Response from Falk, Guruge and Gordon

Janaki  Lelwala guruge

Response from Falk, Guruge and Gordon

Janaki Lelwala guruge

1998, Trends in Microbiology

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COMMENT Such phase, or antigenic, variation could be important in determining host specificity during colonization and in bacterial persistence during chronic infection. Phase variation is a mechanism used by other mucosal pathogens, such as Haemophilus influenzae and Neisseria species, to increase diversity. Such variation occurs by reversible onor off-switching of specific genes coding for surface structures, such as adhesins and lipopolysaccharide (LPS). Phase variation in H. pylori LPS has recently been described8. Re-analysis of the H. pylori strain 26695 genome has identified 27 genes with either dinucleotide repeats or homopolymeric tracts, including babB (Ref. 9). Slippedstrand mispairing within such repeats is a documented feature of another mechanism of phase variation. H. pylori 26695 has no Lebbinding activity, which may be explained by the presence of a babA1 homologue but the absence of a babA2 homologue. Repeat sequence analysis of the cloned babA2 gene in Escherichia coli has revealed frequent deletion of the repeat motif and convergence to the silent babA1 gene, suggesting ‘hot spots’ for phase variation within the bab gene family. Clearly, phase variation contributes to the heterogenicity of H. pylori and it might explain the finding that several highly related yet different isolates can be obtained from one patient 8. Disease variation A microbial basis for autoimmunity in several chronic inflammatory diseases has been proposed but remains largely unproven. Parietal cell autoantibodies correlate with the occurrence of severe corpus gastritis and gastric mucosal atrophy in H. pylori-infected individuals10. Further work by Guruge et al. has shown that attachment of H. pylori promotes the development of autoantibodies to parietal cells, resulting in chronic gastritis and loss of parietal cells6. The mechanisms underlying autoantibody production might include molecular mimicry between constitutively expressed bacterial LPS and parietal cellassociated Lex epitopes11. Transgenic mice with autoantibodies have higher titres of serum antibodies to H. pylori LPS-associated Lex than transgenic or normal mice without detectable autoantibodies6. However, in humans, evidence is lacking for a role for expression of human Le antigens by H. pylori LPS in gastric autoimmunity and inflammation12,13. Indeed, it is suggested that the epitopes that mimic the structures of the Le antigens in H. pylori are not those that predominate during natural infection in humans14. In addition to increasing our understanding of the pathogenesis of H. pylori, these studies raise other questions. Autoantibodies have been detected in 87% of transgenic mice and 26% of normal mice in a model biased towards expression of the Leb receptor and the BabA adhesin6. Other receptors and adhesins must be involved in colonization, possibly with the course of infection skewed towards other disease outcomes. These studies show that adherence of H. pylori to gastric epithelial cells promotes antigen uptake and the generation of antigen-specific immune responses. Differences in the mechanism and site of adherence, combined with variation of antigen production, might play a role Response from Falk, Guruge and Gordon I n a gastric ecosystem, ‘socially appropriate’ responses depend upon the host as well as the guest. We concur with Dorrell et al. that it is likely that Helicobacter pylori uses a series of its gene products for assembly of functional adhesins that are ‘appropriate’ for the receptor environment of the gastric ecosystem it colonizes. The question is whether expression of ‘appropriate’ adhesins represents (1) the result of selection of H. pylori strains that constitutively produce an adhesin that matches an available receptor repertoire, (2) whether the bacterium is able to sense its environment and specifically induce expression of a ‘relevant’ adhesin or (3) whether the bacterial guest Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0966 842X/98/$19.00 TRENDS IN MICROBIOLOGY 380 in the diversity of disease associated with H. pylori infection. Acknowledgements N.D. is funded by the Joint Research Board, St Bartholomew’s Hospital. Work in the laboratory of J.E.C. is undertaken with financial support from Yorkshire Cancer Research and the European Commission (Contract number IC 18CT950024). References 1 Blaser, M.J. (1997) J. Clin. Invest. 100, 759–762 2 Kuipers, E.J. (1997) Aliment. Pharmacol. Ther. 11, 71–88 3 Cover, T.L. and Blaser, M.J. (1996) Adv. Intern. Med. 41, 85–117 4 Tomb, J.F. et al. (1997) Nature 388, 539–547 5 Labigne, A. and de Reuse, H. (1996) Infect. Agents Dis. 5, 191–202 6 Guruge, J.L. et al. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 3925–3930 7 Ilver, D. et al. (1998) Science 279, 373–377 8 Appelmelk, B.J. et al. (1998) Infect. Immun. 66, 70–76 9 Saunders, N.J. et al. (1998) Mol. Microbiol. 27, 1091–1098 10 Faller, G. et al. (1997) Gut 41, 619–623 11 Appelmelk, B.J. et al. (1997) Trends Microbiol. 5, 70–73 12 Wirth, H.P. et al. (1996) Infect. Immun. 64, 4598–4605 13 Amano, K. et al. (1997) Clin. Diagn. Lab. Immunol. 4, 540–544 14 Yokota, S.I. et al. (1998) Infect. Immun. 