An enzymatic ruler modulates Lewis antigen glycosylation of Helicobacter pylori LPS during persistent infection

ABSTRACTLewis (Le) antigens are fucosylated oligosaccharides present in theHelicobacter pylorilipopolysaccharide. Expression of these antigens is believed to be important forH. pyloricolonization, since Le antigens also are expressed on the gastric epithelia in humans. A galactosyltransferase encoded by β-(1,3)galTis essential for production of type 1 (Leaand Leb) antigens. The upstream genejhp0562, which is present in many but not allH. pyloristrains, is homologous to β-(1,3)galTbut is of unknown function. BecauseH. pyloridemonstrates extensive intragenomic recombination, we hypothesized that these two genes could undergo DNA rearrangement. A PCR screen and subsequent sequence analyses revealed that the two genes can recombine at both the 5′ and 3′ ends. Chimeric β-(1,3)galT-like alleles can restore function in a β-(1,3)galTnull mutant, but neither native nor recombinantjhp0562can. Mutagenesis ofjhp0562revealed that it is essential for synthesis of both type 1 and type 2 Le antigens. Transcriptional analyses of both loci showed β-(1,3)galTexpression in all wild-type (WT) and mutant strains tested, whereasjhp0562was not expressed injhp0562null mutants, as expected. Sincejhp0562unexpectedly displayed functions in both type 1 and type 2 Le synthesis, we asked whethergalT, part of the type 2 synthesis pathway, had analogous functions in type 1 synthesis. Mutagenesis and complementation analysis confirmed thatgalTis essential for Lebproduction. In total, these results demonstrate thatgalTandjhp0562have functions that cross the expected Le synthesis pathways and thatjhp0562provides a substrate for intragenomic recombination to generate diverse Le synthesis enzymes.

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Helicobacter pylori VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection

mBio ◽

10.1128/mbio.00261-19 ◽

2019 ◽

Vol 10 (2) ◽

Cited By ~ 9

Author(s):

Aleksandra Altobelli ◽

Michael Bauer ◽

Karelia Velez ◽

Timothy L. Cover ◽

Anne Müller

Keyword(s):

Helicobacter Pylori ◽

T Cell ◽

Persistent Infection ◽

Myeloid Cells ◽

T Cell Responses ◽

T Cell Differentiation ◽

Content Type ◽

Effector T Cell ◽

Cell Responses ◽

H Pylori

ABSTRACT The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3+) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.

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Genotypic and Phenotypic Variation of Lewis Antigen Expression in Geographically Diverse Helicobacter pylori Isolates

Helicobacter ◽

10.1111/j.1523-5378.2011.00897.x ◽

2011 ◽

Vol 16 (6) ◽

pp. 475-481 ◽

Cited By ~ 5

Author(s):

Mary Ann Pohl ◽

William Zhang ◽

Sunny N. Shah ◽

Edgardo L. Sanabria-Valentín ◽

Guillermo I. Perez-Perez ◽

...

Keyword(s):

Helicobacter Pylori ◽

Phenotypic Variation ◽

Antigen Expression ◽

Lewis Antigen

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Comparison of the Serological Reactivity of Lipopolysaccharides from Japanese and Western Strains of Helicobacter pylori to Sera from H. pylori-Positive Humans

ISRN Microbiology ◽

10.5402/2012/162816 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Ken-ichi Amano ◽

Shin-ichi Yokota ◽

Mario A. Monteiro

Keyword(s):

Helicobacter Pylori ◽

Monoclonal Antibodies ◽

Japanese Patients ◽

Lewis Antigens ◽

Lewis Antigen ◽

Serological Reactivity ◽

H Pylori ◽

Antigenic Epitopes

We compared the serological reactivity of lipopolysaccharides (LPS) isolated from Japanese and Western strains of Helicobacter pylori against anti-Lewis antigen monoclonal antibodies and H. pylori-positive Japanese sera. The two LPS from Western strains (26695 and O:2) did not react with any sera from Japanese patients, while all LPS from Japanese strains and the Sydney strain reacted with these sera. We propose that LPS of all Japanese smooth strains share either one of two epitopes, which are termed highly antigenic and weakly antigenic epitopes, present in the O-polysaccharide portion, and these epitopes are independent the Lewis antigens. The present findings indicated that the two Western strains lacked the two epitopes, which are shared by all Japanese strains.

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Design and immunological properties of Helicobacter pylori glycoconjugates based on a truncated lipopolysaccharide lacking Lewis antigen and comprising an α-1,6-glucan chain

Vaccine ◽

10.1016/j.vaccine.2012.04.035 ◽

2012 ◽

Vol 30 (50) ◽

pp. 7332-7341 ◽

Cited By ~ 13

Author(s):

Eleonora Altman ◽

Vandana Chandan ◽

Blair A. Harrison ◽

Roberto Veloso-Pita ◽

Jianjun Li ◽

...

Keyword(s):

Helicobacter Pylori ◽

Immunological Properties ◽

Lewis Antigen ◽

Glucan Chain

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Two Distinct Antigenic Types of the Polysaccharide Chains of Helicobacter pylori Lipopolysaccharides Characterized by Reactivity with Sera from Humans with Natural Infection

Infection and Immunity ◽

10.1128/iai.68.1.151-159.2000 ◽

2000 ◽

Vol 68 (1) ◽

pp. 151-159 ◽

Cited By ~ 24

Author(s):

Shin-Ichi Yokota ◽

Ken-Ichi Amano ◽

Yoshiko Shibata ◽

Mizuho Nakajima ◽

Miyuki Suzuki ◽

...

