Expression of the Blood-Group-Related Gene B4galnt2 Alters Susceptibility to Salmonella Infection

Glycans play important roles in host-microbe interactions. Tissue-specific expression patterns of the blood group glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) are variable in wild mouse populations, and loss of B4galnt2 expression is associated with altered intestinal microbiota. We hypothesized that variation in B4galnt2 expression alters susceptibility to intestinal pathogens. To test this, we challenged mice genetically engineered to express different B4galnt2 tissue-specific patterns with a Salmonella Typhimurium infection model. We found B4galnt2 intestinal expression was strongly associated with bacterial community composition and increased Salmonella susceptibility as evidenced by increased intestinal inflammatory cytokines and infiltrating immune cells. Fecal transfer experiments demonstrated a crucial role of the B4galnt2-dependent microbiota in conferring susceptibility to intestinal inflammation, while epithelial B4galnt2 expression facilitated epithelial invasion of S. Typhimurium. These data support a critical role for B4galnt2 in gastrointestinal infections. We speculate that B4galnt2-specific differences in host susceptibility to intestinal pathogens underlie the strong signatures of balancing selection observed at the B4galnt2 locus in wild mouse populations.

[1]  Jacqueline A. Keane,et al.  Epithelial IL-22RA1-Mediated Fucosylation Promotes Intestinal Colonization Resistance to an Opportunistic Pathogen , 2014, Cell host & microbe.

[2]  R. Kannagi,et al.  Therapeutic adenoviral gene transfer of a glycosyltransferase for prevention of peritoneal dissemination and metastasis of gastric cancer , 2014, Cancer Gene Therapy.

[3]  B. Becher,et al.  Innate lymphoid cells regulate intestinal epithelial cell glycosylation , 2014, Science.

[4]  Rustem F. Ismagilov,et al.  Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness , 2014, Nature.

[5]  M. Mortuaire,et al.  B4GALNT2 gene expression controls the biosynthesis of Sda and sialyl Lewis X antigens in healthy and cancer human gastrointestinal tract. , 2014, The international journal of biochemistry & cell biology.

[6]  F. Haesebrouck,et al.  A comparison of Helicobacter pylori and non‐Helicobacter pylori Helicobacter spp. Binding to Canine Gastric Mucosa with Defined Gastric Glycophenotype , 2014, Helicobacter.

[7]  F. Bongers,et al.  Changing drivers of species dominance during tropical forest succession , 2014 .

[8]  T. Hennet,et al.  Selective proliferation of intestinal Barnesiella under fucosyllactose supplementation in mice , 2014, British Journal of Nutrition.

[9]  R. Gomulkiewicz,et al.  Revisiting Darwin's conundrum reveals a twist on the relationship between phylogenetic distance and invasibility , 2013, Proceedings of the National Academy of Sciences.

[10]  D. Monniaux,et al.  The Highly Prolific Phenotype of Lacaune Sheep Is Associated with an Ectopic Expression of the B4GALNT2 Gene within the Ovary , 2013, PLoS genetics.

[11]  B. Weimer,et al.  Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens , 2013, Nature.

[12]  P. Edwards,et al.  Convergent succession of plant communities is linked to species’ functional traits , 2013 .

[13]  Bernard Henrissat,et al.  The abundance and variety of carbohydrate-active enzymes in the human gut microbiota , 2013, Nature Reviews Microbiology.

[14]  M. Hartmann,et al.  Temporal stability of the mouse gut microbiota in relation to innate and adaptive immunity. , 2013, Environmental microbiology reports.

[15]  Simon A. Levin,et al.  Monographs in Population Biology , 2013 .

[16]  T. van der Poll,et al.  Host–Pathogen Interaction in Invasive Salmonellosis , 2012, PLoS pathogens.

[17]  A. Young,et al.  Fecal Lipocalin 2, a Sensitive and Broadly Dynamic Non-Invasive Biomarker for Intestinal Inflammation , 2012, PloS one.

[18]  Jonathan Friedman,et al.  Inferring Correlation Networks from Genomic Survey Data , 2012, PLoS Comput. Biol..

[19]  C. Gieger,et al.  Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. , 2012, Journal of hepatology.

[20]  D. Tilman,et al.  Phylogenetic diversity promotes ecosystem stability , 2012 .

[21]  Nicholas Mirotchnick,et al.  Phylogenetic diversity and the functioning of ecosystems. , 2012, Ecology letters.

[22]  E. Martens,et al.  How glycan metabolism shapes the human gut microbiota , 2012, Nature Reviews Microbiology.

[23]  J. Gordon,et al.  Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin 2. , 2012, Cell host & microbe.

