In JoVE (1)

Other Publications (24)

Articles by Pascal Gagneux in JoVE

Other articles by Pascal Gagneux on PubMed

Evidence for an Ancient Selective Sweep in the MHC Class I Gene Repertoire of Chimpanzees

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2002  |  Pubmed ID: 12186979

MHC class I molecules play an essential role in the immune defense against intracellular infections. The hallmark of the MHC is its extensive degree of polymorphism at the population level. However, the present comparison of MHC class I gene intron variation revealed that chimpanzees have experienced a severe repertoire reduction at the orthologues of the HLA-A, -B, and -C loci. The loss of variability predates the (sub)speciation of chimpanzees and did not effect other known gene systems. Therefore the selective sweep in the MHC class I gene may have resulted from a widespread viral infection. Based on the present results and the fact that chimpanzees have a natural resistance to the development of AIDS, we hypothesize that the selective sweep was caused by the chimpanzee-derived simian immunodeficiency virus (SIVcpz), the closest relative of HIV-1, or a closely related retrovirus. Hence, the contemporary chimpanzee populations represent the offspring of AIDS-resistant animals, the survivors of a HIV-like pandemic that took place in the distant past.

The Genus Pan: Population Genetics of an Endangered Outgroup

Trends in Genetics : TIG. Jul, 2002  |  Pubmed ID: 12127763

Human Uptake and Incorporation of an Immunogenic Nonhuman Dietary Sialic Acid

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2003  |  Pubmed ID: 14523234

Humans are genetically unable to produce the sialic acid N-glycolylneuraminic acid (Neu5Gc), because of a mutation that occurred after our last common ancestor with great apes. Although Neu5Gc is presumed absent from normal humans, small amounts have been claimed to exist in human tumors and fetal meconium. We have generated an antibody with high specificity and avidity for Neu5Gc. Fetal tissues, normal adult tissues, and breast carcinomas from humans showed reactivity to this antibody, primarily within secretory epithelia and blood vessels. The presence of small amounts of Neu5Gc was confirmed by MS. Absent any known alternate pathway for its synthesis, we reasoned that these small amounts of Neu5Gc might originate from exogenous sources. Indeed, human cells fed with Neu5Gc incorporated it into endogenous glycoproteins. When normal human volunteers ingested Neu5Gc, a portion was absorbed and eliminated in urine, and small quantities were incorporated into newly synthesized glycoproteins. Neu5Gc has never been reported in plants or microbes to our knowledge. We found that Neu5Gc is rare in poultry and fish, common in milk products, and enriched in red meats. Furthermore, normal humans have variable amounts of circulating IgA, IgM, and IgG antibodies against Neu5Gc, with the highest levels comparable to those of the previously known anti-alpha-galactose xenoreactive antibodies. This finding represents an instance wherein humans absorb and metabolically incorporate a nonhuman dietary component enriched in foods of mammalian origin, even while generating xenoreactive, and potentially autoreactive, antibodies against the same molecule. Potential implications for human diseases are briefly discussed.

Human-specific Regulation of Alpha 2-6-linked Sialic Acids

The Journal of Biological Chemistry. Nov, 2003  |  Pubmed ID: 14500706

Many microbial pathogens and toxins recognize animal cells via cell surface sialic acids (Sias) that are alpha 2-3- or alpha 2-8-linked to the underlying glycan chain. Human influenza A/B viruses are unusual in preferring alpha 2-6-linked Sias, undergoing a switch from alpha 2-3 linkage preference during adaptation from animals to humans. This correlates with the expression of alpha 2-6-linked Sias on ciliated human airway epithelial target cells and of alpha 2-3-linked Sias on secreted soluble airway mucins, which are unable to inhibit virus binding. Given several known differences in Sia biology between humans and apes, we asked whether this pattern of airway epithelial Sia linkages is also human-specific. Indeed, we show that since the last common ancestor with apes, humans underwent a concerted bidirectional switch in alpha 2-6-linked Sia expression between airway epithelial cell surfaces and secreted mucins. This can explain why the chimpanzee appears relatively resistant to experimental infection with human Influenza viruses. Other tissues showed additional examples of human-specific increases or decreases in alpha 2-6-linked Sia expression and only one example of a change specific to certain great apes. Furthermore, while human and great ape leukocytes both express alpha 2-6-linked Sias, only human erythrocytes have markedly up-regulated expression. These cell type-specific changes in alpha 2-6-Sia expression during human evolution represent another example of a human-specific change in Sia biology. Because the data set involves multiple great apes, we can also conclude that Sia linkage expression patterns can be conserved during millions of years of evolution within some vertebrate taxa while undergoing sudden major changes in other closely related ones.

