Lewis Blood-group Antigens Are Associated With Altered Susceptibility to Shigellosis.
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ABSTRACT:
SUBMITTER: Leslie JL
PROVIDER: S-EPMC8315233 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Noroviruses, an important cause of acute gastroenteritis in humans, recognize the histo-blood group antigens (HBGAs) as host susceptible factors in a strain-specific manner. The crystal structures of the HBGA-binding interfaces of two A/B/H-binding noroviruses, the prototype Norwalk virus (GI.1) and a predominant GII.4 strain (VA387), have been elucidated. In this study we determined the crystal structures of the P domain protein of the first Lewis-binding norovirus (VA207, GII.9) that has a distinct binding property from those of Norwalk virus and VA387. Co-crystallization of the VA207 P dimer with Le(y) or sialyl Le(x) tetrasaccharides showed that VA207 interacts with these antigens through a common site found on the VA387 P protein which is highly conserved among most GII noroviruses. However, the HBGA-binding site of VA207 targeted at the Lewis antigens through the ?-1, 3 fucose (the Lewis epitope) as major and the ?-N-acetyl glucosamine of the precursor as minor interacting sites. This completely differs from the binding mode of VA387 and Norwalk virus that target at the secretor epitopes. Binding pocket of VA207 is formed by seven amino acids, of which five residues build up the core structure that is essential for the basic binding function, while the other two are involved in strain-specificity. Our results elucidate for the first time the genetic and structural basis of strain-specificity by a direct comparison of two genetically related noroviruses in their interaction with different HBGAs. The results provide insight into the complex interaction between the diverse noroviruses and the polymorphic HBGAs and highlight the role of human HBGA as a critical factor in norovirus evolution.
| S-EPMC3141052 | biostudies-literature
Project description:The molecular mechanisms behind infection and propagation of human restricted pathogens such as human norovirus (HuNoV) have defied interrogation because they were previously unculturable. However, human intestinal enteroids (HIEs) have emerged to offer unique ex vivo models for targeted studies of intestinal biology, including inflammatory and infectious diseases. Carbohydrate-dependent histo-blood group antigens (HBGAs) are known to be critical for clinical infection. To explore whether HBGAs of glycosphingolipids contribute to HuNoV infection, we obtained HIE cultures established from stem cells isolated from jejunal biopsies of six individuals with different ABO, Lewis, and secretor genotypes. We analyzed their glycerolipid and sphingolipid compositions and quantified interaction kinetics and the affinity of HuNoV virus-like particles (VLPs) to lipid vesicles produced from the individual HIE-lipid extracts. All HIEs had a similar lipid and glycerolipid composition. Sphingolipids included HBGA-related type 1 chain glycosphingolipids (GSLs), with HBGA epitopes corresponding to the geno- and phenotypes of the different HIEs. As revealed by single-particle interaction studies of Sydney GII.4 VLPs with glycosphingolipid-containing HIE membranes, both binding kinetics and affinities explain the patterns of susceptibility toward GII.4 infection for individual HIEs. This is the first time norovirus VLPs have been shown to interact specifically with secretor gene-dependent GSLs embedded in lipid membranes of HIEs that propagate GII.4 HuNoV ex vivo, highlighting the potential of HIEs for advanced future studies of intestinal glycobiology and host-pathogen interactions.
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Project description:Tumor-associated carbohydrate antigens Lewis X (Lex), Lewis Y (Ley), and KH-1 are useful targets for cancer immunotherapy. In this regard, an insight into the structure-immunogenicity relationships of these antigens is important but this has not been systematically investigated yet. In the current study, Lex, Ley, and KH-1 antigens with a lactose unit at the reducing end as a spacer were synthesized and coupled with keyhole limpet hemocyanin (KLH) protein. Immunological evaluations of the resultant conjugates revealed that they all could elicit robust immune responses whilst the Ley conjugate could provoke the highest titers of total and IgG antibodies. The binding assays of their antisera to each antigen and to cancer cells showed that each antiserum had extensive cross-reaction with all three antigens as protein conjugates and strong but somewhat antigen-selective binding towards MCF-7 cancer cell. Moreover, none of these antisera had obvious binding to SKMEL-28 cancer cell that does not express Lex, Ley and KH-1. The results of assays of these antisera to mediate complement-dependent cytotoxicity (CDC) to MCF-7 and SKMEL-28 cancer cells were very similar to the results of binding assays. Thus, it was concluded that all three antigens could form effective conjugate vaccines whereas the Ley conjugate induced the most robust immune responses and the antiserum of Lex had the highest binding and cytotoxicity to target cancer cells. In addition, as the antibodies induced by each antigen had extensive cross-reaction with other two antigens, either Lex or Ley or the two combined can be utilized to formulate effective conjugate vaccines for cancer immunotherapy. Another paradigm-shifting discovery of this study is that the presentation of Lex, Ley, and KH-1 antigens on cancer cell can be different from that in synthetic conjugates, which should be taken into consideration during the design and optimization of related cancer vaccines or immunotherapies.
