205 research outputs found
Inflammasome activation by helicobacter pylori and its implications for persistence and immunity
No full textInfection with the Gram-negative pathogen Helicobacter pylori is the most prevalent chronic bacterial infection affecting about 50 % of the human world population and is the main risk factor for gastric cancer development. The pro-inflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors, and polymorphisms in the IL-1 gene cluster resulting in increased IL-1β production have been associated with increased risk for gastric cancer. Recently, Helicobacter pylori was postulated to activate the inflammasome in human and mouse immune cells, and the molecular mechanisms and the bacterial virulence factors activating the inflammasome were elucidated in cell culture as well as animal models. It appears that H. pylori-induced IL-1β secretion is mediated by activation of toll-like receptor 2 (TLR-2), Nod-like receptor family member NLRP3 and caspase-1. The cag pathogenicity island-encoded type IV secretion system, lipopolysaccharide, vacuolating cytotoxin, and urease B subunit appear to play a role in inflammasome activation. In addition, recent results indicate that the TLR-2 → NLRP3 → caspase-1 → IL-18 axis is critical to H. pylori-specific immune regulation conferring protection against allergen-induced asthma and inflammatory bowel disease in murine models. The present chapter will review the proposed mechanisms of NLRP3 inflammasome activation during H. pylori infection and discuss the recent progress in this important research field
The Cag pathogenicity island and interaction between TLR 2/ NOD 2 and NLRP 3 regulate IL ‐1β production in Helicobacter pylori infected dendritic cells
No full textPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100315/1/eji2723.pd
An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA
No full textConradi J, Tegtmeyer N, Wozna M, et al. An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Frontiers in Cellular and Infection Microbiology. 2012;2:70.Helicobacter pylori is a specific gastric pathogen that colonizes the stomach in more than 50% of the world’s human population. Infection with this bacterium can induce several types of gastric pathology, ranging from chronic gastritis to peptic ulcers and even adenocarcinoma. Virulent H. pylori isolates encode components of a type IV secretion system (T4SS), which form a pilus for the injection of virulence proteins such as CagA into host target cells. This is accomplished by a specialized adhesin on the pilus surface, the protein CagL, a putative VirB5 ortholog, which binds to host cell β1 integrin, triggering subsequent delivery of CagA across the host cell membrane. Like the human extracellular matrix protein fibronectin, CagL contains an RGD (Arg-Gly-Asp) motif and is able to trigger intracellular signaling pathways by RGD-dependent binding to integrins. While CagL binding to host cells is mediated primarily by the RGD motif, we identified an auxiliary binding motif for CagL–integrin interaction. Here, we report on a surface exposed FEANE (Phe-Glu-Ala-Asn-Glu) interaction motif in spatial proximity to the RGD sequence, which enhances the interactions of CagL with integrins. It will be referred to as RGD helper sequence (RHS). Competitive cell adhesion assays with recombinant wild type CagL and point mutants, competition experiments with synthetic cyclic and linear peptides, and peptide array experiments revealed amino acids essential for the interaction of the RHS motif with integrins. Infection experiments indicate that the RHS motif plays a role in the early interaction of H. pylori T4SS with integrin, to trigger signaling and to inject CagA into host cells. We thus postulate that CagL is a versatile T4SS surface protein equipped with at least two motifs to promote binding to integrins, thereby causing aberrant signaling within host cells and facilitating translocation of CagA into host cells, thus contributing directly to H. pylori pathogenesis
Cell Communication and Signaling / Transmigration route of Campylobacter jejuni across polarized intestinal epithelial cells: paracellular, transcellular or both?
