The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Acid Responsive Helicobacter pylori Adherence : Implications for Chronic Infection and Disease

Ecological and evolutionary forces shaping the normal and abnormal microflora of the genital econiche are discussed, in particular those related to bacterial vaginosis, which worldwide is the most common vaginal infection, with numerous obstetrical and gynecological complications, including acquisition and transmission of HIV and other sexually transmitted infections (STIs). Characterized by a heavy overgrowth of Gram‐negative and Gram‐positive anaerobes with no signs of inflammation, bacterial vaginosis has been regarded a microbiological and immunological enigma. Immune tolerance to both normal and abnormal vaginal microbiota, mainly derived from gut microflora, as a result of coevolution with humans might explain the absence of inflammation, supported by short‐chain fatty acids, known to modulate immune responses, that are produced in large quantities by anaerobes. Recent studies have implicated the development of a vaginal biofilm with Gardnerella vaginalis and Atopobium vaginae as main players in the pathogenesis of bacterial vaginosis. Supporting this conclusion are data such as those demonstrating heavy growth of G. vaginalis and diversified anaerobes with numerous “clue cells” that are sloughing off from the biofilm. Gardnerella and Atopobium organisms attached to these clue cells can be demonstrated in the male genital econiche, likely reflecting a heterosexual transmission of the disorder.

