• Helicobacter pylori
• Bacteria
• DNA methyltransferases
• Epigenetic changes
• Epigenetics
• High-throughput sequencing
• Methylome

• Helicobacter pylori/genetics
• DNA Methylation
• Genome, Bacterial/genetics
• Homeostasis
• Cytosine/metabolism
• Sequence Analysis, DNA/methods
• High-Throughput Nucleotide Sequencing/methods

• 06.820 Deutsches Zentrum für Infektionsforschung
• 06.824 Deutsches Zentrum für Infektionsforschung
• Ludwig-Maximilians-Universität München (1024)

• Helicobacter pylori
• activators of transcription
• environmental response
• repressors of transcription
• two-component systems

• DNA recombination
• Helicobacter pylori
• genome analysis
• nucleotide excision repair

Helicobacter himalayensis was isolated from Marmota himalayana in the Qinghai-Tibet Plateau, China, and is a new non-H. pylori species, with unclear taxonomy, phylogeny, and pathogenicity.

A comparative genomic analysis was performed between the H. himalayensis type strain 80(YS1)^T and other the genomes of Helicobacter species present in the National Center for Biotechnology Information (NCBI) database to explore the molecular evolution and potential pathogenicity of H. himalayensis. H. himalayensis 80(YS1)^T formed a clade with H. cinaedi and H. hepaticus that was phylogenetically distant from H. pylori. The H. himalayensis genome showed extensive collinearity with H. hepaticus and H. cinaedi. However, it also revealed a low degree of genome collinearity with H. pylori. The genome of 80(YS1)^T comprised 1,829,936 bp, with a 39.89% GC content, a predicted genomic island, and 1769 genes. Comparatively, H. himalayensis has more genes for functions in “cell wall/membrane/envelope biogenesis” and “coenzyme transport and metabolism” sub-branches than the other compared helicobacters, and its genome contained 42 virulence factors genes, including that encoding cytolethal distending toxin (CDT).

We characterized the H. himalayensis 80(YS1)^T genome, its phylogenetic position, and its potential pathogenicity. However, further understanding of the pathogenesis of this potentially pathogenic bacterium is required, which might help to manage H. himalayensis-induced diseases.

The online version contains supplementary material available at 10.1186/s12864-020-07245-y.

• Comparative genomics
• Helicobacter
• Helicobacter himalayensis
• Virulence factor

• Bi(III) coordination polymers
• Helicobacter pylori
• holodirected and hemidirected geometry
• photoluminescence
• pyridine-2,3-dicarboxylic acid

• Anti-Bacterial Agents/chemistry
• Anti-Bacterial Agents/pharmacology
• Bismuth/chemistry
• Coordination Complexes/chemistry
• Coordination Complexes/pharmacology
• Dicarboxylic Acids/chemistry
• Fluorescent Dyes/chemistry
• Fluorescent Dyes/pharmacology
• Helicobacter pylori/growth & development
• Pyridines/chemistry

The biogenesis of bacterial cell-envelope polysaccharides requires the translocation, across the plasma membrane, of sugar sub-units that are produced inside the cytoplasm. To this end, the hydrophilic sugars are anchored to a lipid phosphate carrier (undecaprenyl phosphate (C₅₅-P)), yielding membrane intermediates which are translocated to the outer face of the membrane. Finally, the glycan moiety is transferred to a nascent acceptor polymer, releasing the carrier in the “inactive” undecaprenyl pyrophosphate (C₅₅-PP) form. Thus, C₅₅-P is generated through the dephosphorylation of C₅₅-PP, itself arising from either de novo synthesis or recycling. Two types of integral membrane C₅₅-PP phosphatases were described: BacA enzymes and a sub-group of PAP2 enzymes (type 2 phosphatidic acid phosphatases). The human pathogen Helicobacter pylori does not contain BacA homologue but has four membrane PAP2 proteins: LpxE, LpxF, HP0350 and HP0851. Here, we report the physiological role of HP0851, renamed HupA, via multiple and complementary approaches ranging from a detailed biochemical characterization to the assessment of its effect on cell envelope metabolism and microbe-host interactions. HupA displays a dual function as being the main C₅₅-PP pyrophosphatase (UppP) and phosphatidylglycerol phosphate phosphatase (PGPase). Although not essential in vitro, HupA was essential in vivo for stomach colonization. In vitro, the remaining UppP activity was carried out by LpxE in addition to its lipid A 1-phosphate phosphatase activity. Both HupA and LpxE have crucial roles in the biosynthesis of several cell wall polysaccharides and thus constitute potential targets for new therapeutic strategies.

