Pylori Pathogenesis Research Articles

Targeting Helicobacter pylori Through the “Muco-Microbiotic Layer” Lens: The Challenge of Probiotics and Microbiota Nanovesicles

The muco-microbiotic layer represents a critical biological frontier in gastroenterology, emphasizing the intricate interplay between the protective mucus, its resident microbiota, and extracellular vesicles. This review explores the functional morphology of the gastric mucosa, focusing on the gastric muco-microbiotic layer, its role as a protective barrier, and its dynamic interaction with some of the most insidious pathogens such as Helicobacter pylori (H. pylori). Highlighting the multifaceted mechanisms of H. pylori pathogenesis, we have delved into bacterial virulence factors, host immune responses, and the microbiota’s regulatory effects. Novel therapeutic strategies for H. pylori eradication, including traditional antibiotic therapies and emerging adjuvant treatments like probiotics and probiotic-derived extracellular vesicles, are critically examined. These findings underscore the potential of targeting nanovesicular interactions in the gastric mucosa, proposing a paradigm shift in the management of H. pylori infections to improve patient outcomes while mitigating antibiotic resistance.

The Aging Stomach: Clinical Implications of H. pylori Infection in Older Adults-Challenges and Strategies for Improved Management.

Aging is a multifactorial biological process characterized by a decline in physiological function and increasing susceptibility to various diseases, including malignancies and gastrointestinal disorders. Helicobacter pylori (H. pylori) infection is highly prevalent among older adults, particularly those in institutionalized settings, contributing to conditions such as atrophic gastritis, peptic ulcer disease, and gastric carcinoma. This review examines the intricate interplay between aging, gastrointestinal changes, and H. pylori pathogenesis. The age-associated decline in immune function, known as immunosenescence, exacerbates the challenges of managing H. pylori infection. Comorbidities and polypharmacy further increase the risk of adverse outcomes in older adults. Current clinical guidelines inadequately address the specific needs of the geriatric population, who are disproportionately affected by antibiotic resistance, heightened side effects, and diagnostic complexities. This review focuses on recent advancements in understanding H. pylori infection among older adults, including epidemiology, diagnostics, therapeutic strategies, and age-related gastric changes. Diagnostic approaches must consider the physiological changes that accompany aging, and treatment regimens need to be carefully tailored to balance efficacy and tolerability. Emerging strategies, such as novel eradication regimens and adjunctive probiotic therapies, show promise for improving treatment outcomes. However, significant knowledge gaps persist regarding the impact of aging on H. pylori pathogenesis and treatment efficacy. A multidisciplinary approach involving gastroenterologists, geriatricians, and other specialists is crucial to providing comprehensive care for this vulnerable population. Future research should focus on refining diagnostic and therapeutic protocols to bridge these gaps, ultimately enhancing clinical outcomes and reducing the burden of H. pylori-associated diseases in the aging population.

Helicobacter pylori PldA modulates TNFR1-mediated p38 signaling pathways to regulate macrophage responses for its survival

ABSTRACT Helicobacter pylori, a dominant member of the gastric microbiota was associated with various gastrointestinal diseases and presents a significant challenge due to increasing antibiotic resistance. This study identifies H. pylori’s phospholipase A (PldA) as a critical factor in modulating host macrophage responses, facilitating H. pylori ‘s evasion of the immune system and persistence. PldA alters membrane lipids through reversible acylation and deacylation, affecting their structure and function. We found that PldA incorporates lysophosphatidylethanolamine into macrophage membranes, disrupting their bilayer structure and impairing TNFR1-mediated p38-MK2 signaling. This disruption results in reduced macrophage autophagy and elevated RIP1-dependent apoptosis, thereby enhancing H. pylori survival, a mechanism also observed in multidrug-resistant strains. Pharmacological inhibition of PldA significantly decreases H. pylori viability and increases macrophage survival. In vivo studies corroborate PldA’s essential role in H. pylori persistence and immune cell recruitment. Our findings position PldA as a pivotal element in H. pylori pathogenesis through TNFR1-mediated membrane modulation, offering a promising therapeutic target to counteract bacterial resistance.

Roles of the components of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori.

The Helicobacter pylori (H. pylori) cytotoxin-associated gene pathogenicity island (cagPAI) encodes 31 genes that assemble the cag type IV secretion system (T4SS) apparatus, which includes structures such as the outer membrane core complex, periplasmic ring, inner membrane complex and bacterial hairs. These proteins interact with each other to inject CagA into the host gastric epithelium. There are also individual unique functions that help H. pylori interfere with host cellular pathways, modulate the immune response and colonize the host for a long time. However, the functions of some of the proteins remain unclear. This review summarizes what is known about the structure and function of these auxiliary components and discusses their role in H. pylori pathogenesis.