| S-EPMC7261630 | biostudies-literature
Project description:Far from being just "bugs in our guts," the microbiota interacts with the body in previously unimagined ways. Research into the genome and the microbiome has revealed that the human body and the microbiota have a long-established but only recently recognized symbiotic relationship; homeostatic balance between them regulates body function. That balance is fragile, easily disturbed, and plays a fundamental role in human health-our very survival depends on the healthy functioning of these microorganisms. Increasing rates of cardiovascular, autoimmune, and inflammatory diseases, as well as epidemics in obesity and diabetes in recent decades are believed to be explained, in part, by unintended effects on the microbiota from vaccinations, poor diets, environmental chemicals, indiscriminate antibiotic use, and "germophobia." Discovery and exploration of the brain-gut-microbiota axis have provided new insights into functional diseases of the gut, autoimmune and stress-related disorders, and the role of probiotics in treating certain affective disorders; it may even explain some aspects of autism. Research into dietary effects on the human gut microbiota led to its classification into three proposed enterotypes, but also revealed the surprising role of blood group antigens in shaping those populations. Blood group antigens have previously been associated with disease risks; their subsequent association with the microbiota may reveal mechanisms that lead to development of nutritional interventions and improved treatment modalities. Further exploration of associations between specific enteric microbes and specific metabolites will foster new dietary interventions, treatment modalities, and genetic therapies, and inevitably, their application in personalized healthcare strategies. This article is categorized under: Laboratory Methods and Technologies > Metabolomics Translational, Genomic, and Systems Medicine > Translational Medicine Physiology > Mammalian Physiology in Health and Disease.
| S-EPMC5902424 | biostudies-literature
Project description:Background:High-frequency blood group antigens (HFA) are present in >90% of the human population, according to some reports even in >99% of individuals. Therefore, patients lacking HFA may become challenging for transfusion support because compatible blood is hardly found, and if the patient carries alloantibodies, the cross-match will be positive with virtual every red cell unit tested. Methods:In this study, we applied high-throughput blood group SNP genotyping on >37,000 Swiss blood donors, intending to identify homozygous carriers of low-frequency blood group antigens (LFA). Results:326 such individuals were identified and made available to transfusion specialists for future support of patients in need of rare blood products. Conclusion:Thorough comparison of minor allele frequencies using population genetics revealed heterogeneity of allele distributions among Swiss blood donors which may be explained by the topographical and cultural peculiarities of Switzerland. Moreover, geographically localized donor subpopulations are described which contain above-average numbers of individuals carrying rare blood group genotypes.
| S-EPMC6158591 | biostudies-literature
Project description:FUT2 is a gene for a fucosyltransferase that encodes expression of ABO blood group antigens found on gastrointestinal mucosa and secretions. We hypothesized that the fecal microbiomes of healthy subjects, with blood group antigens A, B, and O, have differing compositions. We analyzed 33 fecal and blood specimens from healthy subjects for FUT2 genotype, and the fecal microbiome was determined by 454 pyrosequencing. Our data show that being a blood group secretor is associated with less diversity at higher orders of taxonomy; and the presence of blood group A antigens in the secretor subjects are associated with an expansion families of bacteria within the gut. Furthermore, our study confirms the previous findings that secretors and nonsecretors have differing bacterial taxa. This extends the previous findings by demonstrating that the impact of being a nonsecretor is higher than that of individual blood group antigens. Additionally, we demonstrate that both secretor status and blood group antigen expression especially affect the Lachnospiraceae family of bacteria within the gut microbiome, with lower abundances noted in nonsecretors and higher abundances in secretors of various blood groups. We further note specific differences in blood group A-secretors demonstrating that the genus Blautia is lower in the group A-secretors compared with the non-A-secretors and that this reduction is accompanied by higher abundances of members of the Rikenellaceae, Peptostreptococcaceae, Clostridiales, and Turicibacter This study offers a first insight into the relationship between the fecal microbiome and blood group antigens in secretors.