66, 3006–3011 is able to influence the expression of receptors by its host. This question, which has general applicability to other host–microorganism relationships, begs an experimental system that is sufficiently well controlled and manipulatable to test the relevance of these three possibilities. The ability of H. pylori to insinuate itself into human gastric ecosystems is governed by complex factors. Gastric ecosystems will vary not only between individuals in a given locale but also within an individual, as a function of development, environmental factors or acquired pathological processes that affect the gastric epithelium or underlying immune system. Phase variation might influence the phenotype of a given colonizing strain. In view of host and bacterial variation, we believe that it is hazardous PII: S0966-842X(98)01368-7 VOL. 6 NO. 10 OCTOBER 1998 COMMENT at this time to implicate one specific adhesin–receptor interaction as more relevant than another for understanding pathogenesis, for predicting the outcome of infection in individuals or populations, or for use as a therapeutic target that is generally applicable (e.g. for vaccine production). We do not know to what extent the H. pylori adhesin–Lewis b (Leb) receptor interaction in our transgenic model simulates interactions that occur in human gastric ecosystems. Nonetheless, we believe the potential value of this type of model is to simplify the ecosystem so that the role of bacterial adhesion in pathogenesis can be assessed under more-controlled conditions. By using a given bacterial strain, a given genetically defined transgenic host with an engineered receptor that recognizes adhesins produced during colonization by that strain, and genetically identical nontrans- genic littermates as controls, it becomes possible to address the issue of whether and how attachment affects bacterial and/or host gene expression, as well as disease outcome. For example, DNA microarray techniques can be employed to catalogue whole bacterial and host genome transcriptional responses to attachment. Changes in bacterial gene expression as a function of attachment can be examined using promoter trap strategies1. One final point raised by Dorrell et al. revolves around the issue of molecular mimicry between epitopes produced by colonizing bacteria and epitopes expressed by host cell lineages. Such mimicry appears to underlie the attachment-related production of antibodies that crossreact with bacterial lipopolysaccharide (LPS) and host parietal cell epitopes in our Leb model. However, just as adhesin–receptor interactions must not be stereotyped, analysis of the role of molecular mimicry in pathogenes is should not be limited by trying to promote the relevance of a particular epitope to a general population. A more-profound understanding is needed of how attach-ment affects the expression of bacterial and host epitopes and how bacterial epitopes are presented and processed by the, as yet, poorly understood gastric mucosal immune system. Response from Borén and Arnqvist scenario would adapt H. pylori to the different microecological host environments that it will encounter during the colonization process (e.g. gastric or duodenal epithelial tissues, the mucus layer, cells of the immune systems and connective tissues). The importance of microbial adherence as a virulence factor, particularly in turbid environments such as the gastrointestinal and urinary tracts, is well established for several microbial pathogens (see Ref. 5 for an update). In gastric biopsy material, ~5–20% of H. pylori cells adhere to the epithelial cell surfaces, but the majority of cells are located in the mucus layer that covers the epithelial cells. There is probably an equilibrium between microbial adherence properties (i.e. the different adhesin proteins) and flagellar-mediated motility/chemotaxis that is optimized for the specific individual host environment6. Several receptor candidates have been described for H. pylori (reviewed in Ref. 7), most of which are present in a variety of vertebrate tissues; however, specific adherence of H. pylori to gastric epithelial cells in vitro seems to be restricted to human and primate tissue8. We identified the gastric surface mucous cell receptor as the Lewis b (Leb) histo-blood group antigen, which is abundant in the human gastrointestinal lining9. The high receptor specificity for this humanspecific histo-blood group antigen is intriguing and suggests that the host and tissue tropism for human and primate gastric mucosa is dependent on the receptor–ligand interaction. The H. pylori–Leb antigen interaction also has an unusually high affinity constant (in the range of 1010 M21)10. Such a high affinity is rare for protein–carbohydrate interactions and suggests that the Leb receptors are used by the microorganisms for targeted and specific attachment to the surface mucous cells. High affinity binding is also important for obtaining nutrients and modulating immune responses. Once on the cell surface, additional receptors, such as sulfatides and phospholipids, might contribute to the intimate adherence process (reviewed in Refs 5,7). As Dr Dorrell et al. indicated, we identified and purified the adhesin T he article by Dr Dorrell et al. points to the complexity and diversity of Helicobacter pylori as the contributing factor in a multitude of gastrointestinal diseases. Macrorestriction patterns have revealed extensive variation in H. pylori genomic organization1. However, comparison of the H. pylori genome sequenced by The Institute for Genomic Research (TIGR)2 and the second H. pylori genome sequenced by Genome Therapeutics/ Astra3 suggests a high degree of gene and sequence conservation. For subsequent host adaptation, H. pylori might use systems that favor gene recombination events, possibly aided by the activity of transposons in combination with mechanisms of natural competence for transformation. This is exemplified by the acquisition of the virulence-associated cag pathogenicity island (PAI)4. A flexible genetic system would also have the potential to select for an optimal set of adherence mechanisms, by phase-variation mechanisms. This Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0966 842X/98/$19.00 TRENDS IN MICROBIOLOGY 381 Per G. Falk, Janaki L. Guruge and Jeffrey I. Gordon Dept of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA Reference 1 Valdivia, R.H. and Falkow, S. (1997) Trends Microbiol. 5, 360–363 PII: S0966-842X(98)01324-9 VOL. 6 NO. 10 OCTOBER 1998

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