Helicobacter pylori adhesin HopQ disrupts trans dimerization in human CEACAMs

The human gastric pathogen Helicobacter pylori is a major causative agent of gastritis, peptic ulcer disease, and gastric cancer. As part of its adhesive lifestyle, the bacterium targets members of the carcinoembryonic antigen‐related cell adhesion molecule (CEACAM) family by the conserved outer membrane adhesin HopQ. The HopQ–CEACAM1 interaction is associated with inflammatory responses and enables the intracellular delivery and phosphorylation of the CagA oncoprotein via a yet unknown mechanism. Here, we generated crystal structures of HopQ isotypes I and II bound to the N‐terminal domain of human CEACAM1 (C1ND) and elucidated the structural basis of H. pylori specificity toward human CEACAM receptors. Both HopQ alleles target the β‐strands G, F, and C of C1ND, which form the trans dimerization interface in homo‐ and heterophilic CEACAM interactions. Using SAXS, we show that the HopQ ectodomain is sufficient to induce C1ND monomerization and thus providing H. pylori a route to influence CEACAM‐mediated cell adherence and signaling events.     

Expression of CEACAM1 or CEACAM5 in AZ‐521 cells restores the type IV secretion deficiency for translocation of CagA by Helicobacter pylori

Helicobacter pylori represents an important pathogen involved in diseases ranging from gastritis, peptic ulceration, to gastric malignancies. Prominent virulence factors comprise the vacuolating cytotoxin VacA and the cytotoxin‐associated genes pathogenicity island (cagPAI)‐encoded type IV secretion system (T4SS). The T4SS effector protein CagA can be translocated into AGS and other gastric epithelial cells followed by phosphorylation through c‐Src and c‐Abl tyrosin kinases to hijack signalling networks. The duodenal cell line AZ‐521 has been recently introduced as novel model system to investigate CagA delivery and phosphorylation in a VacA‐dependent fashion. In contrast, we discovered that AZ‐521 cells display a T4SS incompetence phenotype for CagA injection, which represents the first reported gastrointestinal cell line with a remarkable T4SS defect. We proposed that this deficiency may be due to an imbalanced coexpression of T4SS receptor integrin‐β₁ or carcinoembryonic antigen‐related cell adhesion molecules (CEACAMs), which were described recently as novel H. pylori receptors. We demonstrate that AZ‐521 cells readily express integrin‐β₁, but overexpression of integrin‐β₁ constructs did not restore the T4SS defect. We further show that AZ‐521 cells lack the expression of CEACAMs. We demonstrate that genetic introduction of either CEACAM1 or CEACAM5, but not CEACAM6, in AZ‐521 cells is sufficient to permit injection and phosphorylation of CagA by H. pylori to degrees observed in the AGS cell model. Expression of CEACAM1 or CEACAM5 in infected AZ‐521 cells was also accompanied by tyrosine dephosphorylation of the cytoskeletal proteins vinculin and cortactin, a hallmark of H. pylori‐infected AGS cells. Our results suggest the existence of an integrin‐β₁‐ and CEACAM1‐ or CEACAM5‐dependent T4SS delivery pathway for CagA, which is clearly independent of VacA. The presence of two essential host protein receptors during infection with H. pylori represents a unique feature in the bacterial T4SS world. Further detailed investigation of these T4SS functions will help to better understand infection strategies by bacterial pathogens.     

Review: Pathogenesis of Helicobacter pylori infection

In this review, we shall focus on the last year progression understanding the pathogenesis of Helicobacter pylori infection in the light of recent data related to adaptation of H pylori to the harsh acidic environment in the stomach, colonization of gastric mucosa via interaction with mucin 5 (MUC5AC) and other host cell receptors, the ability to form biofilm, interference with the host metabolic pathways, and induction of neuroimmune cross‐talk as well as downregulation of gastric barrier homeostasis and its consequences for the disease development. The role of the membrane vesicles of these bacteria has been emphasized as an important source of virulence factors. Furthermore, we shall describe molecular and functional studies on new aspects of VacA and CagA virulence, including the role of urease in the upregulation of VacA toxicity, an epithelial‐mesenchymal transition mediated by CagA, and the role of interaction of HopQ adhesin with carcinoembryonic antigen‐related cell adhesion molecules (CEACAMs) in CagA translocation into the host cells by the type IV secretion system (T4SS). The role of molecular mimicry between a common sequence (ATVLA) of H pylori heat shock protein (Hsp) B and human Hsp60 in the induction of potentially autoreactive antibodies is discussed. All these new data illustrate further progress in understanding H pylori pathogenicity and facilitate the search for new therapeutic targets as well as development of immunoprophylaxis methods based on new chimeric UreB and HpA proteins.     