[24]  F. Bäckhed,et al.  Expression of the blood-group-related glycosyltransferase B4galnt2 influences the intestinal microbiota in mice , 2012, The ISME Journal.

[25]  K. Ley,et al.  Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. , 2011, Blood.

[26]  Philip Rosenstiel,et al.  Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype , 2011, Proceedings of the National Academy of Sciences.

[27]  J. Baines,et al.  Long-term balancing selection at the blood group-related gene B4galnt2 in the genus Mus (Rodentia; Muridae). , 2011, Molecular biology and evolution.

[28]  R. Nielsen,et al.  Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution , 2011, PLoS genetics.

[29]  E. Pamer,et al.  Role of the commensal microbiota in normal and pathogenic host immune responses. , 2011, Cell host & microbe.

[30]  P. Reich,et al.  High plant diversity is needed to maintain ecosystem services , 2011, Nature.

[31]  A. Moran,et al.  Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract , 2011, Gut.

[32]  K. Nelson,et al.  Draft Genome Sequence of Turicibacter sanguinis PC909, Isolated from Human Feces , 2010, Journal of bacteriology.

[33]  James Rosindell,et al.  Unified neutral theory of biodiversity and biogeography , 2010, Scholarpedia.

[34]  Miquel De Cáceres,et al.  Improving indicator species analysis by combining groups of sites , 2010 .

[35]  Dror Berel,et al.  Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. , 2010, Human molecular genetics.

[36]  J. Sirard,et al.  The Microbiota Mediates Pathogen Clearance from the Gut Lumen after Non-Typhoidal Salmonella Diarrhea , 2010, PLoS pathogens.

[37]  Campbell O. Webb,et al.  Picante: R tools for integrating phylogenies and ecology , 2010, Bioinform..

[38]  Paramvir S. Dehal,et al.  FastTree 2 – Approximately Maximum-Likelihood Trees for Large Alignments , 2010, PloS one.

[39]  M. Loreau.  Linking biodiversity and ecosystems: towards a unifying ecological theory , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[40]  C. von Mering,et al.  Like Will to Like: Abundances of Closely Related Species Can Predict Susceptibility to Intestinal Colonization by Pathogenic and Commensal Bacteria , 2010, PLoS pathogens.

[41]  J. Borneman,et al.  Bacteria Associated with Immunoregulatory Cells in Mice , 2009, Applied and Environmental Microbiology.

[42]  Jeremiah D. Degenhardt,et al.  Targets of balancing selection in the human genome. , 2009, Molecular biology and evolution.

[43]  A. Dell,et al.  Fut2-null mice display an altered glycosylation profile and impaired BabA-mediated Helicobacter pylori adhesion to gastric mucosa. , 2009, Glycobiology.

[44]  N. Stanietsky,et al.  The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity , 2009, Proceedings of the National Academy of Sciences.

[45]  Martin Hartmann,et al.  Introducing mothur: Open-Source, Platform-Independent, Community-Supported Software for Describing and Comparing Microbial Communities , 2009, Applied and Environmental Microbiology.

[46]  N. Kaminski,et al.  FACS-assisted microarray profiling implicates novel genes and pathways in zebrafish gastrointestinal tract development. , 2009, Gastroenterology.

[47]  J. Bertranpetit,et al.  A natural history of FUT2 polymorphism in humans. , 2009, Molecular biology and evolution.

[48]  G. Hansson,et al.  A complex, but uniform O-glycosylation of the human MUC2 mucin from colonic biopsies analyzed by nanoLC/MSn. , 2009, Glycobiology.

[49]  Michael D. George,et al.  Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. , 2009, Cell host & microbe.

[50]  M. Fukuda,et al.  Roles of gastric mucin-type O-glycans in the pathogenesis of Helicobacter pylori infection. , 2009, Glycobiology.

[51]  M. Fukuda,et al.  Role of sulfated O-glycans expressed by high endothelial venule-like vessels in pathogenesis of chronic inflammatory gastrointestinal diseases. , 2009, Biological & pharmaceutical bulletin.

[52]  A. Bäumler,et al.  Salmonella enterica serotype Typhimurium Std fimbriae bind terminal α(1,2)fucose residues in the cecal mucosa , 2009, Molecular microbiology.

[53]  D. Tautz,et al.  Selection on cis-Regulatory Variation at B4galnt2 and Its Influence on von Willebrand Factor in House Mice , 2008, Molecular biology and evolution.

[54]  Todd H. Oakley,et al.  Evolutionary history and the effect of biodiversity on plant productivity , 2008, Proceedings of the National Academy of Sciences.

[55]  Les Dethlefsen,et al.  The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S rRNA Sequencing , 2008, PLoS biology.