Prevalence of cagA, cagM, vacA and oipA genes in isolates of Helicobacter pylori obtained from hospital patients in Northeast Brazil.

Helicobacter pylori is a major cause of gastrointestinal disorders such as chronic gastritis, peptic ulcers, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. It is estimated that around half of the world's population is infected with this pathogen, with underdeveloped countries reporting the highest frequencies. The genes cagA, cagM, vacA, and oipA are some of the most important virulence factors of H. pylori; however, there are no recent studies from Recife-PE demonstrating their frequency, and their relationship with severe gastric modifications. This work aims to use qualitative PCR to detect the virulence genes cagA, cagM, vacA, and oipA in H. pylori isolates obtained from patients in a public hospital in Recife (PE). We collected samples from the stomach's body and antrum of 147 patients, from which 71 (48%) tested positive for H. pylori. Among positive samples, the most frequently infected gender was female (44/71, 62%), and the most frequently infected age group was those above the age of 46 (31/71, 44%). Histological examination of H. pylori-positive samples revealed alterations other than chronic gastritis, including metaplasia and atrophy. The frequency of cagA, cagM, and oipA genes were identified in 84%, 56%, and 69% of the samples tested, respectively, as well as the vacA-s1m1 allelic combination (77%). However, there was no statistically significant variation in the occurrence of these genes, therefore they cannot be considered unique markers of severity in our setting. New research with larger samples and investigations of other genetic markers can aid uncover local risk factors and lead to a better understanding of H. pylori's pathogenesis.

Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating β-Catenin nuclear translocation

IntroductionHelicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in H. pylori pathogenesis and gastric cancer (GC) remains poorly understood. ObjectivesTo investigate the potential role of LRP8 in H. pylori infection and gastric carcinogenesis. MethodsThree-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with in vivo and in vitro studies were conducted to investigate the potential involvement of LRP8 in H. pylori-induced GC. ResultsWe found that H. pylori infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to β-catenin, thereby promoting nuclear translocation and transcriptional activity of β-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/β-catenin complex. This complex further amplifies H. pylori-induced β-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC. ConclusionOur findings provide valuable information on the molecular intricacies of H. pylori-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.

Unraveling the crystal structure of the HpaA adhesin: insights into cell adhesion function and epitope localization of a Helicobacter pylori vaccine candidate.

Helicobacter pylori is a bacterium that can cause chronic gastritis, peptic ulcers, and gastric cancers. The bacterium adheres to the lining of the stomach using proteins called adhesins. One of these proteins, HpaA, is particularly important for H. pylori colonization and is considered a promising vaccine candidate against H. pylori infections. In this work, we determined the atomic structure of HpaA, identifying a characteristic protein fold to the Helicobacter family and delineating specific amino acids that are crucial to support the attachment to the gastric cells. Additionally, we discovered that HpaA can trigger the production of TNF-α, a proinflammatory molecule, in macrophages. These findings provide valuable insights into how H. pylori causes disease and suggest that HpaA has a dual role in both attachment and immune activation. This knowledge could contribute to the development of improved vaccine strategies for preventing H. pylori infections.

Helicobacter pylori secretory Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation

Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91phox (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91phox expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS.This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.

The Helicobacter pylori Genome Project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics.

Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori-induced gastric cancer.

H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.

The interaction between autophagy, Helicobacter pylori, and gut microbiota in gastric carcinogenesis.

Chronic infection with Helicobacter pylori is the primary risk factor for the development of gastric cancer. Hindering our ability to comprehend the precise role of autophagy during H. pylori infection is the complexity of context-dependent autophagy signaling pathways. Recent and ongoing progress in understanding H. pylori virulence allows new frontiers of research for the crosstalk between autophagy and H. pylori. Novel approaches toward discovering autophagy signaling networks have further revealed their critical influence on the structure of gut microbiota and the metabolome. Here we intend to present a holistic view of the perplexing role of autophagy in H. pylori pathogenesis and carcinogenesis. We also discuss the intermediate role of autophagy in H. pylori-mediated modification of gut inflammatory responses and microbiota structure.