Dynamics of the Cag‐type IV secretion system of Helicobacter pylori as studied by bacterial co‐infections

Many pathogenic Gram‐negative bacteria possess type IV secretion systems (T4SS) to inject effector proteins directly into host cells to modulate cellular processes to their benefit. The human bacterial pathogen Helicobacter pylori, a major aetiological agent in the development of chronic gastritis, duodenal ulcer and gastric carcinoma, harbours the cag‐T4SS to inject the cytotoxin associated Antigen (CagA) into gastric epithelial cells. This results in deregulation of major signalling cascades, actin‐cytoskeletal rearrangements and eventually gastric cancer. We show here that a pre‐infection with live H. pylori has a dose‐dependent negative effect on the CagA translocation efficiency of a later infecting strain. This effect of the ‘first’ strain was independent of any of its T4SS, the vacuolating cytotoxin (VacA) or flagella. Other bacterial pathogens, e.g. pathogenic Escherichia coli, Campylobacter jejuni, Staphylococcus aureus, or commensal bacteria, such as lactobacilli, were unable to interfere with H. pylori's CagA translocation capacity in the same way. This interference was independent of the β1 integrin receptor availability for H. pylori, but certain H. pylori outer membrane proteins, such as HopI, HopQ or AlpAB, were essential for the effect. We suggest that the specific interference mechanism induced by H. pylori represents a cellularresponse to restrict and control CagA translocation into a host cell to control the cellular damage.     

Dissecting virulence function from recognition: cell death suppression in Nicotiana benthamiana by XopQ/HopQ1‐family effectors relies on EDS1‐dependent immunity

Many Gram‐negative plant pathogenic bacteria express effector proteins of the XopQ/HopQ1 family which are translocated into plant cells via the type III secretion system during infection. In Nicotiana benthamiana, recognition of XopQ/HopQ1 proteins induces an effector‐triggered immunity (ETI) reaction which is not associated with strong cell death but renders plants immune against Pseudomonas syringae and Xanthomonas campestris pv. vesicatoria strains. Additionally, XopQ suppresses cell death in N. benthamiana when transiently co‐expressed with cell death inducers. Here, we show that representative XopQ/HopQ1 proteins are recognized similarly, likely by a single resistance protein of the TIR‐NB‐LRR class. Extensive analysis of XopQ derivatives indicates the recognition of structural features. We performed Agrobacterium‐mediated protein expression experiments in wild‐type and EDS1‐deficient (eds1) N. benthamiana leaves, not recognizing XopQ/HopQ1. XopQ recognition limits multiplication of Agrobacterium and attenuates levels of transiently expressed proteins. Remarkably, XopQ fails to suppress cell death reactions induced by different effectors in eds1 plants. We conclude that XopQ‐mediated cell death suppression in N. benthamiana is due to the attenuation of Agrobacterium‐mediated protein expression rather than the cause of the genuine XopQ virulence activity. Thus, our study expands our understanding of XopQ recognition and function, and also challenges the commonly used co‐expression assays for elucidation of in planta effector activities, at least under conditions of ETI induction.     

Characterization of CagI in the Cag Pathogenicity Island of <Emphasis Type="Italic">Helicobacter pylori</Emphasis>

Helicobacter pylori is a highly successful human-specific gastric pathogen that infects up to 50% of the world’s population. Virulent H. pylori isolates harbor the cytotoxin-associated genes pathogenicity island (cag-PAI), which encodes a type IV secretion system that translocates bacterial effector (e.g., CagA oncoprotein) molecules into host cells. Although some cag-PAI genes are shown to be required for CagA delivery or localization, the majority have no known function. In the current study, the authors performed a cell components fractionation assay and showed that CagI, one of the cag-PAI proteins located in the bacterial membrane, was not translocated into host cells. The homologous recombination method then was used to construct the isogenic mutant of H. pylori cagI, and the translocation assay was performed. The results showed that the isogenic mutant of H. pylori NCTC 11637 cagI could cause a reduction in the degree of CagA translocation. Overall, the results suggested that CagI might be an accessory component of the CagA secretion system not translocated into host cells and that it is located in the bacterial membrane.     