The Chimpanzee Model: Contributions and Considerations for Studies of Hepatitis B Virus

Methods in Molecular Medicine. 2004  |  Pubmed ID: 14762278

Subspecies Composition and Founder Contribution of the Captive U.S. Chimpanzee (Pan Troglodytes) Population

American Journal of Primatology. Oct, 2005  |  Pubmed ID: 16229023

Chimpanzees are presently classified into three subspecies: Pan troglodytes verus from west Africa, P.t. troglodytes from central Africa, and P.t. schweinfurthii from east Africa. A fourth subspecies (P.t. vellerosus), from Cameroon and northern Nigeria, has been proposed. These taxonomic designations are based on geographical origins and are reflected in sequence variation in the first hypervariable region (HVR-I) of the mtDNA D-loop. Although advances have been made in our understanding of chimpanzee phylogenetics, little has been known regarding the subspecies composition of captive chimpanzees. We sequenced part of the mtDNA HVR-I region in 218 African-born population founders and performed a phylogenetic analysis with previously characterized African sequences of known provenance to infer subspecies affiliations. Most founders were P.t. verus (95.0%), distantly followed by the troglodytes schweinfurthii clade (4.6%), and a single P.t. vellerosus (0.4%). Pedigree-based estimates of genomic representation in the descendant population revealed that troglodytes schweinfurthii founder representation was reduced in captivity, vellerosus representation increased due to prolific breeding by a single male, and reproductive variance resulted in uneven representation among male P.t.verus founders. No increase in mortality was evident from between-subspecies interbreeding, indicating a lack of outbreeding depression. Knowledge of subspecies and their genomic representation can form the basis for phylogenetically informed genetic management of extant chimpanzees to preserve rare genetic variation for research, conservation, or possible future breeding.

The Ethics of Research on Great Apes

Nature. Sep, 2005  |  Pubmed ID: 16136111

Evolution of Human-chimpanzee Differences in Malaria Susceptibility: Relationship to Human Genetic Loss of N-glycolylneuraminic Acid

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2005  |  Pubmed ID: 16126901

Chimpanzees are the closest evolutionary cousins of humans, sharing >99% identity in most protein sequences. Plasmodium falciparum is the major worldwide cause of malaria mortality. Plasmodium reichenowi, a morphologically identical and genetically very similar parasite, infects chimpanzees but not humans. Conversely, experimental P. falciparum infection causes brief moderate parasitization and no severe infection in chimpanzees. This surprising host specificity remains unexplained. We modified and enhanced traditional methods for measuring sialic acid (Sia)-dependent recognition of glycophorins by merozoite erythrocyte-binding proteins, eliminating interference caused by endogenous Sias on transfected cells, and by using erythroleukemia cells to allow experimental manipulation of Sia content. We present evidence that these remarkable differences among such closely related host-parasite pairs is caused by species-specific erythrocyte-recognition profiles, apparently related to the human-specific loss of the common primate Sia N-glycolylneuraminic acid. The major merozoite-binding protein erythrocyte-binding antigen-175 of P. falciparum apparently evolved to take selective advantage of the excess of the Sia N-acetylneuraminic acid (the precursor of N-glycolylneuraminic acid) on human erythrocytes. The contrasting preference of P. reichenowi erythrocyte-binding antigen-175 for N-glycolylneuraminic acid is likely the ancestral condition. The surprising ability of P. falciparum to cause disease in New World Aotus monkeys (geographically isolated from P. falciparum until arrival of peoples from the Old World) can be explained by parallel evolution of a human-like Sia expression pattern in these distantly related primates. These results also have implications for the prehistory of hominids and for the genetic origins and recent emergence of P. falciparum as a major human pathogen.