Helicobacter pylori-derived outer membrane vesicles suppress liver autophagy: A novel mechanism for H. pylori-mediated hepatic disorder

BackgroundHelicobacter pylori outer membrane vesicles (OMVs) are nano-sized structures, which have been recently suggested to play a crucial role in H. pylori pathogenesis. There are growing evidence indicating the relationship of H. pylori infection with extra-gastroduodenal diseases, especially liver-related disorders. This study was aimed to investigate the effects of H. pylori-derived OMVs on autophagy in hepatic stellate cells (HSCs). Material and methodsA selection of five clinical strains of H. pylori with different virulence genotypes were included. The OMVs were isolated by ultracentrifugation and characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS). The protein concentration of OMVs was measured by BCA assay. MTT assay was used to determine the viability of LX-2 cells (human HSCs) treated with OMVs. The expression level of MTOR, AKT, PI3K, BECN1, ATG16 and LC3B genes was assessed in OMVs-treated LX-2 cells using quantitative real-time PCR. Moreover, immunocytochemistry was performed to evaluate the protein expression of MTOR and LC3B autophagy markers. ResultsH. pylori strains produced round shape nano-vesicles ranging from 50 to 500 nm. Treatment of HSCs with H. pylori-derived OMVs at concentration of 10 μg/mL for 24 h significantly elevated the expression of autophagy inhibitory markers (PI3K, AKT, and MTOR) and suppressed the mRNA expression level of autophagy core proteins (BECN1, ATG16 and LC3B). Immunocytochemistry also presented a substantial reduction in the concentration of LC3B autophagy core protein, and a marked elevation in the amount of MTOR autophagy inhibitory protein. ConclusionThis study revealed that H. pylori-derived OMVs could potentially suppress autophagy flux in HSCs as a novel mechanism for H. pylori-mediated liver autophagy impairment and liver disease development. Further studies are required to elucidate the exact role of OMV-carried contents in liver autophagy, and liver-associated disorders.

Comparative genomics of two Vietnamese Helicobacter pylori strains, CHC155 from a non-cardia gastric cancer patient and VN1291 from a duodenal ulcer patient

Helicobacter pylori is involved in the etiology and severity of several gastroduodenal diseases; however, plasticity of the H. pylori genome makes complete genome assembly difficult. We report here the full genomes of H. pylori strains CHC155 and VN1291 isolated from a non-cardia gastric cancer patient and a duodenal ulcer patient, respectively, and their virulence demonstrated by in vitro infection. Whole-genome sequences were obtained by combining long- and short-reads with a hybrid-assembly approach. Both CHC155 and VN1291 genome possessed four kinds of genomic island: a cag pathogenicity island (cagPAI), two type 4 secretion system islands within an integrative and conjugative element (tfs ICE), and prophage. CHC155 and VN1291 carried East Asian-type cagA and vacA s1m1, and outer membrane protein genes, including two copies of oipA. Corresponded to genetic determinants of antibiotic resistance, chromosomal mutations were identified in CHC155 (rdxA, gyrA, and 23S rRNA) and VN1291 (rdxA, 23S rRNA, and pbp1A). In vitro infection of AGS cells by both strains induced the cell scattering phenotype, tyrosine phosphorylation of CagA, and promoted high levels of IL8 secretion, indicating fully intact phenotypes of the cagPAI. Virulence genes in CHC155 and VN1291 genomes are crucial for H. pylori pathogenesis and are risk factors in the development of gastric cancer and duodenal ulcer. Our in vitro studies indicate that the strains CHC155 and VN1291 carry the pathogenic potential.

YAP and β-catenin cooperate to drive H. pylori-induced gastric tumorigenesis

ABSTRACT H. pylori infection is the strongest known risk factor for gastric carcinoma. The activation of the yes-associated protein 1 (YAP) and β-catenin pathways has been associated with multiple tumor types. In this study, we investigated the crosstalk between the YAP and β-catenin pathways in H. pylori-associated gastric tumorigenesis. Immunohistochemical analysis of YAP and β-catenin expression was performed in human gastric cancer tissues. The small molecules Super-TDU and KYA1797K, pharmacological inhibitors of YAP and β-catenin, respectively, were used to investigate the role of these signaling pathways in H. pylori-induced gastric carcinogenesis in murine models of infection. The common downstream targets of YAP and β-catenin signaling were evaluated by RNA sequencing (RNA-seq). Western blot, immunofluorescence, luciferase, RT-PCR, immunoprecipitation, cell counting kit-8 (CCK8), EdU and spheroid assays were used. H. pylori infection promoted YAP and β-catenin nuclear accumulation and transcriptional activity in gastric epithelial cells and transgenic insulin–gastrin (INS-GAS) mice, whereas silencing of both YAP and β-catenin synergistically inhibited H. pylori-induced cell proliferation and expansion. In addition, YAP was found to directly interact with β-catenin and knockdown of YAP suppressed H. pylori-induced nuclear translocation of β-catenin. Moreover, downstream genes caudal-type homeobox 2 (CDX2), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and RuvB like AAA ATPase 1 (RUVBL1) were shared by both YAP and β-catenin signaling. Furthermore, treatment with the YAP inhibitor Super-TDU or β-catenin inhibitor KYA1797A significantly alleviated gastric inflammation and epithelial DNA damage in H. pylori-infected mice. Finally, the elevation of gastric YAP was positively correlated with β-catenin expression in human gastric cancer tissues. These findings indicate that YAP and β-catenin synergistically promote H. pylori-induced gastric carcinogenesis via their physical interaction and reveal that CDX2, LGR5 and RUVBL1 are the downstream genes shared by both the YAP and β-catenin signaling pathways, and potentially contribute to H. pylori pathogenesis.