Superoxide dismutase from Helicobacter pylori suppresses the production of pro‐inflammatory cytokines during in vivo infection

Background

Helicobacter pylori has undergone considerable adaptation to allow chronic persistence within the gastric environment. While H. pylori‐associated diseases are driven by an excessive inflammation, severe gastritis is detrimental to colonization by this pathogen. Hence, H. pylori has developed strategies to minimize the severity of gastritis it triggers in its host. Superoxide dismutase (SOD) is well known for its role in protecting against oxidative attack; less recognized is its ability to inhibit immunity, shown for SOD from mammalian sources and those of some bacterial species. This study examined whether H. pylori SOD (HpSOD) has the ability to inhibit the host immune response to these bacteria.

Materials and Methods

The ability of recombinant HpSOD to modify the response to LPS was measured using mouse macrophages. A monoclonal antibody against HpSOD was generated and injected into H. pylori‐infected mice.

Results

Addition of HpSOD to cultures of mouse macrophages significantly inhibited the pro‐inflammatory cytokine response to LPS stimulation. A monoclonal antibody was generated that was specific for SOD from H. pylori. When injected into mice infected with H. pylori for 3 months, this antibody was readily detected in both sera and gastric tissues 5 days later. While treatment with anti‐HpSOD had no effect on H. pylori colonization at this time point, it significantly increased the levels of a range of pro‐inflammatory cytokines in the gastric tissues. This did not occur with antibodies against other antioxidant enzymes.

Conclusions

SOD from H. pylori can inhibit the production of pro‐inflammatory cytokine during in vivo infection.     

The Importance of Toll‐like Receptors in NF‐κB Signaling Pathway Activation by Helicobacter pylori Infection and the Regulators of this Response

Helicobacter pylori (H. pylori) is a common pathogenic bacterium in the stomach that infects almost half of the population worldwide and is closely related to gastric diseases and some extragastric diseases, including iron‐deficiency anemia and idiopathic thrombocytopenic purpura. Both the Maastricht IV/Florence consensus report and the Kyoto global consensus report have proposed the eradication of H. pylori to prevent gastric cancer as H.pylori has been shown to be a major cause of gastric carcinogenesis. The interactions between H. pylori and host receptors induce the release of the proinflammatory cytokines by activating proinflammatory signaling pathways such as nuclear factor kappa B (NF‐κB), which plays a central role in inflammation, immune response, and carcinogenesis. Among these receptors, Toll‐like receptors (TLRs) are classical pattern recognition receptors in the recognition of H. pylori and the mediation of the host inflammatory and immune responses to H. pylori. TLR polymorphisms also contribute to the clinical consequences of H. pylori infection. In this review, we focus on the functions of TLRs in the NF‐κB signaling pathway activated by H. pylori, the regulators modulating this response, and the functions of TLR polymorphisms in H.pylori‐related diseases.     

幽门螺杆菌CagA蛋白及其致病机制的研究进展

幽门螺杆菌感染是导致从胃炎到胃癌等一系列胃相关疾病的主要病因,但具体的致病机制仍不是很清楚。细胞毒素相关蛋白A(cytotoxin-associated gene A,Cag A)是幽门螺杆菌编码的一种重要毒力因子,且作为细菌来源的唯一癌蛋白被大量研究。Cag A蛋白是由幽门螺杆菌Ⅳ型分泌系统介导并注入宿主胃上皮细胞内,一旦进入细胞,Cag A能够与多个分子发生相互作用,扰乱细胞正常的信号通路,引起细胞病变和转化,而动物实验也证明了Cag A蛋白的致癌特点。本文重点对Cag A蛋白的序列特征,转位方式及致病机制等方面的最新进展进行了综述,希望能进一步阐释Cag A介导的幽门螺杆菌的致病机制,为以后的研究提供一定的方向和指导。     

Haem oxygenase‐1 inhibits phosphorylation of the Helicobacter pylori oncoprotein CagA in gastric epithelial cells