Annals of the New York Academy of SciencesVolume 1230, Issue 1 p. xiii-xix Introduction to The Evolution of Infectious Agents in Relation to Sex André Nahmias, André Nahmias Emory University, Atlanta, GeorgiaSearch for more papers by this authorDan Danielsson, Dan Danielsson Örebro University Hospital, Örebro, SwedenSearch for more papers by this author André Nahmias, André Nahmias Emory University, Atlanta, GeorgiaSearch for more papers by this authorDan Danielsson, Dan Danielsson Örebro University Hospital, Örebro, SwedenSearch for more papers by this author First published: 08 August 2011 https://doi.org/10.1111/j.1749-6632.2011.06142.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Charles Darwin. 1871. The Descent of Man, and Selection in Relation to Sex. John Murray. London . 2 R. Bellig & G. Stevens, Eds. 1988. The Evolution of Sex. Nobel Conference XXIII. Harper & Row. San Francisco . 3 Lockhart, A.B., P.H. Thrall & J. Antonovics. 1996. The distribution and characteristics of sexually transmitted diseases in animals: ecological and evolutionary implications. Biol. Rev. Camb. Philos. Soc. 71: 415–471. 4 D. Danielsson, L. Juhlin & P-A. Mårdh, Eds. 1975. Genital Infections and Their Complications. A Wellcome Foundation Symposium, 9–11 October, 1974. Stockholm, Sweden. Almqvist & Wiksell International. Uppsala , Sweden . 5 Sandström, E. & D. Danielsson. 1980. Serology of Neisseria gonorrhoeae. Classification by co-agglutination. Acta Pathol. Microbiol. Scand. B. 88(1): 27–38. 6 Nahmias, A. & W. Dowdle. 1968. Antigenic and biologic differences in herpes simplex virus. Prog. Med. Virol. 10: 110–159. 7 Nahmias, A. & D. Reanney. 1977. The evolution of viruses. Ann. Rev. Ecol. System. 8: 29–49. 8 A. Nahmias & R. O’Reilly, Eds. 1981. Immunology of Human Infection. Part I: Bacteria, Mycoplasmae, Chlamydiae, and Fungi. 1982. Part II: Viruses and Parasites; Immunodiagnosis and Prevention of Infectious Diseases. Plenum Press. New York . 9 Carroll, S.B. 2008. Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134(1): 25–36. 10 Nahmias, A., S. Schollin & C. Abramowsky. 2011. Evolutionary–developmental perspectives on immune system interactions among the pregnant woman, placenta, and fetus and responses to sexually transmitted infectious agents. Ann. N.Y. Acad. Sci. 1230: 25–47. 11 Nahmias, A., J. Weiss, X. Yao, et al . 1986. Evidence for human infection with an HTLV-III/LAV-like virus in Central Africa, 1959. Lancet ii: 1279. 12 Zhu, T., B.T. Korber, A.J. Nahmias, et al . 1998. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature 391: 594–597. 13 R. Schinazi & S. Nahmias, Eds. 1988. AIDS in Children, Adolescents and Heterosexual Adults. Elsevier Science Publisher. New York . 14 D. Danielsson & E. Lycke, Eds. 1990. Sexually Transmitted Infections. Current epidemiological perspectives on world-wide infections with aspects on transmission, molecular biology, epidemiological control and prevention. Berzelius Symposium XVII, 22–24 May 1989. Uppsala , Sweden . Scand. J. Infect. Dis. Supplement 69. 15 Nesse, R.M. & B. Foxman. 2011. Evolutionary approaches to sexually transmitted infections. Ann. N.Y. Acad. Sci. 1230: 1–3. 16 Antonovics, J., M. Boots, J. Abbate, C. Baker, Q. McFrederick & V. Panjeti. 2011. Biology and evolution of sexual transmission. Ann. N.Y. Acad. Sci. 1230: 12–24. 17 Currier, R.W. & J.H. Steele. 2011. One Health—One Medicine: unifying human and animal medicine within an evolutionary paradigm. Ann. N.Y. Acad. Sci. 1230: 4–11. 18 Danielsson D, P.K. Teigen & H. Moi. 2011. The genital econiche: focus on microbiota and bacterial vaginosis. Ann. N.Y. Acad. Sci. 1230: 48–58. 19 Reed, D.L., R.W. Currier, S.F. Walton, M. Conrad, S. Sullivan, J.M. Carlton, T.D. Read, A. Severini, S. Tyler, R. Eberle, W.E. Johnson, G. Silvestri, I.N. Clarke, T. Lagergård, S.A. Lukehart, M. Unemo, W.M. Shafer, R.P. Beasley, T. Bergström, P. Norberg, A.J. Davison, J. Blomberg, P.M. Sharp & B.H. Hahn. 2011. The evolution of infectious agents in relation to sex in animals and humans: brief discussions of some individual organisms. Ann. N.Y. Acad. Sci. 1230: 74–107. 20 Beckman Nahmias, S & D. Nahmias. 2011. Society, sex, and STIs: human behavior and the evolution of sexually transmitted diseases and their agents. Ann. N.Y. Acad. Sci. 1230: 59–73. 21 Skar, H., C. Hedskog & J. Albert. 2011. HIV-1 evolution in relation to molecular epidemiology and antiretroviral resistance. Ann. N.Y. Acad. Sci. 1230: 108–118. Citing Literature Volume1230, Issue1The Evolution of Infectious Agents in Relation to SexAugust 2011Pages xiii-xix ReferencesRelatedInformation

APMISVolume 115, Issue 5 p. 406-408 Developments in the recent past—immunology URBAN FORSUM, URBAN FORSUMSearch for more papers by this authorDAN DANIELSSON, DAN DANIELSSONSearch for more papers by this author URBAN FORSUM, URBAN FORSUMSearch for more papers by this authorDAN DANIELSSON, DAN DANIELSSONSearch for more papers by this author First published: 11 May 2007 https://doi.org/10.1111/j.1600-0463.2007.apm_683.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Volume115, Issue5May 2007Pages 406-408 RelatedInformation