Helicobacter pylori colonizes the human’s gastric mucosa and infects around 50% of the world’s population. This pathogen is responsible for chronic gastritis, peptic ulcers and in worst cases leads to gastric cancer. It has been classified as a class I carcinogen by the World Health Organization in 1994. Here, we show that HP0851, renamed HupA, is the major undecaprenyl pyrophosphate (C₅₅-PP) phosphatase (UppP) and the major phosphatidylglycerol phosphate phosphatase (PGPase). This enzyme is also involved in cationic antimicrobial peptide (CAMP) resistance to which H. pylori hupA mutant shows an increased sensitivity (4 fold). This mutant was unable to colonize the stomach in mouse model of infection showing that even if hupA was not essential in vitro, this gene was essential in vivo. Both HupA and LpxE have crucial roles in the biosynthesis of several cell wall polysaccharides and thus constitute potential targets for new therapeutic strategies.

• Bacterial two hybrid (BACTH)
• Helicobacter pylori
• Protein secretion
• Protein-protein interaction
• Type IV Secretion System (T4SS)
• cagPAI

Rosacea is a chronic skin disease characterized by facial erythema and telangiectasia. Despite the fact that many hypotheses have been proposed, its etiology remains unknown. In the present review, the possible link and clinical significance of Helicobacter pylori in the pathogenesis of rosacea are being sought. A PubMed and Google Scholar search was performed using the terms “rosacea”, “H.pylori”, “gastrointestinal disorders and H.pylori”, “microorganisms and rosacea”, “pathogenesis and treatment of rosacea”, and “risk factors of rosacea”, and selected publications were studied and referenced in text. Although a possible pathogenetic link between H. pylori and rosacea is advocated by many authors, evidence is still interpreted differently by others. We conclude that further studies are needed in order to fully elucidate the pathogenesis of rosacea.

• Helicobacter pylori
• eradication
• pathogenesis
• rosacea

Highly virulent Helicobacter pylori cause proinflammatory signaling inducing the transcriptional activation and secretion of cytokines such as IL-8 in epithelial cells. Responsible in part for this signaling is the cag pathogenicity island (cagPAI) that codetermines the risk for pathological sequelae of an H. pylori infection such as gastric cancer. The Cag type IV secretion system (CagT4SS), encoded on the cagPAI, can translocate various molecules into cells, the effector protein CagA, peptidoglycan metabolites and DNA. Although these transported molecules are known to contribute to cellular responses to some extent, a major part of the cagPAI-induced signaling leading to IL-8 secretion remains unexplained. We report here that biosynthesis of heptose-1,7-bisphosphate (HBP), an important intermediate metabolite of LPS inner heptose core, contributes in a major way to the H. pylori cagPAI-dependent induction of proinflammatory signaling and IL-8 secretion in human epithelial cells. Mutants defective in the genes required for synthesis of HBP exhibited a more than 95% reduction of IL-8 induction and impaired CagT4SS-dependent cellular signaling. The loss of HBP biosynthesis did not abolish the ability to translocate CagA. The human cellular adaptor TIFA, which was described before to mediate HBP-dependent activity in other Gram-negative bacteria, was crucial in the cagPAI- and HBP pathway-induced responses by H. pylori in different cell types. The active metabolite was present in H. pylori lysates but not enriched in bacterial supernatants. These novel results advance our mechanistic understanding of H. pylori cagPAI-dependent signaling mediated by intracellular pattern recognition receptors. They will also allow to better dissect immunomodulatory activities by H. pylori and to improve the possibilities of intervention in cagPAI- and inflammation-driven cancerogenesis.