Expression Assessment of the Helicobacter pyloribabA and sabA Genes in Patients with Peptic Ulcer, Duodenal Ulcer and Gastric Cancer.

Helicobacter pylori as a common gastrointestinal (GI) pathogen must possess certain virulence characteristics to colonize the stomach, evade host immune responses, and subsequently induce GI diseases. This research aimed to investigate the expression level of two important genes, the sialic acid-binding adherence (SabA) and the blood group antigen-binding adhesion (BabA) in H. pylori strains isolated from adult patients living in the northern part of Iran, and their association with peptic ulcer disease (PUD) and gastric cancer (GC). This cross-sectional study was carried out on adult patients referring to the GI clinic of the hospitals affiliated to Babol University of Medical Sciences, Iran. New cases diagnosed with gastritis, peptic ulcer or gastric cancer were included. Endoscopic-guided gastric biopsies were examined and H. pylori positive colonies were analyzed to determine the expression of babA and sabA genes, utilizing specific primers and the SYBR Green dye. Among 175 patients with mean age of 51.6±15.6 years, 101 (57.7%) of the individuals tested positive for H. pylori infection. Statistical analysis revealed a significant correlation between sabA (P=0.003) and babA (P=0.002) gene expression and development of PUD and GC. Smoking (P=0.052), gender (P=0.004) and positive babA gene expression (P=0.009) had the greatest association with occurrence of PUD or GC in H. pylori positive patients. In summary, the presence of the sabA gene in people infected with H. pylori increased the risk of GC compared to gastritis, while, the presence of the babA gene was significantly increased in gastric ulcer patients. Considering the diversity of H. pylori isolates and the varying results observed in different geographical regions, further comprehensive studies are required to evaluate the function of these genes in H. pylori pathogenesis and their relationship with clinical outcomes.

Lactobacilli Downregulate Transcription Factors in Helicobacter pylori That Affect Motility, Acid Tolerance and Antimicrobial Peptide Survival

Helicobacter pylori infection triggers inflammation that may lead to gastritis, stomach ulcers and cancer. Probiotic bacteria, such as Lactobacillus, have been of interest as treatment options, however, little is known about the molecular mechanisms of Lactobacillus-mediated inhibition of H. pylori pathogenesis. In this work, we investigated the effect of Lactobacillus culture supernatants, so-called conditioned medium (CM), from two gastric isolates, L. gasseri and L. oris, on the expression of transcriptional regulators in H. pylori. Among the four known two-component systems (TCSs), i.e., ArsRS, FlgRS, CheAY and CrdRS, the flagellar regulator gene flgR and the acid resistance associated arsS gene were down-regulated by L. gasseri CM, whereas expression of the other TCS-genes remained unaffected. L. gasseri CM also reduced the motility of H. pylori, which is in line with reduced flgR expression. Furthermore, among six transcription factors of H. pylori only the ferric uptake regulator gene fur was regulated by L. gasseri CM. Deletion of fur further led to dramatically increased sensitivity to the antimicrobial peptide LL-37. Taken together, the results highlight that released/secreted factors of some lactobacilli, but not all, downregulate transcriptional regulators involved in motility, acid tolerance and LL-37 sensitivity of H. pylori.

Helicobacter pyhlori regulated microRNA map of human gastric cells.

Helicobacter pylori is an infection of concern for its chronic colonization leading to peptic ulcers and gastric cancer. In recent times, microRNAs have been extensively studied to understand their role in the pathogenesis of this bacteria in diverse contexts of gastric diseases. The current analysis reports the microRNA-mRNA interactions that are associated with effective survival and virulence of this pathogen. We convened differentially regulated human microRNAs responsive to H. pylori infection (HP-hDEmiRs) at different multiplicity of infection and time points in human gastric cell lines through retrospective data mining of experimental studies. In view of the molecular disparity of clinical samples and animal models, data from tissue, serum/plasma, urine, and ascites were excluded. Further, we utilized diverse bioinformatics approaches to retrieve experimentally validated, high-confidence targets of the HP-hDEmiRs to analyze the microRNA-mRNA interactions that are relevant to H. pylori pathogenesis. A total of 39 HP-hDEmiRs that showed unidirectional expression of either overexpression or downregulation were identified to modulate 23 targets explicitly studied under this infection. We also identified 476 experimentally validated targets regulated by at least 4 of the HP-hDEmiRs. In addition to the pathways prior-associated with H. pylori infection, the microRNA-mRNA interactome analysis identified several cellular processes and pathways highly associated with cell cycle, cell division, migration, and carcinogenesis. This study generated a platform to study the mechanisms utilized by this pathogen using microRNAs as surrogate.