[56]  Michael D. George,et al.  T Cells Help To Amplify Inflammatory Responses Induced by Salmonella enterica Serotype Typhimurium in the Intestinal Mucosa , 2008, Infection and Immunity.

[57]  B. Finlay,et al.  Chronic enteric salmonella infection in mice leads to severe and persistent intestinal fibrosis. , 2008, Gastroenterology.

[58]  P. Tucker,et al.  The endothelial-specific regulatory mutation, Mvwf1, is a common mouse founder allele , 2008, Mammalian Genome.

[59]  W. Ludwig,et al.  SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB , 2007, Nucleic acids research.

[60]  G. Dougan,et al.  Salmonella enterica Serovar Typhimurium Exploits Inflammation to Compete with the Intestinal Microbiota , 2007, PLoS biology.

[61]  S. Carpenter,et al.  Stability and Diversity of Ecosystems , 2007, Science.

[62]  J. Tiedje,et al.  Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy , 2007, Applied and Environmental Microbiology.

[63]  A. Varki.  Nothing in Glycobiology Makes Sense, except in the Light of Evolution , 2006, Cell.

[64]  K. Hornik,et al.  A Lego System for Conditional Inference , 2006 .

[65]  Marti J. Anderson,et al.  Distance‐Based Tests for Homogeneity of Multivariate Dispersions , 2006, Biometrics.

[66]  R. Knight,et al.  UniFrac: a New Phylogenetic Method for Comparing Microbial Communities , 2005, Applied and Environmental Microbiology.

[67]  Toshio Shimizu,et al.  Introduction of Sd(a) carbohydrate antigen in gastrointestinal cancer cells eliminates selectin ligands and inhibits metastasis. , 2005, Cancer research.

[68]  B. Finlay,et al.  Salmonella enterica Serovar Typhimurium Pathogenicity Island 2 Is Necessary for Complete Virulence in a Mouse Model of Infectious Enterocolitis , 2005, Infection and Immunity.

[69]  Benjamin P. Westover,et al.  Glycan Foraging in Vivo by an Intestine-Adapted Bacterial Symbiont , 2005, Science.

[70]  J. Marth,et al.  Core 2 branching beta1,6-N-acetylglucosaminyltransferase and high endothelial cell N-acetylglucosamine-6-sulfotransferase exert differential control over B- and T-lymphocyte homing to peripheral lymph nodes. , 2004, Blood.

[71]  Mariella Chiricolo,et al.  Molecular cloning of the human beta1,4 N-acetylgalactosaminyltransferase responsible for the biosynthesis of the Sd(a) histo-blood group antigen: the sequence predicts a very long cytoplasmic domain. , 2003, Journal of biochemistry.

[72]  J. Lowe,et al.  Glycan-dependent leukocyte adhesion and recruitment in inflammation. , 2003, Current opinion in cell biology.

[73]  Xi Jiang,et al.  Human susceptibility and resistance to Norwalk virus infection , 2003, Nature Medicine.

[74]  M. Hogardt,et al.  Pretreatment of Mice with Streptomycin Provides a Salmonella enterica Serovar Typhimurium Colitis Model That Allows Analysis of Both Pathogen and Host , 2003, Infection and Immunity.

[75]  G. Ruiz-Palacios,et al.  Campylobacter jejuni Binds Intestinal H(O) Antigen (Fucα1, 2Galβ1, 4GlcNAc), and Fucosyloligosaccharides of Human Milk Inhibit Its Binding and Infection* , 2003, The Journal of Biological Chemistry.

[76]  S. Knapp,et al.  The Unified Neutral Theory of Biodiversity and Biogeography , 2003 .

[77]  Campbell O. Webb,et al.  Phylogenies and Community Ecology , 2002 .

[78]  O. Petchey,et al.  Species richness, environmental fluctuations, and temporal change in total community biomass , 2002 .

[79]  R. Zbinden,et al.  Turicibacter sanguinis gen. nov., sp. nov., a novel anaerobic, Gram-positive bacterium. , 2002, International journal of systematic and evolutionary microbiology.

[80]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[81]  B. Schmid,et al.  Diversity-dependent production can decrease the stability of ecosystem functioning , 2002, Nature.

[82]  Y. Kim,et al.  Sd(a)-antigen-like structures carried on core 3 are prominent features of glycans from the mucin of normal human descending colon. , 2001, The Biochemical journal.

[83]  S. Henry.  Molecular diversity in the biosynthesis of GI tract glycoconjugates. A blood-group-related chart of microorganism receptors. , 2001, Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine.