No full textAbstract: Intact intercellular junctions and cellular matrix contacts are crucial structural components for the formation and >maintenance of epithelial barrier functions in humans to control the commensal flora and protect against intruding microbes. Campylobacter jejuni is one of the most important zoonotic pathogens causing food-borne gastroenteritis and potentially more severe diseases such as reactive arthritis or Guillain–Barré syndrome. Crossing the intestinal epithelial barrier and host cell invasion by C. jejuni are considered to represent the primary reasons of gut tissue damage in humans and various animal model systems including monkeys, piglets, rabbits, hamsters and ferrets. C. jejuni is also able to invade underlying tissues such as the lamina propria, can enter the bloodstream, and possibly reach distinct organs such as spleen, liver or mesenteric lymph nodes. However, the molecular mechanisms as well as major bacterial and host cell factors involved in these activities are poorly understood. Various models exist by which the pathogen can trigger its own transmigration across polarized intestinal epithelial cells in vitro, the paracellular and/or transcellular mechanism. Recent studies suggest that bacterial factors such as flagellum, serine protease HtrA and lipooligosaccharide LOS may play an active role in bacterial transmigration. Here we review our knowledge on transmigration of C. jejuni as well as some other Campylobacter species, and discuss the pros and cons for the route(s) taken to travel across polarized epithelial cell monolayers. These studies provide fresh insights into the infection strategies employed by this important pathogen.Steffen Backert, Manja Boehm, Silja Wessler and Nicole Tegtmeye
Inflammasome Activation and Function During Infection with Mycobacterium tuberculosis
No full textTuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb) and represents one of the most relevant bacterial diseases worldwide. Recent advances have yielded new insights into the molecular basis of the immune response required for restriction of the pathogen and also highlighted determinants of immunopathology in TB. Several innate immune mediators including soluble proteins as well as lipid molecules participate in both processes, and their mechanisms of action during TB have been extensively studies over the past years. Among those mediators, inflammasomes are essential signaling platforms that execute crucial functions in several areas of immunology and beyond. This chapter aims to summarize what is known about the roles of the inflammasome during infection with Mtb from both in vitro studies as well as from in vivo work. A better understanding of the complex interactions between Mtb and the host immune system could reveal novel therapeutic approaches and improve current vaccination protocols in TB.UPABLASSE
Gastric stem cell biology and helicobacter pylori infection
No full textHelicobacter pylori colonizes the human gastric mucosa and persists lifelong. An interactive network between the bacteria and host cells shapes a unique microbial niche within gastric glands that alters epithelial behavior, leading to pathologies such as chronic gastritis and eventually gastric cancer. Gland colonization by the bacterium initiates aberrant trajectories by inducing long-term inflammatory and regenerative gland responses, which involve various specialized epithelial and stromal cells. Recent studies using cell lineage tracing, organoids and scRNA-seq techniques have significantly advanced our knowledge of the molecular "identity" of epithelial and stromal cell subtypes during normal homeostasis and upon infection, and revealed the principles that underly stem cell (niche) behavior under homeostatic conditions as well as upon H. pylori infection. The activation of long-lived stem cells deep in the gastric glands has emerged as a key prerequisite of H. pylori-associated gastric site-specific pathologies such as hyperplasia in the antrum, and atrophy or metaplasia in the corpus, that are considered premalignant lesions. In addition to altering the behaviour of bona fide stem cells, injury-driven de-differentiation and trans-differentation programs, such as "paligenosis", subsequently allow highly specialized secretory cells to re-acquire stem cell functions, driving gland regeneration. This plastic regenerative capacity of gastric glands is required to maintain homeostasis and repair mucosal injuries. However, these processes are co-opted in the context of stepwise malignant transformation in chronic H. pylori infection, causing the emergence, selection and expansion of cancer-promoting stem cells
MALT Lymphoma as a Model of Chronic Inflammation-Induced Gastric Tumor Development