Loss of Siglec Expression on T Lymphocytes During Human Evolution

Proceedings of the National Academy of Sciences of the United States of America. May, 2006  |  Pubmed ID: 16682635

We report here that human T cells give much stronger proliferative responses to specific activation via the T cell receptor (TCR) than those from chimpanzees, our closest evolutionary relatives. Nonspecific activation using phytohemagglutinin was robust in chimpanzee T cells, indicating that the much lower response to TCR simulation is not due to any intrinsic inability to respond to an activating stimulus. CD33-related Siglecs are inhibitory signaling molecules expressed on most immune cells and are thought to down-regulate cellular activation pathways via cytosolic immunoreceptor tyrosine-based inhibitory motifs. Among human immune cells, T lymphocytes are a striking exception, expressing little to none of these molecules. In stark contrast, we find that T lymphocytes from chimpanzees as well as the other closely related "great apes" (bonobos, gorillas, and orangutans) express several CD33-related Siglecs on their surfaces. Thus, human-specific loss of T cell Siglec expression occurred after our last common ancestor with great apes, potentially resulting in an evolutionary difference with regard to inhibitory signaling. We confirmed this by studying Siglec-5, which is prominently expressed on chimpanzee lymphocytes, including CD4 T cells. Ab-mediated clearance of Siglec-5 from chimpanzee T cells enhanced TCR-mediated activation. Conversely, primary human T cells and Jurkat cells transfected with Siglec-5 become less responsive; i.e., they behave more like chimpanzee T cells. This human-specific loss of T cell Siglec expression associated with T cell hyperactivity may help explain the strikingly disparate prevalence and severity of T cell-mediated diseases such as AIDS and chronic active hepatitis between humans and chimpanzees.

Molecular Assays for Detection of Falcon Adenovirus

Journal of Veterinary Diagnostic Investigation : Official Publication of the American Association of Veterinary Laboratory Diagnosticians, Inc. Sep, 2007  |  Pubmed ID: 17823390

Falcon adenovirus is a newly recognized member of the family Aviadenoviridae and includes 2 closely related strains that are pathogenic to several species of falcons. Peregrine falcons appear to be one of the primary reservoirs, but recent outbreaks suggest that other carrier species probably exist. To allow screening of captive birds for virus shedding and investigations of disease outbreaks, conventional and real-time, quantitative polymerase chain reaction (PCR) assays and an in situ hybridization technique were developed. The diagnostic protocols were used on tissue and fecal samples from 7 species or subspecies of falcons infected with adenovirus as well as adenoviruses from other birds and mammals. The assays were specific for falcon adenovirus and detected both strains of virus in fecal samples from living animals or frozen and formalin-fixed, paraffinized tissues. Together with established serologic tests for falcon adenovirus, these molecular assays are valuable tools for management and conservation of falcons in captivity and the wild.

Primate TNF Promoters Reveal Markers of Phylogeny and Evolution of Innate Immunity

PloS One. 2007  |  Pubmed ID: 17637837

Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry.

Functional Evidence for Differences in Sperm Competition in Humans and Chimpanzees