[84]  S. McNaughton,et al.  Determinants of biodiversity regulate compositional stability of communities , 1999, Nature.

[85]  A. Varki,et al.  Evolutionary considerations in relating oligosaccharide diversity to biological function. , 1999, Glycobiology.

[86]  Carolyn R. Bertozzi,et al.  Essentials of Glycobiology , 1999 .

[87]  M. Loreau,et al.  Biodiversity and ecosystem productivity in a fluctuating environment: the insurance hypothesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[88]  K. Mohlke,et al.  Mvwf, a Dominant Modifier of Murine von Willebrand Factor, Results from Altered Lineage-Specific Expression of a Glycosyltransferase , 1999, Cell.

[89]  A. Hastings,et al.  Weak trophic interactions and the balance of nature , 1998, Nature.

[90]  D. Doak,et al.  The Statistical Inevitability of Stability‐Diversity Relationships in Community Ecology , 1998, The American Naturalist.

[91]  K. Cooney,et al.  A novel modifier gene for plasma von Willebrand factor level maps to distal mouse chromosome 11. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Y. Natori,et al.  Detection of N‐acetylgalactosaminyltransferase mRNA which determines expression of Sda blood group carbohydrate structure in human gastrointestinal mucosa and cancer , 1996, International journal of cancer.

[93]  M. Neutra,et al.  Adherence of Salmonella typhimurium to Caco-2 cells: identification of a glycoconjugate receptor , 1996, Infection and immunity.

[94]  D. Tilman.  Biodiversity: Population Versus Ecosystem Stability , 1995 .

[95]  L. Magee,et al.  R 2 Measures Based on Wald and Likelihood Ratio Joint Significance Tests , 1990 .

[96]  L. Lefrançois.  Carbohydrate differentiation antigens of murine T cells: expression on intestinal lymphocytes and intestinal epithelium. , 1987, Journal of immunology.

[97]  J. Cartron,et al.  Identification of a α-NeuAc-(2→3)-β-d-galactopyranosyl N-acetyl-β-d-galactosaminyltransferase in human kidney , 1986 .

[98]  J. Cartron,et al.  Identification of a novel ganglioside on erythrocytes with blood group Cad specificity. , 1985, The Journal of biological chemistry.

[99]  B. Stocker,et al.  Genes aroA and serC of Salmonella typhimurium constitute an operon , 1985, Journal of bacteriology.

[100]  S. McNaughton,et al.  Stability and diversity of ecological communities , 1978, Nature.

[101]  C. S. Holling.  Resilience and Stability of Ecological Systems , 1973 .

[102]  ROBERT M. MAY,et al.  Will a Large Complex System be Stable? , 1972, Nature.

[103]  MARK R. GARDNER,et al.  Connectance of Large Dynamic (Cybernetic) Systems: Critical Values for Stability , 1970, Nature.

[104]  S. Goldhor.  Ecology , 1964, The Yale Journal of Biology and Medicine.

[105]  R. Macarthur.  Fluctuations of Animal Populations and a Measure of Community Stability , 1955 .

[106]  M. Bohnhoff,et al.  Effect of Streptomycin on Susceptibility of Intestinal Tract to Experimental Salmonella Infection.∗ , 1954, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[107]  W. Potts,et al.  The Nature of Selection on the Major Histocompatibility Complex. , 2017, Critical reviews in immunology.

[108]  F. dall’Olio,et al.  The expanding roles of the Sd(a)/Cad carbohydrate antigen and its cognate glycosyltransferase B4GALNT2. , 2014, Biochimica et biophysica acta.

[109]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[110]  Robert C. Edgar,et al.  Search and clustering orders of magnitude faster than BLAST , 2010 .

[111]  A. Varki,et al.  Evolution of Glycan Diversity , 2009 .

[112]  N. Bresolin,et al.  Widespread balancing selection and pathogen-driven selection at blood group antigen genes. , 2009, Genome research.

[113]  K. Barton.  MuMIn : multi-model inference, R package version 0.12.0 , 2009 .

[114]  Quan-Guo Zhang,et al.  Species richness destabilizes ecosystem functioning in experimental aquatic microcosms , 2006 .

[115]  N. Ganguly,et al.  Intestinal mucins: the binding sites forsalmonella typhimurium , 2004, Molecular and Cellular Biochemistry.

[116]  Wang Guo.  Plant Traits and Soil Chemical Variables During a Secondary Vegetation Succession in Abandoned Fields on the Loess Plateau , 2002 .

[117]  Brian H. McArdle,et al.  FITTING MULTIVARIATE MODELS TO COMMUNITY DATA: A COMMENT ON DISTANCE‐BASED REDUNDANCY ANALYSIS , 2001 .