Keyword(s):

Helicobacter Pylori ◽

Lipid A ◽

Inner Core ◽

Antigenic Variation ◽

Natural Infection ◽

Clinical Isolates ◽

Antigenic Epitope ◽

Lewis Antigen ◽

Human Sera ◽

H Pylori

ABSTRACT We have purified lipopolysaccharides (LPS) from 10Helicobacter pylori clinical isolates which were selected on the basis of chemotype and antigenic variation. Data from immunoblotting of the purified LPS with sera from humans with H. pylori infection and from absorption of the sera with LPS indicated the presence of two distinct epitopes, termed the highly antigenic and the weakly antigenic epitopes, on the polysaccharide chains. Among 68 H. pylori clinical isolates, all smooth strains possessed either epitope; the epitopes were each carried by about 50% of the smooth strains. Thus, H. pylori strains can be classified into three types on the basis of their antigenicity in humans: those with smooth LPS carrying the highly antigenic epitope, those with smooth LPS carrying the weakly antigenic epitope, and those with rough LPS. Sera from humans with H. pylori infection could be grouped into three categories: those containing immunoglobulin G (IgG) antibodies against the highly antigenic epitope, those containing IgG against the weakly antigenic epitope, and those containing both specific IgGs; these groups made up about 50%, less than 10%, and about 40%, respectively, of all infected sera tested. In other words, IgG against the highly antigenic epitope were detected in more than 90% of H. pylori-infected individuals with high titers. IgG against the weakly antigenic epitope were detected in about 50% of the sera tested; however, the antibody titers were low. The two human epitopes existed independently from the mimic structures of Lewis antigens, which are known to be an important epitope ofH. pylori LPS. No significant relationship between the reactivities toward purified LPS of human sera and a panel of anti-Lewis antigen antibodies was found. Moreover, the reactivities of the anti-Lewis antigen antibodies, but not human sera, were sensitive to particular α-l-fucosidases. The human epitopes appeared to be located on O-polysaccharide chains containing endo-β-galactosidase-sensitive galactose residues as the backbone. Data from chemical analyses indicated that all LPS commonly contained galactose, glucosamine, glucose, and fucose (except one rough strain) as probable polysaccharide components, together with typical components of inner core and lipid A. We were not able to distinguish between the differences of antigenicity in humans by on the basis of the chemical composition of the LPS.

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Persistent infection of Helicobacter pylori affects weight loss in obese population compared with persistent negative: A case‐control study based on healthy Chinese

Helicobacter ◽

10.1111/hel.12697 ◽

2020 ◽

Vol 25 (4) ◽

Author(s):

Jinshun Zhang ◽

Yahong Chen ◽

Weiling Chen ◽

Hongfang Xu ◽

Huihong Wang ◽

...

Keyword(s):

Weight Loss ◽

Helicobacter Pylori ◽

Persistent Infection ◽

Case Control Study ◽

Case Control ◽

Obese Population ◽

Healthy Chinese ◽

Control Study

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Lewis antigen phenotype is altered in Helicobacter pylori isolated from asymptomatic subjects

Gastroenterology ◽

10.1016/s0016-5085(00)81050-1 ◽

2000 ◽

Vol 118 (4) ◽

pp. A1299 ◽

Cited By ~ 1

Author(s):

David A. Rasko ◽

Monika Keelan ◽

Alan B. Thomson ◽

Diane E. Taylor

Keyword(s):

Helicobacter Pylori ◽

Lewis Antigen ◽

Asymptomatic Subjects

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Protection against Experimental Helicobacter pylori Infection after Immunization with Inactivated H. pylori Whole-Cell Vaccines

Infection and Immunity ◽

10.1128/iai.70.11.6383-6388.2002 ◽

2002 ◽

Vol 70 (11) ◽

pp. 6383-6388 ◽

Cited By ~ 43

Author(s):

S. Raghavan ◽

M. Hjulström ◽

J. Holmgren ◽

A.-M. Svennerholm

Keyword(s):

Helicobacter Pylori ◽

Protective Effect ◽

Cholera Toxin ◽

Oral Immunization ◽

Helicobacter Pylori Infection ◽

The Other ◽

Whole Cell ◽

O Antigen ◽

Lewis Antigen ◽

H Pylori

ABSTRACT The protective effect of therapeutic oral immunization with homologous and heterologous formalin-inactivated Helicobacter pylori cells given together with cholera toxin as an adjuvant was evaluated with C57BL/6 mice infected with H. pylori Sydney strain 1 (SS1). The bacteria used for immunization were strains that were either homologous or heterologous with regard to the O antigen (i.e., the Lewis antigen [Le antigen]) expressed by the lipopolysaccharide of the infecting H. pylori SS1 strain. We found that repeated oral immunization with inactivated H. pylori SS1 cells can significantly inhibit an existing infection (P < 0.001) and that the protection induced by such therapeutic immunization extends to protection against reinfection (P < 0.001). A similar level of protection was also achieved by immunization with another inactivated H. pylori strain having the same O antigen (Le antigen) as the infecting H. pylori SS1 strain. In contrast, immunization with inactivated strains expressing a heterologous O antigen, Lex, provided less protection or no protection. Immunization with H. pylori lysate preparations, on the other hand, resulted in significant comparable protection whether the lysates were prepared from an Lex strain or an Ley strain. Postimmunization gastritis was seen in mice that were protected after vaccination but not in unimmunized or unprotected mice. In conclusion, therapeutic immunization with inactivated H. pylori whole-cell vaccines may provide strong protection both against experimental H. pylori infection and against later reinfection.

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