American Journal of Physical Anthropology. Oct, 2007  |  Pubmed ID: 17632799

Sperm competition occurs when the gametes of or more males compete for opportunities to fertilize a given set of ova. Previous studies have demonstrated that certain morphological characteristics are affected by sperm competition intensity (e.g. relative testes size and sperm midpiece volume). This study examined whether aspects of sperm energetics may also be affected by sexual selection. We compared the membrane potential of mitochondria in live sperm between H. sapiens (single partner mating system) and P. troglodytes (multiple partner mating system). Flow cytometry of sperm stained with the carbocyanine fluorescent dye JC-1 (an assay for mitochondrial membrane potential) revealed marked differences in red fluorescence intensity. P. troglodytes sperm showed significantly higher mitochondrial membrane potential. Mitochondria provide a substantial part of the energy required for sperm motility. A higher mitochondrial loading may therefore be associated with enhanced sperm motility and/or longevity. Additionally, examination of JC-1 red fluorescence levels before and after in vitro capacitation revealed further differences. Whereas chimpanzee sperm showed maintenance of membrane potential after capacitation (in some cases even an increase), sperm from humans consistently showed reduction in membrane potential. These results indicate that the sperm of human beings and chimpanzees exhibit marked differences in mitochondrial function, which are affected by selection pressures relating to sperm competition and that these pressures differ significantly between humans and chimpanzees.

Evolution of Carbohydrate Antigens--microbial Forces Shaping Host Glycomes?

Glycobiology. May, 2007  |  Pubmed ID: 17237137

Many glycans show remarkably discontinuous distribution across evolutionary lineages. These differences play major roles when organisms belonging to different lineages interact as host-pathogen or host-symbiont. Certain lineage-specific glycans have become important signals for multicellular host organisms, which use them as molecular signatures of their pathogens and symbionts through recognition by a toolkit of innate defense molecules. In turn, pathogens have evolved to exploit host lineage-specific glycans and are constantly shaping the glycomes of their hosts. These interactions take place in the face of numerous critical endogenous functions played by glycans within host organisms. Whether due to simple evolutionary divergence or adaptive changes under natural selection resulting from endogenous functional requirements, once different lineages elaborate on differential glycomes these mutual differences provide opportunities for host exploitation and/or pathogen defense between lineages. Such phylogenetic molecular recognition mechanisms will augment and likely contribute to the maintenance of lineage-specific differences in glycan repertoires.

The Use of Optical Tweezers to Study Sperm Competition and Motility in Primates

Journal of the Royal Society, Interface / the Royal Society. Mar, 2008  |  Pubmed ID: 17650470

Optical trapping is a non-invasive biophysical tool which has been widely applied to study physiological and biomechanical properties of cells. Using laser 'tweezers' in combination with custom-designed computer tracking algorithms, the swimming speeds and the relative swimming forces of individual sperm can be measured in real time. This combination of physical and engineering tools has been used to examine the evolutionary effect of sperm competition in primates. The results demonstrate a correlation between mating type and sperm motility: sperm from polygamous (multi-partner) primate species swim faster and with greater force than sperm from polygynous (single partner) primate species. In addition, sperm swimming force linearly increases with swimming speed for each species, yet the regression relating the two parameters is species specific. These results demonstrate the feasibility of using these tools to study rapidly moving (microm s(-1)) biological cells.

Human-specific Evolution of Sialic Acid Targets: Explaining the Malignant Malaria Mystery?

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2009  |  Pubmed ID: 19717444

Innovations in Host and Microbial Sialic Acid Biosynthesis Revealed by Phylogenomic Prediction of Nonulosonic Acid Structure

Proceedings of the National Academy of Sciences of the United States of America. Aug, 2009  |  Pubmed ID: 19666579

Sialic acids (Sias) are nonulosonic acid (NulO) sugars prominently displayed on vertebrate cells and occasionally mimicked by bacterial pathogens using homologous biosynthetic pathways. It has been suggested that Sias were an animal innovation and later emerged in pathogens by convergent evolution or horizontal gene transfer. To better illuminate the evolutionary processes underlying the phenomenon of Sia molecular mimicry, we performed phylogenomic analyses of biosynthetic pathways for Sias and related higher sugars derived from 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids. Examination of approximately 1,000 sequenced microbial genomes indicated that such biosynthetic pathways are far more widely distributed than previously realized. Phylogenetic analysis, validated by targeted biochemistry, was used to predict NulO types (i.e., neuraminic, legionaminic, or pseudaminic acids) expressed by various organisms. This approach uncovered previously unreported occurrences of Sia pathways in pathogenic and symbiotic bacteria and identified at least one instance in which a human archaeal symbiont tentatively reported to express Sias in fact expressed the related pseudaminic acid structure. Evaluation of targeted phylogenies and protein domain organization revealed that the "unique" Sia biosynthetic pathway of animals was instead a much more ancient innovation. Pathway phylogenies suggest that bacterial pathogens may have acquired Sia expression via adaptation of pathways for legionaminic acid biosynthesis, one of at least 3 evolutionary paths for de novo Sia synthesis. Together, these data indicate that some of the long-standing paradigms in Sia biology should be reconsidered in a wider evolutionary context of the extended family of NulO sugars.