The Cag Type IV secretion system, which contributes to inflammation and cancerogenesis during chronic infection, is one of the major virulence and fitness factors of the bacterial gastric pathogen Helicobacter pylori. Up to now, the mechanisms leading to cagPAI-dependent signal transduction and cytokine secretion were not completely understood. We report here that HBP, an intermediate metabolite in LPS core heptose biosynthesis, is translocated into host cells dependent on the CagT4SS, and is a major factor leading to the activation of cellular responses. This response is connected to the human cellular adaptor protein TIFA. The knowledge of this specific response pathway is a major advance in understanding CagT4SS-dependent signaling and will enable us to understand better how H. pylori modulates the immune response repertoire in its human host.

• Dsb proteins
• Helicobacter pylori
• chaperone activity
• disulfide bonds
• oxidoreductases
• protein engineering
• site-directed mutagenesis

As a neutrophilic bacterium, Helicobacter pylori is growth deficient under extreme acidic conditions. The gastric pathogen is equipped with an acid survival kit, regulating urease activity by a pH-gated urea channel, opening below pH 6.5. After overcoming acid stress, the bacterium’s multiplication site is situated at the gastric mucosa with near neutral pH. The pathogen exhibits exceptional genetic variability, mainly due to its capability of natural transformation, termed competence. Using single cell analysis, we show here that competence is highly regulated in H. pylori. DNA uptake complex activity was reversibly shut down below pH 6.5. pH values above 6.5 opened a competence window, in which competence development was triggered by the combination of pH increase and oxidative stress. In contrast, addition of sublethal concentrations of the DNA-damaging agents ciprofloxacin or mitomycin C did not trigger competence development under our conditions. An oxygen-sensitive mutant lacking superoxide dismutase (sodB) displayed a higher competent fraction of cells than the wild type under comparable conditions. In addition, the sodB mutant was dependent on adenine for growth in broth and turned into non-cultivable coccoid forms in its absence, indicating that adenine had radical quenching capacity. Quantification of periplasmically located DNA in competent wild type cells revealed outstanding median imported DNA amounts of around 350 kb per cell within 10 min of import, with maximally a chromosomal equivalent (1.6 Mb) in individual cells, far exceeding previous amounts detected in other Gram-negative bacteria. We conclude that the pathogen’s high genetic diversity is a consequence of its enormous DNA uptake capacity, triggered by intrinsic and extrinsic oxidative stress once a neutral pH at the site of chronic host colonization allows competence development.

Natural transformation, i.e. the capacity to take up DNA from the environment, is one of the crucial means for horizontal gene transfer and genetic diversity in bacteria. The human gastric pathogen Helicobacter pylori is confronted with acid stress before entering its multiplication site, the gastric mucosa. The bacterium causes lifelong chronic gastritis and is perfectly adapted to the human host, crucially by displaying unusual genetic diversity. Using a single cell approach and well-controlled conditions, we show here that the amount of imported DNA in competent H. pylori is outstanding, far exceeding previous measurement with other Gram-negative bacteria. Furthermore, DNA uptake activity was tightly regulated and limited to pH above 6.5, conditions thought to be met in close contact with the gastric mucosa. In addition, we show that within this pH competence window, competence development was triggered by an increase in pH in combination with the level of oxidative stress. Our data provide explanations for the extraordinary high genetic diversity, often referred to as genome plasticity of this unusual microaerobic pathogen.