| S-EPMC5625272 | biostudies-literature
Project description:UnlabelledHuman noroviruses are the dominant cause of outbreaks of gastroenteritis around the world. Human noroviruses interact with the polymorphic human histo-blood group antigens (HBGAs), and this interaction is thought to be important for infection. Indeed, synthetic HBGAs or HBGA-expressing enteric bacteria were shown to enhance norovirus infection in B cells. A number of studies have found a possible relationship between HBGA type and norovirus susceptibility. The genogroup II, genotype 4 (GII.4) noroviruses are the dominant cluster, evolve every other year, and are thought to modify their binding interactions with different HBGA types. Here we show high-resolution X-ray crystal structures of the capsid protruding (P) domains from epidemic GII.4 variants from 2004, 2006, and 2012, cocrystallized with a panel of HBGA types (H type 2, Lewis Y, Lewis B, Lewis A, Lewis X, A type, and B type). Many of the HBGA binding interactions were found to be complex, involving capsid loop movements, alternative HBGA conformations, and HBGA rotations. We showed that a loop (residues 391 to 395) was elegantly repositioned to allow for Lewis Y binding. This loop was also slightly shifted to provide direct hydrogen- and water-mediated bonds with Lewis B. We considered that the flexible loop modulated Lewis HBGA binding. The GII.4 noroviruses have dominated outbreaks over the past decade, which may be explained by their exquisite HBGA binding mechanisms, their fondness for Lewis HBGAs, and their temporal amino acid modifications.ImportanceOur data provide a comprehensive picture of GII.4 P domain and HBGA binding interactions. The exceptionally high resolutions of our X-ray crystal structures allowed us to accurately recognize novel GII.4 P domain interactions with numerous HBGA types. We showed that the GII.4 P domain-HBGA interactions involved complex binding mechanisms that were not previously observed in norovirus structural studies. Many of the GII.4 P domain-HBGA interactions we identified were negative in earlier enzyme-linked immunosorbent assay (ELISA)-based studies. Altogether, our data show that the GII.4 norovirus P domains can accommodate numerous HBGA types.
| S-EPMC4338890 | biostudies-literature
Project description:Noroviruses have been identified as major causative agents of acute nonbacterial gastroenteritis in humans. Histo-blood group antigens (HBGAs) are thought to play a major role among the host cellular factors influencing norovirus infection. Genogroup I, genotype 9 (GI.9) is the most recently identified genotype within genogroup I, whose representative strain is the Vancouver 730 norovirus. However, the molecular interactions between host antigens and the GI.9 capsid protein have not been investigated in detail. In this study, we demonstrate that the GI.9 norovirus preferentially binds Lewis antigens over blood group A, B, and H antigens, as revealed by an HBGA binding assay using virus-like particles. We determined the crystal structures of the protruding domain of the GI.9 capsid protein in the presence or absence of Lewis antigens. Our analysis demonstrated that Lewis fucose (α1-3/4 fucose) represents a key moiety for the GI.9 protein-HBGA interaction, thus suggesting that Lewis antigens might play a critical role during norovirus infection. In addition to previously reported findings, our observations may support the future design of antiviral agents and vaccines against noroviruses.
| S-EPMC8886331 | biostudies-literature
Project description:CONTEXT: The clinically significant antibodies are those active at 37°C and/or by the indirect antiglobulin test. Most of the published literature refers to antibodies of Lewis blood group system to be insignificant, whereas antibodies to M and N blood groups are associated with variable clinical significance. AIMS: The aim of this study is to find the frequency and clinical significance of antibodies to M, N and Lewis blood group systems. SETTINGS AND DESIGN: The study was carried out retrospectively from January 2009 to December 2012. MATERIALS AND METHODS: Antibody screening was performed by solid phase red cell adherence (SPRCA) technique using four cell screening panel on a fully automated platform GALILEO (Immucor Inc. USA). In case of a positive antibody screen, antibody identification was performed using SPRCA (GALILEO, Immucor Inc. USA). RESULTS: A total of 49,077 red cell antibody screens were performed and a total of 427 identifications of red cell antibodies were carried out. A total of 304 specific antibodies were detected: 8.22% of antibodies were of anti-M specificity and 2.96% were of anti-N specificity. Majority (84%) of anti-M and 77.78% of anti-N were of Immunoglobulin G (IgG) class reacting at 37°C. 1.31% of the antibodies were directed against Lewis system antigens of which 0.65% were anti-Lea and 0.65% were anti-Leb. Half of the Lewis system antibodies, i.e., 1 each of anti-Lea and anti-Leb were of IgG class. CONCLUSION: Our study highlights the importance of detecting the thermal amplitude of antibodies with variable clinical significance especially if both IgG and IgM types of antibodies are associated with it so as to establish their clinical significance.
| S-EPMC4140072 | biostudies-other
Project description:Human norovirus interacts with the polymorphic human histo-blood group antigens (HBGAs), and this interaction is thought to be important for infection. The genogroup II genotype 4 (GII.4) noroviruses are the dominant cluster, evolve every other year, and are thought to modify their binding interactions with different HBGA types. Most human noroviruses bind HBGAs, while some strains were found to have minimal or no HBGA interactions. Here, we explain some possible structural constraints for several noroviruses that were found to bind poorly to HBGAs by using X-ray crystallography. We showed that one aspartic acid was flexible or positioned away from the fucose moiety of the HBGAs and this likely hindered binding, although other fucose-interacting residues were perfectly oriented. Interestingly, a neighboring loop also appeared to influence the loop hosting the aspartic acid. These new findings might explain why some human noroviruses bound HBGAs poorly, although further studies are required.
| S-EPMC4894678 | biostudies-literature