Sexual Selection by Female Immunity Against Paternal Antigens Can Fix Loss of Function Alleles

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2011  |  Pubmed ID: 21987817

Humans lack the common mammalian cell surface molecule N-glycolylneuraminic acid (Neu5Gc) due to a CMAH gene inactivation, which occurred approximately three million years ago. Modern humans produce antibodies specific for Neu5Gc. We hypothesized that anti-Neu5Gc antibodies could enter the female reproductive tract and target Neu5Gc-positive sperm or fetal tissues, reducing reproductive compatibility. Indeed, female mice with a human-like Cmah(-/-) mutation and immunized to express anti-Neu5Gc antibodies show lower fertility with Neu5Gc-positive males, due to prezygotic incompatibilities. Human anti-Neu5Gc antibodies are also capable of targeting paternally derived antigens and mediate cytotoxicity against Neu5Gc-bearing chimpanzee sperm in vitro. Models of populations polymorphic for such antigens show that reproductive incompatibility by female immunity can drive loss-of-function alleles to fixation from moderate initial frequencies. Initially, the loss of a cell-surface antigen can occur due to drift in isolated populations or when natural selection favors the loss of a receptor exploited by pathogens, subsequently the same loss-of-function allele can come under sexual selection because it avoids being targeted by the female immune system. Thus, we provide evidence of a link between sexual selection and immune function: Antigenicity in females can select against foreign paternal antigens on sperm and rapidly fix loss-of-function alleles. Similar circumstances existed when the CMAH null allele was polymorphic in ancestral hominins, just before the divergence of Homo from australopithecines.

MtDNA Diversity in Azara's Owl Monkeys (Aotus Azarai Azarai) of the Argentinean Chaco

American Journal of Physical Anthropology. Oct, 2011  |  Pubmed ID: 21826638

Owl monkeys (Aotus spp.) inhabit much of South America yet represent an enigmatic evolutionary branch among primates. While morphological, cytogenetic, and immunological evidence suggest that owl monkey populations have undergone isolation and diversification since their emergence in the New World, problems with adjacent species ranges, and sample provenance have complicated efforts to characterize genetic variation within the genus. As a result, the phylogeographic history of owl monkey species and subspecies remains unclear, and the extent of genetic diversity at the population level is unknown. To explore these issues, we analyzed mitochondrial DNA (mt DNA) variation in a population of wild Azara's owl monkeys (Aotus azarai azarai) living in the Gran Chaco region of Argentina. We sequenced the complete mitochondrial genome from one individual (16,585 base pairs (bp)) and analyzed 1,099 bp of the hypervariable control region (CR) and 696 bp of the cytochrome oxidase II (COII) gene in 117 others. In addition, we sequenced the mitochondrial genome (16,472 bp) of one Nancy Ma's owl monkey (A. nancymaae). Based on the whole mtDNA and COII data, we observed an ancient phylogeographic discontinuity among Aotus species living north, south, and west of the Amazon River that began more than eight million years ago. Our population analyses identified three major CR lineages and detected a high level of haplotypic diversity within A. a. azarai. These data point to a recent expansion of Azara's owl monkeys into the Argentinean Chaco. Overall, we provide a detailed view of owl monkey mtDNA variation at genus, species, and population levels.