No full textMucosa-associated lymphoid tissue (MALT) lymphoma, or extranodal marginal zone lymphoma of MALT, is an indolent B-cell non-Hodgkin lymphoma linked with preexisting chronic inflammation. The stomach is the most commonly affected organ and the MALT lymphoma pathogenesis is clearly associated with Helicobacter pylori gastroduodenitis. Inflammation induces the lymphoid infiltrates in extranodal sites, where the lymphoma then subsequently develops. Genetic aberrations arise through the release of reactive oxygen species (ROS), H. pylori-induced endonucleases, and other effects. The involvement of nuclear factor kappa B (NF-κB) pathway activation, a critical regulator of pro-inflammatory responses, further highlights the role of inflammation in gastric MALT lymphoma. The NF-κB pathway regulates key elements of normal lymphocyte function, including the transcription of proliferation-promoting and anti-apoptotic genes. Aberrant constitutive activation of NF-κB signaling can lead to autoimmunity and malignancy. NF-κB pathway activation can happen through both the canonical and non-canonical pathways and can be caused by multiple genetic aberrations such as t(11;18)(q12;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) translocations, chronic inflammation and even directly by H. pylori-associated mechanisms. Gastric MALT lymphoma is considered one of the best models of how inflammation initiates genetic events that lead to oncogenesis, determines tumor biology, dictates clinical behavior and leads to viable therapeutic targets. The purpose of this review is to present gastric MALT lymphoma as an outstanding example of the close pathogenetic link between chronic inflammation and tumor development and to describe how this information can be integrated into daily clinical practice.status: Publishe
Functional analysis and cryo-electron microscopy of Campylobacter jejuni serine protease HtrA
No full textCampylobacter jejuni is a predominant zoonotic pathogen causing gastroenteritis and other diseases in humans. An important bacterial virulence factor is the secreted serine protease HtrA (HtrA Cj), which targets tight and adherens junctional proteins in the gut epithelium. Here we have investigated the function and structure of HtrA Cj using biochemical assays and cryo-electron microscopy. Mass spectrometry analysis identified differences and similarities in the cleavage site specificity for HtrA Cj by comparison to the HtrA counterparts from Helicobacter pylori and Escherichia coli. We defined the architecture of HtrA Cj at 5.8 Å resolution as a dodecamer, built of four trimers. The contacts between the trimers are quite loose, a fact that explains the flexibility and mobility of the dodecameric assembly. This flexibility has also been studied through molecular dynamics simulation, which revealed opening of the dodecamer to expose the proteolytically active site of the protease. Moreover, we examined the rearrangements at the level of oligomerization in the presence or absence of substrate using size exclusion chromatography, which revealed hexamers, dodecamers and larger oligomeric forms, as well as remarkable stability of higher oligomeric forms (> 12-mers) compared to previously tested homologs from other bacteria. Extremely dynamic decay of the higher oligomeric forms into lower forms was observed after full cleavage of the substrate by the proteolytically active variant of HtrA Cj. Together, this is the first report on the in-depth functional and structural analysis of HtrA Cj, which may allow the construction of therapeutically relevant HtrA Cj inhibitors in the near future
Structural and molecular biology of Type IV Secretion Systems
No full textType IV secretion systems (T4SSs) are nanomachines that Gram-negative, Gram-positive bacteria, and some archaea use to transport macromolecules across their membranes into bacterial or eukaryotic host targets or into the extracellular milieu. They are the most versatile secretion systems, being able to deliver both proteins and nucleoprotein complexes into targeted cells. By mediating conjugation and/or competence, T4SSs play important roles in determining bacterial genome plasticity and diversity; they also play a pivotal role in the spread of antibiotic resistance within bacterial populations. T4SSs are also used by human pathogens such as Legionella pneumophila, Bordetella pertussis, Brucella sp., or Helicobacter pylori to sustain infection. Since they are essential virulence factors for these important pathogens, T4SSs might represent attractive targets for vaccines and therapeutics. The best-characterized conjugative T4SSs of Gram-negative bacteria are composed of twelve components that are conserved across many T4SSs. In this chapter, we will review our current structural knowledge on the T4SSs by describing the structures of the individual components and how they assemble into large macromolecular assemblies. With the combined efforts of X-ray crystallography, nuclear magnetic resonance (NMR), and more recently electron microscopy, structural biology of the T4SS has made spectacular progress during the past fifteen years and has unraveled the properties of unique proteins and complexes that assemble dynamically in a highly sophisticated manner
Helicobacter pylori and Extragastric Diseases
No full textThe Gram-negative bacterium Helicobacter pylori is predominantly known for its tight association with peptic ulcer disease and gastric cancer development. However, recent epidemiological and experimental evidence suggests that chronic infection with H. pylori may at the same time be beneficial to the host by conferring protection against gastroesophageal diseases, asthma, other allergic disease manifestations and inflammatory bowel diseases (IBD). In this chapter, we summarize the epidemiological data that are available to date to support or refute a possible inverse correlation of H. pylori infection with various extragastric diseases. We further examine and discuss the experimental evidence, generated mostly in mouse models of allergic diseases and IBD, showing that these disorders fail to develop in the presence of H. pylori. The proposed mechanisms of the protective effects of H. pylori, which appear to involve the induction of regulatory T-cells (Tregs) with highly suppressive activity, are presented and explained
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