• Adaptation, Physiological/genetics
• DNA, Bacterial/genetics
• Gastric Mucosa/microbiology
• Genetic Variation
• Helicobacter pylori/genetics
• Helicobacter pylori/growth & development
• Humans
• Oxidative Stress/physiology

• Deutsche Forschungsgemeinschaft

The Helicobacter pylori energy sensor TlpD determines tactic behaviour under low energy conditions and is important in vivo. We explored protein-protein interactions of TlpD and their impact on TlpD localisation and function. Pull-down of tagged TlpD identified protein interaction partners of TlpD, which included the chemotaxis histidine kinase CheAY2, the central metabolic enzyme aconitase (AcnB) and the detoxifying enzyme catalase (KatA). We confirmed that KatA and AcnB physically interact with TlpD. While the TlpD-dependent behavioural response appeared not influenced in the interactor mutants katA and acnB in steady-state behavioural assays, acetone carboxylase subunit (acxC) mutant behaviour was altered. TlpD was localised in a bipolar subcellular pattern in media of high energy. We observed a significant change in TlpD localisation towards the cell body in cheAY2-, catalase- or aconitase-deficient bacteria or in bacteria incubated under low energy conditions, including oxidative stress or respiratory inhibition. Inactivation of tlpD resulted in an increased sensitivity to iron limitation and oxidative stress and influenced the H. pylori transcriptome. Oxidative stress, iron limitation and overexpressing the iron-sulfur repair system nifSU altered TlpD-dependent behaviour. We propose that TlpD localisation is instructed by metabolic activity and protein interactions, and its sensory activity is linked to iron-sulfur cluster integrity.

Helicobacter pylori does not encode the classical DsbA/DsbB oxidoreductases that are crucial for oxidative folding of extracytoplasmic proteins. Instead, this microorganism encodes an untypical two proteins playing a role in disulfide bond formation – periplasmic HP0231, which structure resembles that of EcDsbC/DsbG, and its redox partner, a membrane protein HpDsbI (HP0595) with a β-propeller structure. The aim of presented work was to assess relations between HP0231 structure and function. We showed that HP0231 is most closely related evolutionarily to the catalytic domain of DsbG, even though it possesses a catalytic motif typical for canonical DsbA proteins. Similarly, the highly diverged N-terminal dimerization domain is homologous to the dimerization domain of DsbG. To better understand the functioning of this atypical oxidoreductase, we examined its activity using in vivo and in vitro experiments. We found that HP0231 exhibits oxidizing and chaperone activities but no isomerizing activity, even though H. pylori does not contain a classical DsbC. We also show that HP0231 is not involved in the introduction of disulfide bonds into HcpC (Helicobactercysteine-rich protein C), a protein involved in the modulation of the H. pylori interaction with its host. Additionally, we also constructed a truncated version of HP0231 lacking the dimerization domain, denoted HP0231m, and showed that it acts in Escherichia coli cells in a DsbB-dependent manner. In contrast, HP0231m and classical monomeric EcDsbA (E. coli DsbA protein) were both unable to complement the lack of HP0231 in H. pylori cells, though they exist in oxidized forms. HP0231m is inactive in the insulin reduction assay and possesses high chaperone activity, in contrast to EcDsbA. In conclusion, HP0231 combines oxidative functions characteristic of DsbA proteins and chaperone activity characteristic of DsbC/DsbG, and it lacks isomerization activity.

• Dsb proteins
• Helicobacter pylori
• chaperone activity
• disulfide bonds
• oxidoreductase activity

Helicobacter is a genus of Gram-negative bacteria, possessing a characteristic helical shape that has been associated with a wide spectrum of human diseases. Although much research has been done on Helicobacter and many genomes have been sequenced, currently there is no specialized Helicobacter genomic resource and analysis platform to facilitate analysis of these genomes. With the increasing number of Helicobacter genomes being sequenced, comparative genomic analysis on members of this species will provide further insights on their taxonomy, phylogeny, pathogenicity and other information that may contribute to better management of diseases caused by Helicobacter pathogens.