Evolutionary Glycomics: Characterization of Milk Oligosaccharides in Primates

Journal of Proteome Research. Apr, 2011  |  Pubmed ID: 21214271

Free oligosaccharides are abundant components of mammalian milk and have primary roles as prebiotic compounds, in immune defense, and in brain development. A mass spectrometry-based technique is applied to profile milk oligosaccharides from apes (chimpanzee, gorilla, and siamang), new world monkeys (golden lion tamarin and common marmoset), and an old world monkey (rhesus). The purpose of this study is to evaluate the patterns of primate milk oligosaccharide composition from a phylogenetic perspective to assess the extent to which the compositions of HMOs derives from ancestral primate patterns as opposed to more recent evolutionary events. Milk oligosaccharides were quantitated by nanoflow liquid chromatography on chip-based devices. The relative abundances of fucosylated and sialylated milk oligosaccharides in primates were also determined. For a systematic and comprehensive study of evolutionary patterns of milk oligosaccharides, cluster analysis of primate milk was performed using the chromatographic profile. In general, the oligosaccharides in primate milk, including humans, are more complex and exhibit greater diversity compared to the ones in nonprimate milk. A detailed comparison of the oligosaccharides across evolution revealed nonsequential developmental pattern, that is, that primate milk oligosaccharides do not necessarily cluster according to the primate phylogeny. This report represents the first comprehensive and quantitative effort to profile and elucidate the structures of free milk oligosaccharides so that they can be related to glycan function in different primates.

The Annotation of the Asparagine N-linked Glycosylation Pathway in the Reactome Database

Glycobiology. Nov, 2011  |  Pubmed ID: 21199820

Asparagine N-linked glycosylation is one of the most important forms of protein post-translational modification in eukaryotes and is one of the first metabolic pathways described at a biochemical level. Here, we report a new annotation of this pathway for the Human species, published after passing a peer-review process in Reactome. The new annotation presented here offers a high level of detail and provides references and descriptions for each reaction, along with integration with GeneOntology and other databases. The open-source approach of Reactome toward annotation encourages feedback from its users, making it easier to keep the annotation of this pathway updated with future knowledge. Reactome's web interface allows easy navigation between steps involved in the pathway to compare it with other pathways and resources in other scientific databases and to export it to BioPax and SBML formats, making it accessible for computational studies. This new entry in Reactome expands and complements the annotations already published in databases for biological pathways and provides a common reference to researchers interested in studying this important pathway in the human species. Finally, we discuss the status of the annotation of this pathway and point out which steps are worth further investigation or need better experimental validation.

Sialidases on Mammalian Sperm Mediate Deciduous Sialylation During Capacitation

The Journal of Biological Chemistry. Sep, 2012  |  Pubmed ID: 22989879

Sialic acids mediate many biological functions, including molecular recognition during development and immune response and fertilization. A sialic acid-rich glycocalyx coats the surface of sperm, allowing them to survive as allogeneic cells in the female reproductive tract despite female immunity. During capacitation, sperm lose a fraction of their sialic acids. We quantified shed sialic acid monosaccharides released from capacitated sperm and measured sperm sialidase activity. We report the presence of two sialidases (neuraminidases Neu1 and Neu3) on mammalian sperm. These are themselves shed from sperm during capacitation. Inhibiting Sialidase activity interferes with the sperm binding to the zona pellucida of the ovum. A survey of human sperm samples for the presence of sialidases NEU1 and NEU3 identified a lack of one or both sialidases from sperm of some male idiopathic infertility cases. The results contribute new insights into the dynamic remodeling of the sperm glycocalyx prior to fertilization.

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups: RESISTANCE OF α2-8-LINKED N-GLYCOLYLNEURAMINIC ACID TO ENZYMATIC CLEAVAGE

