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Clinical Microbiology Reviews Jul 2001Giardia lamblia is a common cause of diarrhea in humans and other mammals throughout the world. It can be distinguished from other Giardia species by light or electron... (Review)
Review
Giardia lamblia is a common cause of diarrhea in humans and other mammals throughout the world. It can be distinguished from other Giardia species by light or electron microscopy. The two major genotypes of G. lamblia that infect humans are so different genetically and biologically that they may warrant separate species or subspecies designations. Trophozoites have nuclei and a well-developed cytoskeleton but lack mitochondria, peroxisomes, and the components of oxidative phosphorylation. They have an endomembrane system with at least some characteristics of the Golgi complex and encoplasmic reticulum, which becomes more extensive in encysting organisms. The primitive nature of the organelles and metabolism, as well as small-subunit rRNA phylogeny, has led to the proposal that Giardia spp. are among the most primitive eukaryotes. G. lamblia probably has a ploidy of 4 and a genome size of approximately 10 to 12 Mb divided among five chromosomes. Most genes have short 5' and 3' untranslated regions and promoter regions that are near the initiation codon. Trophozoites exhibit antigenic variation of an extensive repertoire of cysteine-rich variant-specific surface proteins. Expression is allele specific, and changes in expression from one vsp gene to another have not been associated with sequence alterations or gene rearrangements. The Giardia genome project promises to greatly increase our understanding of this interesting and enigmatic organism.
Topics: Animals; Antigenic Variation; Antigens, Protozoan; Genes, Protozoan; Giardia lamblia; Giardiasis; Host-Parasite Interactions; Humans
PubMed: 11432808
DOI: 10.1128/CMR.14.3.447-475.2001 -
Nature Reviews. Microbiology Jul 2021Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively... (Review)
Review
Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of 'variants of concern', that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.
Topics: Amino Acids; Antigenic Variation; COVID-19; COVID-19 Vaccines; Epitopes; Humans; Immune Evasion; Mutation; Protein Conformation; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 34075212
DOI: 10.1038/s41579-021-00573-0 -
Frontiers in Immunology 2020Protective vaccines for hypervariable pathogens are urgently needed. It has been proposed that amputating highly variable epitopes from vaccine antigens would induce the...
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 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.
Topics: Animals; Antibodies, Neutralizing; Antigenic Variation; Humans; Immunodominant Epitopes; Mutation; Vaccination; Viral Envelope Proteins; Viral Vaccines; Virus Diseases
PubMed: 33013870
DOI: 10.3389/fimmu.2020.02057 -
British Journal of Haematology Oct 2017Approximately 0·2-1% of routine RhD blood typings result in a "serological weak D phenotype." For more than 50 years, serological weak D phenotypes have been managed... (Review)
Review
Approximately 0·2-1% of routine RhD blood typings result in a "serological weak D phenotype." For more than 50 years, serological weak D phenotypes have been managed by policies to protect RhD-negative women of child-bearing potential from exposure to weak D antigens. Typically, blood donors with a serological weak D phenotype have been managed as RhD-positive, in contrast to transfusion recipients and pregnant women, who have been managed as RhD-negative. Most serological weak D phenotypes in Caucasians express molecularly defined weak D types 1, 2 or 3 and can be managed safely as RhD-positive, eliminating unnecessary injections of Rh immune globulin and conserving limited supplies of RhD-negative RBCs. If laboratories in the UK, Ireland and other European countries validated the use of potent anti-D reagents to result in weak D types 1, 2 and 3 typing initially as RhD-positive, such laboratory results would not require further testing. When serological weak D phenotypes are detected, laboratories should complete RhD testing by determining RHD genotypes (internally or by referral). Individuals with a serological weak D phenotype should be managed as RhD-positive or RhD-negative, according to their RHD genotype.