Proof of causality of most neuromental disorders (NMD's) is largely unavailable. Lessons from four-decade investigations of the epidemiology, immunology, pathogenesis, prevention and therapy of perinatal infectious agents, which invade directly the nervous system, have led us to propose a new indirect effect hypothesis: maternal transplacentally-acquired antibodies, to agents with epitope molecular mimicry with the developing nervous system, can cross the fetus/infant's blood-nervous system barriers to cause NMD's, clinically manifest years later.Further rationale is provided by relevant evolutionary/developmental (EVO-DEVO) considerations-applicable also to some vaccines. The hypothesis is being tested in: ( a) older pregnancy studies with available maternal and newborn sera, and follow-up of the progeny for NMD's; and (b) NMD registry individuals linked to their stored newborn blood spots. Preliminary results support a possible role for schizophrenia of high-tittered antibodies to some agents (toxoplasma, influenza and herpes simplex type 2 virus).A model that includes likely genetic and postnatal influences is schematized and a list of putative agents and factors, based on varying rationales, is tabulated. In case pilot studies are confirmed, the identified agent(s) and antibodies would need to be tested in new prospectively enrolled pregnant women, so as to establish further risk factors leading to possible preventive modalities.

Adherence of bacterial pathogens to host tissues contributes to colonization and virulence and typically involves specific interactions between bacterial proteins called adhesins and cognate oligosaccharide (glycan) or protein motifs in the host that are used as receptors. A given pathogen may have multiple adhesins, each specific for a different set of receptors and, potentially, with different roles in infection and disease. This chapter provides strategies for identifying and analyzing host glycan receptors and the bacterial adhesins that exploit them as receptors, with particular reference to adherence of the gastric pathogen Helicobacter pylori.

Infiltration of neutrophils and monocytes into the gastric mucosa is a hallmark of chronic gastritis caused by Helicobacter pylori. Certain H. pylori strains nonopsonized stimulate neutrophils to production of reactive oxygen species causing oxidative damage of the gastric epithelium. Here, the contribution of some H. pylori virulence factors, the blood group antigen-binding adhesin BabA, the sialic acid-binding adhesin SabA, the neutrophil-activating protein HP-NAP, and the vacuolating cytotoxin VacA, to the activation of human neutrophils in terms of adherence, phagocytosis, and oxidative burst was investigated. Neutrophils were challenged with wild type bacteria and isogenic mutants lacking BabA, SabA, HP-NAP, or VacA. Mutant and wild type strains lacking SabA had no neutrophil-activating capacity, demonstrating that binding of H. pylori to sialylated neutrophil receptors plays a pivotal initial role in the adherence and phagocytosis of the bacteria and the induction of the oxidative burst. The link between receptor binding and oxidative burst involves a G-protein-linked signaling pathway and downstream activation of phosphatidylinositol 3-kinase as shown by experiments using signal transduction inhibitors. Collectively our data suggest that the sialic acid-binding SabA adhesin is a prerequisite for the nonopsonic activation of human neutrophils and, thus, is a virulence factor important for the pathogenesis of H. pylori infection.

The cagA gene, alleles of the vacA gene, random amplified polymorphic DNA (RAPD), and neutrophil activating capacity (HpNAC) were used to examine paired H. pylori isolates from 10 noneradicated individuals 9 years apart. Paired isolates from each patient were indistinguishable with regard to vacA alleles, RAPD, and HpNAC. Isolates from nine patients showed concordance for the cagA gene, which was not detected in the recent isolate of the tenth patient. Antibodies to CagA were, however, demonstrated in the serum specimens 9 years apart and were also present in two other patients whose paired isolates were cagA-, indicating the existence of both cagA+ and cagA− organisms, with the latter predominating in some patients. The present study suggests a greater stability of phenotypic and genotypic markers of H. pylori than previously regarded. This might be true for a community with low infection and transmission rates. Complementary techniques like microarrays might, however, disclose evolutionary changes not identified here.

An in vitro system was used to study the ability of virulent gonococci to adhere to vaginal epithelial cells obtained from healthy donors during the pre- and postmenstrual phases, and from those in early pregnancy. It was found that more gonococci adhered to the cells from donors in the postmenstrual phase than to cells from those in the premenstrual one. This difference was statistically highly significant. The attachment rate of gonococci to vaginal epithelial cells was similar in early pragnancy and in the premenstrual phase.