The cytotoxin‐associated gene A protein (CagA) plays a pivotal role in the aetiology of Helicobacter pylori‐associated gastric diseases. CagA is injected into the cytoplasm of host cells by a type IV secretion system, and is phosphorylated on tyrosine residues by the host enzyme c‐Src. We previously reported that the enzyme haem oxygenase‐1 (HO‐1) inhibits IL‐8 secretion by H. pylori‐infected cells. However, the cellular mechanism by which HO‐1 regulates the innate immune function of infected cells remains unknown. We now show that nitric oxide and haemin, two inducers of HO‐1, decrease the level of phosphorylated CagA (p‐CagA) in H. pylori‐infected gastric epithelial cells and this is blocked by either pharmacological inhibition of HO‐1 or siRNA knockdown of hmox‐1. Moreover, forced expression of HO‐1 by transfection of a plasmid expressing hmox‐1 also results in a strong attenuation of CagA phosphorylation. This occurs through the inhibition of H. pylori‐induced c‐Src phosphorylation/activation by HO‐1.Consequently, H. pylori‐induced cytoskeletal rearrangements and activation of the pro‐inflammatory response mediated by p‐CagA are inhibited in HO‐1‐expressing cells. These data highlight a mechanism by which the innate immune response of the host can restrict the pathogenicity of H. pylori by attenuating CagA phosphorylation in gastric epithelial cells.     

A novel NOD1‐ and CagA‐independent pathway of interleukin‐8 induction mediated by the Helicobacter pylori type IV secretion system

The type IV secretion system (T4SS) of Helicobacter pylori triggers massive inflammatory responses during gastric infection by mechanisms that are poorly understood. Here we provide evidence for a novel pathway by which the T4SS structural component, CagL, induces secretion of interleukin‐8 (IL‐8) independently of CagA translocation and peptidoglycan‐sensing nucleotide‐binding oligomerization domain 1 (NOD1) signalling. Recombinant CagL was sufficient to trigger IL‐8 secretion, requiring activation of α₅β₁ integrin and the arginine–glycine–aspartate (RGD) motif in CagL. Mutation of the encoded RGD motif to arginine‐glycine‐alanine (RGA) in the cagL gene of H. pylori abrogated its ability to induce IL‐8. Comparison of IL‐8 induction between H. pylori ΔvirD4 strains bearing wild‐type or mutant cagL indicates that CagL‐dependent IL‐8 induction can occur independently of CagA translocation. In line with this notion, exogenous CagL complemented H. pylori ΔcagL mutant in activating NF‐κB and inducing IL‐8 without restoring CagA translocation. The CagA translocation‐independent, CagL‐dependent IL‐8induction involved host signalling via integrin α₅β₁, Src kinase, the mitogen‐activated protein kinase (MAPK) pathway and NF‐κB but was independent of NOD1. Our findings reveal a novel pathway whereby CagL, via interaction with host integrins, can trigger pro‐inflammatory responses independently of CagA translocation or NOD1 signalling.     

Helicobacter pylori Infection – A Boon or a Bane: Lessons from Studies in a Low‐Prevalence Population

Helicobacter pylori (H. pylori) infection is etiologically associated with gastric cancer and peptic ulcer diseases which are both important public health burdens which could be largely eliminated by H. pylori eradication. However, some investigators urge caution based on the hypothesis that eradication of H. pylori may result in an increase in the incidence of gastroesophageal reflux disease, esophageal adenocarcinoma, and childhood asthma. The ethnic Malays of northeastern Peninsular Malaysia have long had a low prevalence of H. pylori infection and, as expected, the incidence of gastric cancer and its precursor lesions is exceptionally low. The availability of a population with a low H. pylori prevalence and generally poor sanitation allows separation of H. pylori from the hygiene hypothesis and direct testing of whether absence of H. pylori is associated with untoward consequence. Contrary to predictions, in Malays, erosive esophagitis, Barrett's esophagus, distal esophageal cancers, and childhood asthma are all of low incidence. This suggests that H. pylori is not protective rather the presence of H. pylori infection is likely a surrogate for poor hygiene and not an important source of antigens involved in the hygiene hypothesis. Helicobacter pylori in Malays is related to transmission from H. pylori‐infected non‐Malay immigrants. The factors responsible for low H. pylori acquisition, transmission, and burden of H. pylori infection in Malays remain unclear and likely involves a combination of environmental, host (gene polymorphisms), and strain virulence factors. Based on evidence from this population, absence of H. pylori infection is more likely to be boon than a bane.     