Helicobacter pylori-infected human neutrophils exhibit impaired chemotaxis and a uropod retraction defect.

Helicobacter pylori is a major human pathogen that colonizes the gastric mucosa and plays a causative role in development of peptic ulcers and gastric cancer. Neutrophils are heavily infected with this organism in vivo and play a prominent role in tissue destruction and disease. Recently, we demonstrated that H. pylori exploits neutrophil plasticity as part of its virulence strategy eliciting N1-like subtype differentiation that is notable for profound nuclear hypersegmentation. We undertook this study to test the hypothesis that hypersegmentation may enhance neutrophil migratory capacity. However, EZ-TAXIScan™ video imaging revealed a previously unappreciated and progressive chemotaxis defect that was apparent prior to hypersegmentation onset. Cell speed and directionality were significantly impaired to fMLF as well as C5a and IL-8. Infected cells oriented normally in chemotactic gradients, but speed and direction were impaired because of a uropod retraction defect that led to cell elongation, nuclear lobe trapping in the contracted rear and progressive narrowing of the leading edge. In contrast, chemotactic receptor abundance, adhesion, phagocytosis and other aspects of cell function were unchanged. At the molecular level, H. pylori phenocopied the effects of Blebbistatin as indicated by aberrant accumulation of F-actin and actin spikes at the uropod together with enhanced ROCKII-mediated phosphorylation of myosin IIA regulatory light chains at S19. At the same time, RhoA and ROCKII disappeared from the cell rear and accumulated at the leading edge whereas myosin IIA was enriched at both cell poles. These data suggest that H. pylori inhibits the dynamic changes in myosin IIA contractility and front-to-back polarity that are essential for chemotaxis. Taken together, our data advance understanding of PMN plasticity and H. pylori pathogenesis.

Host Cell Antimicrobial Responses against Helicobacter pylori Infection: From Biological Aspects to Therapeutic Strategies.

The colonization of Helicobacter pylori (H. pylori) in human gastric mucosa is highly associated with the occurrence of gastritis, peptic ulcer, and gastric cancer. Antibiotics, including amoxicillin, clarithromycin, furazolidone, levofloxacin, metronidazole, and tetracycline, are commonly used and considered the major treatment regimens for H. pylori eradication, which is, however, becoming less effective by the increasing prevalence of H pylori resistance. Thus, it is urgent to understand the molecular mechanisms of H. pylori pathogenesis and develop alternative therapeutic strategies. In this review, we focus on the virulence factors for H. pylori colonization and survival within host gastric mucosa and the host antimicrobial responses against H. pylori infection. Moreover, we describe the current treatments for H. pylori eradication and provide some insights into new therapeutic strategies for H. pylori infection.

REVIEW ON STIMULATIONS OF THE SPREAD OF HELICOBACTER PYLORI INFECTION IN IRAQ

Helicobacter pylori (H. pylori) bacteria are microaerophilic Gram-negative bacteria that inhabit the human stomach and duodenum. If left untreated, it can lead to prolonged infection in human life. Numerous studies have shown that H. pylori infection can cause several important gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulcer, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Most modern publications are devoted to the pathogenic properties of microorganisms in the development of chronic gastritis, gastric ulcers, and gastric cancer, and methods for their eradication. Helicobacter pylori was the first officially recognized bacterial carcinogen and one of the most successful human pathogens, as more than half of the world's population is colonized by this Gram-negative bacterium. The disease course is the result of complex interactions between the host and bacteria. Host immunity gene polymorphisms and gastric acid secretion largely determine the ability of bacteria to colonize specific gastric niches. Bacterial virulence factors such as the cytotoxin-related gene pathogenicity island-encoded protein CagA and the vacuolar cytotoxin VacA support this colonization of the gastric mucosa and subsequently appear to regulate the host's immune system. This study focuses on the microbiological, clinical, and immunological aspects of H. pylori pathogenesis; it also reveals the prevalence of H. pylori in some Iraqi governorates