Variation; COVID-19; COVID-19 Vaccines; Epitopes; Humans; Immune Evasion; Models, Structural; Mutation; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 35176090
DOI: 10.1371/journal.ppat.1010260 -
MBio Oct 2023A/H7 avian influenza viruses cause outbreaks in poultry globally, resulting in outbreaks with significant socio-economical impact and zoonotic risks. Occasionally,...
A/H7 avian influenza viruses cause outbreaks in poultry globally, resulting in outbreaks with significant socio-economical impact and zoonotic risks. Occasionally, poultry vaccination programs have been implemented to reduce the burden of these viruses, which might result in an increased immune pressure accelerating antigenic evolution. In fact, evidence for antigenic diversification of A/H7 influenza viruses exists, posing challenges to pandemic preparedness and the design of vaccination strategies efficacious against drifted variants. Here, we performed a comprehensive analysis of the global antigenic diversity of A/H7 influenza viruses and identified the main substitutions in the hemagglutinin responsible for antigenic evolution in A/H7N9 viruses isolated between 2013 and 2019. The A/H7 antigenic map and knowledge of the molecular determinants of their antigenic evolution add value to A/H7 influenza virus surveillance programs, the design of vaccines and vaccination strategies, and pandemic preparedness.
Topics: Animals; Humans; Influenza A Virus, H7N9 Subtype; Hemagglutinins; Hemagglutinin Glycoproteins, Influenza Virus; Antigenic Variation; Disease Outbreaks; Poultry; Influenza in Birds; Influenza, Human
PubMed: 37565755
DOI: 10.1128/mbio.00488-23 -
Bioinformatics (Oxford, England) Jan 2022High plasticity of bacterial genomes is provided by numerous mechanisms including horizontal gene transfer and recombination via numerous flanking repeats. Genome...
MOTIVATION
High plasticity of bacterial genomes is provided by numerous mechanisms including horizontal gene transfer and recombination via numerous flanking repeats. Genome rearrangements such as inversions, deletions, insertions and duplications may independently occur in different strains, providing parallel adaptation or phenotypic diversity. Specifically, such rearrangements might be responsible for virulence, antibiotic resistance and antigenic variation. However, identification of such events requires laborious manual inspection and verification of phyletic pattern consistency.
RESULTS
Here, we define the term 'parallel rearrangements' as events that occur independently in phylogenetically distant bacterial strains and present a formalization of the problem of parallel rearrangements calling. We implement an algorithmic solution for the identification of parallel rearrangements in bacterial populations as a tool PaReBrick. The tool takes a collection of strains represented as a sequence of oriented synteny blocks and a phylogenetic tree as input data. It identifies rearrangements, tests them for consistency with a tree, and sorts the events by their parallelism score. The tool provides diagrams of the neighbors for each block of interest, allowing the detection of horizontally transferred blocks or their extra copies and the inversions in which copied blocks are involved. We demonstrated PaReBrick's efficiency and accuracy and showed its potential to detect genome rearrangements responsible for pathogenicity and adaptation in bacterial genomes.
AVAILABILITY AND IMPLEMENTATION
PaReBrick is written in Python and is available on GitHub: https://github.com/ctlab/parallel-rearrangements.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Phylogeny; Synteny; Genome, Bacterial; Antigenic Variation; Software
PubMed: 34601581
DOI: 10.1093/bioinformatics/btab691 -
Virus Research Dec 2016Emerging and re-emerging coronaviruses cause morbidity and mortality in human and animal populations, resulting in serious public and animal health threats and economic... (Review)
Review
Emerging and re-emerging coronaviruses cause morbidity and mortality in human and animal populations, resulting in serious public and animal health threats and economic losses. The ongoing outbreak of a highly contagious and deadly porcine epidemic diarrhea virus (PEDV) in Asia, the Americas and Europe is one example. Genomic sequence analyses of PEDV variants have revealed important insights into the evolution of PEDV. However, the antigenic variations among different PEDV strains are less explored, although they may contribute to the failure of PEDV vaccines in Asian countries. In addition, the evolution of PEDV results in variants with distinct genetic features and virulence differences; thus PEDV can serve as a model to explore the molecular mechanisms of coronavirus evolution and pathogenesis. In this article, we review the evolution, antigenic relationships and pathologic features of PEDV strains. This information and review of researches will aid in the development of strategies for control and prevention of PED.
Topics: Animals; Antigenic Variation; Coronavirus; Coronavirus Infections; Cross Protection; Cross Reactions; Evolution, Molecular; Global Health; Phylogeny; Porcine epidemic diarrhea virus; Swine; Swine Diseases; Viral Vaccines; Virulence
PubMed: 27288724
DOI: 10.1016/j.virusres.2016.05.023 -
Viruses Jun 2023Owing to the rapid changes in the antigenicity of influenza viruses, it is difficult for humans to obtain lasting immunity through antiviral therapy. Hence, tracking the...
Owing to the rapid changes in the antigenicity of influenza viruses, it is difficult for humans to obtain lasting immunity through antiviral therapy. Hence, tracking the dynamic changes in the antigenicity of influenza viruses can provide a basis for vaccines and drug treatments to cope with the spread of influenza viruses. In this paper, we developed a novel quantitative prediction method to predict the antigenic distance between virus strains using attribute network embedding techniques. An antigenic network is built to model and combine the genetic and antigenic characteristics of the influenza A virus H3N2, using the continuous distributed representation of the virus strain protein sequence (ProtVec) as a node attribute and the antigenic distance between virus strains as an edge weight. The results show a strong positive correlation between supplementing genetic features and antigenic distance prediction accuracy. Further analysis indicates that our prediction model can comprehensively and accurately track the differences in antigenic distances between vaccines and influenza virus strains, and it outperforms existing methods in predicting antigenic distances between strains.
Topics: Humans; Influenza, Human; Influenza A Virus, H3N2 Subtype; Antigens, Viral; Influenza A virus; Amino Acid Sequence; Hemagglutinin Glycoproteins, Influenza Virus; Antigenic Variation; Influenza Vaccines
PubMed: 37515165
DOI: 10.3390/v15071478 -
Viruses Oct 2014Vaccination is by far the most effective way of preventing morbidity and mortality due to infection of the upper respiratory tract by influenza virus. Current vaccines... (Review)
Review
Vaccination is by far the most effective way of preventing morbidity and mortality due to infection of the upper respiratory tract by influenza virus. Current vaccines require yearly vaccine updates as the influenza virus can escape vaccine-induced humoral immunity due to the antigenic variability of its surface antigens. In case of a pandemic, new vaccines become available too late with current vaccine practices. New technologies that allow faster production of vaccine seed strains in combination with alternative production platforms and vaccine formulations may shorten the time gap between emergence of a new influenza virus and a vaccine becoming available. Adjuvants may allow antigen-sparing, allowing more people to be vaccinated with current vaccine production capacity. Adjuvants and universal vaccines can target immune responses to more conserved influenza epitopes, which eventually will result in broader protection for a longer time. In addition, further immunological studies are needed to gain insights in the immune features that contribute to protection from influenza-related disease and mortality, allowing redefinition of correlates of protection beyond virus neutralization in vitro.
Topics: Adjuvants, Immunologic; Antibodies, Viral; Antigenic Variation; Humans; Immunity, Humoral; Influenza Vaccines; Influenza, Human; Orthomyxoviridae; Pandemics; Vaccination; Vaccines, Synthetic
PubMed: 25302957
DOI: 10.3390/v6103809