Dual roles of CagA protein in Helicobacterpylori-induced chronic gastritis in mice

Cytotoxin-associated gene A (CagA) acts directly on gastric epithelial cells. However, the roles of CagA in host adaptive immunity against Helicobacter pylori (H. pylori) infection are not fully understood. In this study, to investigate the roles of CagA in the development of H. pylori-induced chronic gastritis, we used an adoptive-transfer model in which spleen cells from C57BL/6 mice with or without H. pylori infection were transferred into RAG2^−/− mice, with gastric colonization of either CagA⁺H. pylori or CagA⁻H. pylori. Colonization of CagA⁺H. pylori but not CagA⁻H. pylori in the host gastric mucosa induced severe chronic gastritis in RAG2^−/− mice transferred with spleen cells from H. pylori-uninfected mice. In addition, when CagA⁺H. pylori-primed spleen cells were transferred into RAG2^−/− mice, CD4⁺ T cell infiltration in the host gastric mucosa were observed only in RAG2^−/− mice infected with CagA⁺H. pylori but not CagA⁻H. pylori, suggesting that colonization of CagA⁺H. pylori in the host gastric mucosa is essential for the migration of H. pylori-primed CD4⁺ T cells. On the other hand, transfer of CagA⁻H. pylori-primed spleen cells into CagA⁺H. pylori-infected RAG2^−/− mice induced more severe chronic gastritis with less Foxp3⁺ regulatory T-cell infiltration as compared to transfer of CagA⁺H. pylori-primed spleen cells. In conclusion, CagA in the stomach plays an important role in the migration of H. pylori-primed CD4⁺ T cells in the gastric mucosa, whereas CagA-dependent T-cell priming induces regulatory T-cell differentiation, suggesting dual roles for CagA in the pathophysiology of H. pylori-induced chronic gastritis.     

CagA of Helicobacter pylori interacts with and inhibits the serine‐threonine kinase PRK2

CagA is a multifunctional toxin of Helicobacter pylori that is secreted into host epithelial cells by a type IV secretion system. Following host cell translocation, CagA interferes with various host–cell signalling pathways. Most notably this toxin is involved in the disruption of apical–basolateral cell polarity and cell adhesion, as well as in the induction of cell proliferation, migration and cell morphological changes. These are processes that also play an important role in epithelial‐to‐mesenchymal transition and cancer cell invasion. In fact, CagA is considered as the only known bacterial oncoprotein. The cellular effects are triggered by a variety of CagA activities including the inhibition of serine–threonine kinase Par1b/MARK2 and the activation of tyrosine phosphatase SHP‐2. Additionally, CagA was described to affect the activity of Src family kinases and C‐terminal Src kinase (Csk) suggesting that interference with multiple cellular kinase‐ and phosphatase‐associated signalling pathways is a major function of CagA. Here, we describe the effect of CagA on protein kinase C‐related kinase 2 (PRK2), which acts downstream of Rho GTPases and is known to affect cytoskeletal rearrangements and cell polarity. CagA interacts with PRK2 and inhibits its kinase activity. Because PRK2 has been linked to cytoskeletal rearrangements and establishment of cell polarity, we suggest that CagA may hijack PRK2 to further manipulate cancer‐related signalling pathways.     

Brief report: Lactobacillus bulgaricus GLB44 (Proviotic™) plus esomeprazole for Helicobacter pylori eradication: A pilot study

Background

Recent studies of Lactobacillus delbrueckii subsp. bulgaricus GLB44 plus a proton‐pump inhibitor (PPI) reported cures of more than 90% of patients with active Helicobacter pylori infections.

Aim

To confirm the high H. pylori cure rates reported previously.

Method

A pilot study was done in healthy H. pylori‐infected volunteers using 3‐gram sachet (3 billion cells) of L. delbrueckii GLB44 plus 22.3 mg of esomeprazole b.i.d., for 14 days. The result was determined by urea breath testing 4 weeks after therapy. Stopping rules required for ending enrollment if less than 3 of the first 10 subjects were cured.

Results

Nine subjects were entered and because all failed to achieve negative urea breath test, the stopping rule required the study to end.

Conclusion

We were unable to confirm reports of achieving a high H. pylori cure rate with L. delbrueckii GLB44 plus a PPI.     

Macrolide use in the previous years is associated with failure to eradicate Helicobacter pylori with clarithromycin‐containing regimens

Background

There is some evidence that prior use of macrolide antibiotics is a useful predictor of the likelihood of standard triple therapy failure in Helicobacter pylori eradication. In this study, we have evaluated whether previous intake of macrolides correlates with failure to eradicate H. pylori using two different first‐line clarithromycin‐containing regimens.