The seroprevalence of Helicobacter pylori among secluded Indian populations of South America was determined to gain insight into the evolutionary history and possible transmission patterns of the organism. Serum samples obtained from 1024 donors in 22 different villages were tested by enzyme-linked immunosorbent assay for immunoglobulin G antibodies, and the results were confirmed by Western blot. The overall seroprevalence was 92%: >80% of children tested positive by 3 years of age, the highest prevalence in populations studied to date. Comparison of H. pylori prevalence with that of herpes simplex virus type 1, which is known to be transmitted orally, demonstrated a linear correlation in their prevalence rates, suggesting that these pathogens share risk factors. However, H. pylori seroprevalence was consistently higher, indicating that additional routes of transmission exist and/or that the organism is more transmissible. Seroprevalence did not correlate with the length of contact with the outside world. These results suggest that H. pylori was indigenous to the South American Indians and was not introduced by contact with outsiders.

The binding of Helicobacter pylori to glycosphingolipids was examined by binding of35S-labeled bacteria to glycosphingolipids on thin-layer chromatograms. In addition to previously reported binding specificities, a selective binding to a non-acid tetraglycosylceramide of human meconium was found. This H. pylori binding glycosphingolipid was isolated and, on the basis of mass spectrometry, proton NMR spectroscopy, and degradation studies, were identified as Galβ3GlcNAcβ3Galβ4Glcβ1Cer (lactotetraosylceramide). When using non-acid glycosphingolipid preparations from human gastric epithelial cells, an identical binding of H. pylori to the tetraglycosylceramide interval was obtained in one of seven samples. Evidence for the presence of lactotetraosylceramide in the binding-active interval was obtained by proton NMR spectroscopy of intact glycosphingolipids and by gas chromatography-electron ionization mass spectrometry of permethylated tetrasaccharides obtained by ceramide glycanase hydrolysis. The lactotetraosylceramide binding property was detected in 65 of 74 H. pylori isolates (88%). Binding of H. pylori to lactotetraosylceramide on thin-layer chromatograms was inhibited by preincubation with lactotetraose but not with lactose. Removal of the terminal galactose of lactotetraosylceramide by galactosidase hydrolysis abolished the binding as did hydrazinolysis of the acetamido group of theN-acetylglucosamine. Therefore, Galβ3GlcNAc is an essential part of the binding epitope.

Aims—To investigate the association of cagA positivity and non-opsonic neutrophil activation capacity in wild-type Helicobacter pylori strains with peptic ulcer disease or chronic gastritis only. Methods—Helicobacter pylori were isolated from antral biopsies of 53 consecutive patients with chronic antral gastritis, of whom 24 had peptic ulcer disease endoscopically. The presence of cagA, a marker for the cag pathogenicity island, was determined by polymerase chain reaction with specific oligonucleotide primers, and non-opsonic neutrophil activation capacity by luminol enhanced chemiluminescence. Results—The cagA gene was present in 39 of 53 (73.6%) strains, 20 of which (83.3%) were from the 24 patients with peptic ulcer disease and 19 (65.5%) from the 29 patients with chronic gastritis only. Non-opsonic neutrophil activation was found in 29 (54.7%) strains, 16 of which (66.7%) were from patients with peptic ulcer disease, and 13 (44.8%) from those with chronic gastritis. Non-opsonic neutrophil activation was found more frequently in cagA+ than cagA− strains (59% v 42.9%). Whereas four of the 14 cagA− strains and eight of the 24 non-opsonic neutrophil activation negative strains were from patients with peptic ulcer disease, only two of 24 (8.3%) peptic ulcer disease strains expressed neither cagA nor non-opsonic neutrophil activation. The cagA gene and non-opsonic neutrophil activation capacity were co-expressed in 14 of 24 (58.3%) strains from patients with peptic ulcer disease, and in nine of 29 (31%) strains from individuals with chronic gastritis. Conclusions—Positivity for cagA and non-opsonic neutrophil activation occur independently in wild-type H pylori strains. However, co-expression of the two markers enhanced the prediction of peptic ulcer disease.