To facilitate the ongoing research on Helicobacter, a specialized central repository and analysis platform for the Helicobacter research community is needed to host the fast-growing amount of genomic data and facilitate the analysis of these data, particularly comparative analysis. Here we present HelicoBase, a user-friendly Helicobacter resource platform with diverse functionality for the analysis of Helicobacter genomic data for the Helicobacter research communities. HelicoBase hosts a total of 13 species and 166 genome sequences of Helicobacter spp. Genome annotations such as gene/protein sequences, protein function and sub-cellular localisation are also included. Our web implementation supports diverse query types and seamless searching of annotations using an AJAX-based real-time searching system. JBrowse is also incorporated to allow rapid and seamless browsing of Helicobacter genomes and annotations. Advanced bioinformatics analysis tools consisting of standard BLAST for similarity search, VFDB BLAST for sequence similarity search against the Virulence Factor Database (VFDB), Pairwise Genome Comparison (PGC) tool for comparative genomic analysis, and a newly designed Pathogenomics Profiling Tool (PathoProT) for comparative pathogenomic analysis are also included to facilitate the analysis of Helicobacter genomic data.

HelicoBase offers access to a range of genomic resources as well as tools for the analysis of Helicobacter genome data. HelicoBase can be accessed at http://helicobacter.um.edu.my.

The online version of this article (doi:10.1186/1471-2164-15-600) contains supplementary material, which is available to authorized users.

Helicobacter pylori (H. pylori), a major pathogen colonizing the human stomach, shows great genetic variation. Comparative analysis of strains from different H. pylori populations revealed that the genome size of strains from East Asia decreased to 1.60 Mbp, which is significantly smaller than that from Europe or Africa. In parallel with the genome reduction, the number of protein coding genes was decreased, and the guanine-cytosine content was lowered to 38.9%. Elimination of non-essential genes by mutations is likely to be a major cause of the genome reduction. Bacteria with a small genome cost less energy. Thus, H. pylori strains from East Asia may have proliferation and growth advantages over those from Western countries. This could result in enhanced capacity of bacterial spreading. Therefore, the reduced genome size potentially contributes to the high prevalence of H. pylori in East Asia.

• Helicobacter pylori
• Genome
• Mutation
• Epidemiology
• Recombination

• Asia
• Genetic Variation
• Genome Size
• Genome, Bacterial
• Helicobacter Infections/epidemiology
• Helicobacter Infections/microbiology
• Helicobacter pylori/genetics
• Humans
• Mutation
• Phylogeny
• Prevalence
• Recombination, Genetic
• Stomach/microbiology

• Carcinogen
• Gastric cancer
• Gastric diseases
• Helicobacter pylori
• p53 mutation

• Diet
• Genetic Variation
• Geography
• Helicobacter Infections/complications
• Helicobacter Infections/epidemiology
• Helicobacter pylori/genetics
• Humans
• India/epidemiology
• Peptic Ulcer/microbiology
• Prevalence
• Smoking
• Social Class
• Species Specificity
• Stomach Neoplasms/complications
• Stomach Neoplasms/epidemiology
• Stomach Neoplasms/microbiology

• Genomes
• adaptation
• evolution
• genomic diversity
• virulence

The purpose of this table is to provide the community with a citable record of publications of ongoing genome sequencing projects that have led to a publication in the scientific literature. While our goal is to make the list complete, there is no guarantee that we may have omitted one or more publications appearing in this time frame. Readers and authors who wish to have publications added to subsequent versions of this list are invited to provide the bibliographic data for such references to the SIGS editorial office.

The purpose of this table is to provide the community with a citable record of publications of ongoing genome sequencing projects that have led to a publication in the scientific literature. While our goal is to make the list complete, there is no guarantee that we may have omitted one or more publications appearing in this time frame. Readers and authors who wish to have publications added to subsequent versions of this list are invited to provide the bibliographic data for such references to the SIGS editorial office.

The purpose of this table is to provide the community with a citable record of publications of ongoing genome sequencing projects that have led to a publication in the scientific literature. While our goal is to make the list complete, there is no guarantee that we may have omitted one or more publications appearing in this time frame. Readers and authors who wish to have publications added to subsequent versions of this list are invited to provide the bibliographic data for such references to the SIGS editorial office.