Materials and Methods

Retrospective study of 212 patients with H. pylori infection treated with one of two first‐line clarithromycin‐containing regimens: 108 patients treated with triple therapy for 10 days and 104 patients treated with concomitant therapy for 10 days. The intake of macrolides (clarithromycin, azithromycin, and other macrolides) prior to the eradication therapy was obtained from the electronic medical record, which contains information regarding all the medication prescribed to the patients since the year 2004.

Results

One hundred of 212 patients (47.2%) had received at least one treatment with macrolides during the years prior to the eradication therapy. H. pylori eradication rates were significantly lower in patients with previous use compared to patients without previous use of macrolides, both with triple therapy (60.8% vs 92.9%; P < .0001) and with concomitant therapy (85.7% vs 98.2%; P = .024).

Conclusions

Previous use of macrolides correlates with a low H. pylori eradication rate with triple and concomitant clarithromycin‐containing regimens. In addition, our study shows that in patients without previous use of macrolides, triple therapy achieves per‐protocol eradication rates over 90%.     

Seroprevalence of Helicobacter pylori in Korea: A multicenter,nationwide study conducted in 2015 and 2016

Background

The Korean College of Helicobacter and Upper Gastrointestinal Research has studied Helicobacter pylori (H. pylori) prevalence since 1998 and found a dynamic change in its prevalence in Korea. The aim of this study was to determine the recent H. pylori prevalence rate and compare it with that of previous studies according to socioeconomic variables.

Methods

We planned to enroll 4920 asymptomatic Korean adults from 21 centers according to the population distribution of seven geographic areas (Seoul, Gyeonggi, Gangwon, Chungcheong, Kyungsang, Cholla, and Jeju). We centrally collected serum and tested H. pylori serum IgG using a chemiluminescent enzyme immunoassay.

Results

We analyzed 4917 samples (4917/4920 = 99.9%) from January 2015 to December 2016. After excluding equivocal serologic results, the H. pylori seropositivity rate was 51.0% (2414/4734). We verified a decrease in H. pylori seroprevalence compared with previous studies performed in 1998, 2005, and 2011 (P < .0001). The H. pylori seroprevalence rate differed by area: Cholla (59.5%), Chungcheong (59.2%), Kyungsang (55.1%), Jeju (54.4%), Gangwon (49.1%), Seoul (47.4%), and Gyeonggi (44.6%). The rate was higher in those older than 40 years (38.1% in those aged 30‐39 years and 57.7% in those aged 40‐49 years) and was lower in city residents than in noncity residents at all ages.

Conclusions

Helicobacter pylori seroprevalence in Korea is decreasing and may vary according to population characteristics. This trend should be considered to inform H. pylori‐related policies.     

Helicobacter pylori Eradication in Patients with Immune Thrombocytopenic Purpura: A Review and the Role of Biogeography

Idiopathic thrombocytopenic purpura (ITP) is typically a diagnosis of exclusion, assigned by clinicians after ruling out other identifiable etiologies. Since a report by Gasbarrini et al. in 1998, an accumulating body of evidence has proposed a pathophysiological link between ITP and chronic Helicobacter pylori (H. pylori) infection. Clinical reports have described a spontaneous resolution of ITP symptoms in about 50% of chronic ITP patients following empirical treatment of H. pylori infection, but response appears to be geography dependent. Studies have also documented that ITP patients in East Asian countries are more likely to express positive antibody titers against H. pylori‐specific cytotoxic‐associated gene A (CagA), a virulence factor that is associated with an increased risk for gastric diseases including carcinoma. While a definitive mechanism by which H. pylori may induce thrombocytopenia remains elusive, proposed pathways include molecular mimicry of CagA by host autoantibodies against platelet surface glycoproteins, as well as perturbations in the phagocytic activity of monocytes. Traditional treatments of ITP have been largely empirical, involving the use of immunosuppressive agents and immunoglobulin therapy. However, based on the findings of clinical reports emerging over the past 20 years, health organizations around the world increasingly suggest the detection and eradication of H. pylori as a treatment for ITP. Elucidating the exact molecular mechanisms of platelet activation in H. pylori‐positive ITP patients, while considering biogeographical differences in response rates, could offer insight into how best to use clinical H. pylori eradication to treat ITP, but will require well‐designed studies to confirm the suggested causative relationship between bacterial infection and an autoimmune disease state.