Certain strains of Helicobacter pylori have nonopsonic neutrophil-activating capacity. Some H. pylori strains and the neutrophil-activating protein of H.pylori (HPNAP) bind selectively to gangliosides of human neutrophils. To determine if there is a relationship between the neutrophil-activating capacity and the ganglioside-binding ability, a number of H. pylori strains, and HPNAP, were incubated with oligosaccharides, and the effects on the oxidative burst of subsequently challenged neutrophils was measured by chemiluminescence and flow cytometry. Both by chemiluminescence and flow cytometry a reduced response was obtained by incubation of H.pylori with sialic acid-terminated oligosaccharides, whereas lactose had no effect. The reductions obtained with different sialylated oligosaccharides varied to some extent between the H. pylori strains, but in general 3'-sialyllactosamine was the most efficient inhibitor. Challenge of neutrophils with HPNAP gave no response in the chemiluminescence assay, and a delayed moderate response with flow cytometry. Preincubation of the protein with 3'-sialyllactosamine gave a slight reduction of the response, while 3'-sialyllactose had no effect. The current results suggest that the nonopsonic H. pylori-induced activation of neutrophils occurs by lectinophagocytosis, the recognition of sialylated glycoconjugates on the neutrophil cell surface by a bacterial adhesin leads to phagocytosis and an oxidative burst with the production of reactive oxygen metabolites.

Department of Obstetrics and Gynaecology and Department of Clinical Bacteriology and Immunology, Central County Hospital, S-701 85 Orebro, Sweden

Objectives: We analysed the epidemiology of ectopic pregnancy (EP) during a 28 year period, 1970–97, using methods applicable to ecological studies in order to test the hypothesis that a reduction of pelvic inflammatory disease (PID) will be associated with a decrease of EP. Methods: Hospital records of patients aged 15–54 admitted to our department of gynaecology were reviewed for EP and PID for the period 1 January 1970 to 31 December 1997. EP for the period 1970–4 was based on available statistics. The total number for EP was 1270 and for PID 2559. The total population for the catchment area was 100 000–120 000 during the study period. Incidences were age standardised and calculated using official population statistics to represent the average female population in the five 5 year periods 1970–4, 1975–9, 1980–4, 1985–9, 1990–4, and in each of the consecutive years 1995, 1996, and 1997. Incidences for EP were calculated per 1000 women and per 1000 pregnancies while those for PID per 1000 women. National statistical data of EP were available for 1975–94 and were used for comparison with the local study. Results: The EP incidences increased from 7.7 per 1000 pregnancies in the first 5 year period to 13.4 in the second, and continued to rise for another decade reaching the peak figures of 16.6 in 1985–9—that is, more than a twofold increase. Since then and to 1997 the EP incidence has decreased by 30%. PID admissions increased during the study period from 2.7 per 1000 women in the first 5 year period to 3.2 in the second. From then on they continuously decreased and reached a low of 0.5 in 1997. The greatest changes occurred in women ≤24 years of age. The peak incidence for this age group was 7.7 in 1975–9, and the lowest was 0.4 per 1000 women in 1996. The greatest reduction of EPs was noted for women ≤24 years old, from a high of 10.0 in 1975–9, coinciding with the peak incidence of PID, to a low of 4.0 in 1997, a reduction of 58.4%. The incidence of EP was two to three times higher in women ≥25 years old, most obvious in those ≥30 years, with peak figures of 20.9 per 1000 pregnancies in 1985–9, and 13.9 in 1997, a reduction of 33.4% and the lowest figures for the past 23 years. For women aged 25–29 years the incidence peaked in the previous 5 year period 1980–4—that is, one 5 year period later than for those ≤24 years, which we interpret as cohort effects in relation to PID. Conclusions: Reduction of PID was strongly associated with a decline of EP. The decline was greater and immediate for women ≤24 years old, than for those ≥25 years. The two to three times higher EP incidence in women ≥25 years of age was most probably due to a cohort effect as the peak of PID occurred a decade earlier in women ≤24 years old. Prevention of PID may not only reduce EP but also reduce adverse effects on tubal patency.