Topics: Amino Acid Substitution; Antigenic Variation; Blood Grouping and Crossmatching; Blood Transfusion; Cost-Benefit Analysis; Female; Gene Expression; Genotype; Humans; Isoantibodies; Mutation; Phenotype; Practice Guidelines as Topic; Pregnancy; Prevalence; Rh-Hr Blood-Group System; Serologic Tests
PubMed: 28508413
DOI: 10.1111/bjh.14757 -
Current Opinion in Microbiology Dec 2022Survival of the African trypanosome within its mammalian hosts, and hence transmission between hosts, relies upon antigenic variation, where stochastic changes in the... (Review)
Review
Survival of the African trypanosome within its mammalian hosts, and hence transmission between hosts, relies upon antigenic variation, where stochastic changes in the composition of their protective variant-surface glycoprotein (VSG) coat thwart effective removal of the pathogen by adaptive immunity. Antigenic variation has evolved remarkable mechanistic complexity in Trypanosoma brucei, with switching of the VSG coat executed by either transcriptional or recombination reactions. In the former, a single T. brucei cell selectively transcribes one telomeric VSG transcription site, termed the expression site (ES), from a pool of around 15. Silencing of the active ES and activation of one previously silent ES can lead to a co-ordinated VSG coat switch. Outside the ESs, the T. brucei genome contains an enormous archive of silent VSG genes and pseudogenes, which can be recombined into the ES to execute a coat switch. Most such recombination involves gene conversion, including copying of a complete VSG and more complex reactions where novel 'mosaic' VSGs are formed as patchworks of sequences from several silent (pseudo)genes. Understanding of the cellular machinery that directs transcriptional and recombination VSG switching is growing rapidly and the emerging picture is of the use of proteins, complexes and pathways that are not limited to trypanosomes, but are shared across the wider grouping of kinetoplastids and beyond, suggesting co-option of widely used, core cellular reactions. We will review what is known about the machinery of antigenic variation and discuss if there remains the possibility of trypanosome adaptations, or even trypanosome-specific machineries, that might offer opportunities to impair this crucial parasite-survival process.
Topics: Animals; Variant Surface Glycoproteins, Trypanosoma; Antigenic Variation; Trypanosoma; Trypanosoma brucei brucei; Genome; Mammals
PubMed: 36215868
DOI: 10.1016/j.mib.2022.102209 -
Microbiology and Molecular Biology... Mar 2014Bacterial genomes are remarkably stable from one generation to the next but are plastic on an evolutionary time scale, substantially shaped by horizontal gene transfer,... (Review)
Review
Bacterial genomes are remarkably stable from one generation to the next but are plastic on an evolutionary time scale, substantially shaped by horizontal gene transfer, genome rearrangement, and the activities of mobile DNA elements. This implies the existence of a delicate balance between the maintenance of genome stability and the tolerance of genome instability. In this review, we describe the specialized genetic elements and the endogenous processes that contribute to genome instability. We then discuss the consequences of genome instability at the physiological level, where cells have harnessed instability to mediate phase and antigenic variation, and at the evolutionary level, where horizontal gene transfer has played an important role. Indeed, this ability to share DNA sequences has played a major part in the evolution of life on Earth. The evolutionary plasticity of bacterial genomes, coupled with the vast numbers of bacteria on the planet, substantially limits our ability to control disease.
Topics: Antigenic Variation; Biological Evolution; DNA Transposable Elements; Gene Transfer, Horizontal; Genome, Bacterial; Genomic Instability; Homologous Recombination; Inteins; Inverted Repeat Sequences
PubMed: 24600039
DOI: 10.1128/MMBR.00035-13 -
Future Microbiology Jul 2010With their reduced genome bound by a single membrane, bacteria of the Mycoplasma species represent some of the simplest autonomous life forms. Yet, these minute... (Review)
Review
With their reduced genome bound by a single membrane, bacteria of the Mycoplasma species represent some of the simplest autonomous life forms. Yet, these minute prokaryotes are able to establish persistent infection in a wide range of hosts, even in the presence of a specific immune response. Clues to their success in host adaptation and survival reside, in part, in a number of gene families that are affected by frequent, stochastic genotypic changes. These genetic events alter the expression, the size and the antigenic structure of abundant surface proteins, thereby creating highly versatile and dynamic surfaces within a clonal population. This phenomenon provides these wall-less pathogens with a means to escape the host immune response and to modulate surface accessibility by masking and unmasking stably expressed components that are essential in host interaction and survival.