The Journal of Biological Chemistry. Aug, 2012  |  Pubmed ID: 22692207

The sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative N-glycolylneuraminic acid (Neu5Gc) differ by one oxygen atom. CMP-Neu5Gc is synthesized from CMP-Neu5Ac, with Neu5Gc representing a highly variable fraction of total Sias in various tissues and among different species. The exception may be the brain, where Neu5Ac is abundant and Neu5Gc is reported to be rare. Here, we confirm this unusual pattern and its evolutionary conservation in additional samples from various species, concluding that brain Neu5Gc expression has been maintained at extremely low levels over hundreds of millions of years of vertebrate evolution. Most explanations for this pattern do not require maintaining neural Neu5Gc at such low levels. We hypothesized that resistance of α2-8-linked Neu5Gc to vertebrate sialidases is the detrimental effect requiring the relative absence of Neu5Gc from brain. This linkage is prominent in polysialic acid (polySia), a molecule with critical roles in vertebrate neural development. We show that Neu5Gc is incorporated into neural polySia and does not cause in vitro toxicity. Synthetic polymers of Neu5Ac and Neu5Gc showed that mammalian and bacterial sialidases are much less able to hydrolyze α2-8-linked Neu5Gc at the nonreducing terminus. Notably, this difference was not seen with acid-catalyzed hydrolysis of polySias. Molecular dynamics modeling indicates that differences in the three-dimensional conformation of terminal saccharides may partly explain reduced enzymatic activity. In keeping with this, polymers of N-propionylneuraminic acid are sensitive to sialidases. Resistance of Neu5Gc-containing polySia to sialidases provides a potential explanation for the rarity of Neu5Gc in the vertebrate brain.

Membrane-Bound Mucins and Mucin Terminal Glycans Expression in Idiopathic or Helicobacter Pylori, NSAID Associated Peptic Ulcers

Digestive Diseases and Sciences. May, 2012  |  Pubmed ID: 22576713

BACKGROUND: The ratio of Helicobacter pylori/NSAID-negative gastric ulcers is increasing. Idiopathic gastric ulcers have unique clinical and endoscopic features, and are associated with more bleeding complications and a higher mortality. Alterations in gastric mucin expression and sialylation pattern may be important in ulcer pathogenesis. AIMS: The purpose of this study was to determine the expression pattern of membrane-bound mucins and side chain sugars in H. pylori associated-, NSAID-, and idiopathic-gastric ulcers. METHODS: We randomly selected 92 patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for T-cell CD4/CD8, MUC1, MUC4, MUC17, and ECA and SNA lectins staining was performed on sections from the ulcer margins. Inflammation score was assessed according to the Sydney system. RESULTS: Bleeding and mortality rates were significantly higher in group 4. CD4 positive T cell count was higher in H. pylori positive patients (P = 0.009). Staining intensity of MUC17 was higher in group 1 than in group 4, foveola and glands alike, with 11.50 ± 3.47 versus 6.80 ± 4.02, and 9.61 ± 4.26 versus 7.59 ± 3.26, respectively (P < 0.0001). This was a mirror image with MUC1. SNA lectin staining was increased in group 4, in parallel to MUC1 expression, indicating more abundant α2-6 sialylation in that group. CONCLUSIONS: Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was demonstrated for MUC1. This observation might be important, since different mucins with altered sialylation patterns likely differ in their protection efficiency against acid and pepsin.

Multifarious Roles of Sialic Acids in Immunity

Annals of the New York Academy of Sciences. Apr, 2012  |  Pubmed ID: 22524423

Sialic acids are a diverse family of monosaccharides widely expressed on all cell surfaces of vertebrates and so-called "higher" invertebrates, and on certain bacteria that interact with vertebrates. This overview surveys examples of biological roles of sialic acids in immunity, with emphasis on an evolutionary perspective. Given the breadth of the subject, the treatment of individual topics is brief. Subjects discussed include biophysical effects regulation of factor H; modulation of leukocyte trafficking via selectins; Siglecs in immune cell activation; sialic acids as ligands for microbes; impact of microbial and endogenous sialidases on immune cell responses; pathogen molecular mimicry of host sialic acids; Siglec recognition of sialylated pathogens; bacteriophage recognition of microbial sialic acids; polysialic acid modulation of immune cells; sialic acids as pathogen decoys or biological masks; modulation of immunity by sialic acid O-acetylation; sialic acids as antigens and xeno-autoantigens; antisialoglycan antibodies in reproductive incompatibility; and sialic-acid-based blood groups.

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