Topics: Animals; Antigenic Variation; Gene Expression Regulation, Bacterial; Humans; Immune Evasion; Models, Biological; Mycoplasma; Mycoplasma Infections; Recombination, Genetic
PubMed: 20632806
DOI: 10.2217/fmb.10.71 -
Clinical Microbiology Reviews Jul 2004Phase and antigenic variation result in a heterogenic phenotype of a clonal bacterial population, in which individual cells either express the phase-variable protein(s)... (Review)
Review
Phase and antigenic variation result in a heterogenic phenotype of a clonal bacterial population, in which individual cells either express the phase-variable protein(s) or not, or express one of multiple antigenic forms of the protein, respectively. This form of regulation has been identified mainly, but by no means exclusively, for a wide variety of surface structures in animal pathogens and is implicated as a virulence strategy. This review provides an overview of the many bacterial proteins and structures that are under the control of phase or antigenic variation. The context is mainly within the role of the proteins and variation for pathogenesis, which reflects the main body of literature. The occurrence of phase variation in expression of genes not readily recognizable as virulence factors is highlighted as well, to illustrate that our current knowledge is incomplete. From recent genome sequence analysis, it has become clear that phase variation may be more widespread than is currently recognized, and a brief discussion is included to show how genome sequence analysis can provide novel information, as well as its limitations. The current state of knowledge of the molecular mechanisms leading to phase variation and antigenic variation are reviewed, and the way in which these mechanisms form part of the general regulatory network of the cell is addressed. Arguments both for and against a role of phase and antigenic variation in immune evasion are presented and put into new perspective by distinguishing between a role in bacterial persistence in a host and a role in facilitating evasion of cross-immunity. Finally, examples are presented to illustrate that phase-variable gene expression should be taken into account in the development of diagnostic assays and in the interpretation of experimental results and epidemiological studies.
Topics: Amino Acid Sequence; Antigenic Variation; Bacteria; Bacterial Proteins; Base Sequence; Gene Expression Regulation, Bacterial; Humans; Molecular Sequence Data
PubMed: 15258095
DOI: 10.1128/CMR.17.3.581-611.2004 -
BioEssays : News and Reviews in... Dec 2018The process of antigenic variation in parasitic African trypanosomes is a remarkable mechanism for outwitting the immune system of the mammalian host, but it requires a... (Review)
Review
The process of antigenic variation in parasitic African trypanosomes is a remarkable mechanism for outwitting the immune system of the mammalian host, but it requires a delicate balancing act for the monoallelic expression, folding and transport of a single variant surface glycoprotein (VSG). Only one of hundreds of VSG genes is expressed at time, and this from just one of ≈15 dedicated expression sites. By switching expression of VSGs the parasite presents a continuously shifting antigenic facade leading to prolonged chronic infections lasting months to years. The basics of VSG structure and switching have been known for several decades, but recent studies have brought higher resolution to many aspects this process. New VSG structures, in silico modeling of infections, studies of VSG codon usage, and experimental ablation of VSG expression provide insights that inform how this remarkable system may have evolved.
Topics: Africa; Antigenic Variation; Gene Expression Regulation; Membrane Glycoproteins; Protozoan Proteins; Trypanosoma
PubMed: 30370931
DOI: 10.1002/bies.201800181 -
Annual Review of Virology Sep 2020Seasonal influenza vaccines prevent influenza-related illnesses, hospitalizations, and deaths. However, these vaccines are not as effective as other viral vaccines, and... (Review)
Review
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.
Topics: Antigenic Variation; Evolution, Molecular; History, 20th Century; Humans; Immunogenicity, Vaccine; Influenza Vaccines; Influenza, Human; Orthomyxoviridae
PubMed: 32392457
DOI: 10.1146/annurev-virology-010320-044746