CAIP-Induced ROS Production Contributes to Sustaining Atherosclerotic Process Associated with Helicobacter cinaedi Infection through Macrophages and Endothelial Cells Activation.

Several lines of evidence have linked the intestinal bacterium Helicobacter cinaedi with the pathogenesis of atherosclerosis, identifying the Cinaedi Antigen Inflammatory Protein (CAIP) as a key virulence factor. Oxidative stress and inflammation are crucial in sustaining the atherosclerotic process and oxidized LDL (oxLDL) uptake. Primary human macrophages and endothelial cells were pre-incubated with 10 µM diphenyl iodonium salt (DPI) and stimulated with 20 µg/mL CAIP. Lectin-like oxLDL receptor (LOX-1) expression was evaluated by FACS analysis, reactive oxygen species (ROS) production was measured using the fluorescent probe H2DCF-DA, and cytokine release was quantified by ELISA assay. Foam cells formation was assessed by Oil Red-O staining, and phosphorylation of p38 and ERK1/2 MAP kinases and NF-κB pathway activation were determined by Western blot. This study demonstrated that CAIP triggered LOX-1 over-expression and increased ROS production in both macrophages and endothelial cells. Blocking ROS abrogated LOX-1 expression and reduced LDL uptake and foam cells formation. Additionally, CAIP-mediated pro-inflammatory cytokine release was significantly affected by ROS inhibition. The signaling pathway induced by CAIP-induced oxidative stress led to p38 MAP kinase phosphorylation and NF-κB activation. These findings elucidate the mechanism of action of CAIP, which heightens oxidative stress and contributes to the atherosclerotic process in H. cinaedi-infected patients.

Cytolethal distending toxin induces the formation of transient messenger-rich ribonucleoprotein nuclear invaginations in surviving cells.

Humans are frequently exposed to bacterial genotoxins involved in digestive cancers, colibactin and Cytolethal Distending Toxin (CDT), the latter being secreted by many pathogenic bacteria. Our aim was to evaluate the effects induced by these genotoxins on nuclear remodeling in the context of cell survival. Helicobacter infected mice, coculture experiments with CDT- and colibactin-secreting bacteria and hepatic, intestinal and gastric cells, and xenograft mouse-derived models were used to assess the nuclear remodeling in vitro and in vivo. Our results showed that CDT and colibactin induced-nuclear remodeling can be associated with the formation of deep cytoplasmic invaginations in the nucleus of giant cells. These structures, observed both in vivo and in vitro, correspond to nucleoplasmic reticulum (NR). The core of the NR was found to concentrate ribosomes, proteins involved in mRNA translation, polyadenylated RNA and the main components of the complex mCRD involved in mRNA turnover. These structures are active sites of mRNA translation, correlated with a high degree of ploidy, and involve MAPK and calcium signaling. Additional data showed that insulation and concentration of these adaptive ribonucleoprotein particles within the nucleus are dynamic, transient and protect the cell until the genotoxic stress is relieved. Bacterial genotoxins-induced NR would be a privileged gateway for selected mRNA to be preferably transported therein for local translation. These findings offer new insights into the context of NR formation, a common feature of many cancers, which not only appears in response to therapies-induced DNA damage but also earlier in response to genotoxic bacteria.

Review: Other Helicobacter species.

This review covers the most important, accessible, and relevant literature published between April 2019 and April 2020 in the field of non-Helicobacter pylori Helicobacter species (NHPH). The initial part of the review covers new insights regarding the presence of gastric and enterohepatic NHPH in humans and animals, while the subsequent section focuses on the progress in our understanding of animal models, the pathogenicity and omics of these species. Over the last year, the clinical relevance of gastric NHPH infections in humans was highlighted. With regard to NHPH in animals, the ancestral source of Helicobacter suis was further established showing that Cynomolgus macaques are the common ancestor of the pig-associated H. suis population, and 3 novel Helicobacter species isolated from the gastric mucosa of red foxes were described. "Helicobacter burdigaliensis" sp nov. and "Helicobacter labetoulli" sp nov. were proposed as novel enterohepatic Helicobacter species associated with human digestive diseases. An analysis of Helicobacter cinaedi recurrent infections in humans proposed long-term antibiotic therapies. Several studies using rodent models further elucidated the mechanisms underlying the development of NHPH-related disease, as well as intestinal immunity in inflammatory bowel disease models. Omics approaches supported Helicobacteraceae taxonomy and unraveled the transcriptomic signatures of H. suis and Helicobacter heilmannii upon adherence to the human gastric epithelium. With regard to virulence, data showed that the nuclear remodeling promoted by cytolethal distending toxin of Helicobacters involves the MAFB oncoprotein and is associated with nucleoplasmic reticulum formation in surviving cells.

Bacterial Biogeography of the Colon in Dogs With Chronic Inflammatory Enteropathy.

The intestinal microbiota is believed to play a role in the pathogenesis of inflammatory bowel disease in humans and chronic inflammatory enteropathy (CIE) in dogs. While most previous studies have described the gut microbiota using sequencing methods, it is fundamental to assess the spatial distribution of the bacteria for a better understanding of their relationship with the host. The microbiota in the colonic mucosa of 22 dogs with CIE and 11 control dogs was investigated using fluorescence in situ hybridization (FISH) with a universal eubacterial probe (EUB338) and specific probes for select bacterial groups. The number of total bacteria labeled with EUB338 probe was lower within the colonic crypts of dogs with CIE compared to controls. Helicobacter spp. and Akkermansia spp. were decreased on the colonic surface and in the crypts of dogs with CIE. Dogs with CIE had increased number of Escherichia coli/Shigella spp. on the colonic surface and within the crypts compared to control dogs. In conclusion, the bacterial microbiota in the colonic mucosa differed between dogs with and without CIE, with depletion of the crypt bacteria in dogs with CIE. The crypt bacterial species that was intimately associated with the host mucosa in control dogs was composed mainly of Helicobacter spp.

Review: Other Helicobacter species.

This article is a review of the most important, accessible, and relevant literature published between April 2018 and April 2019 in the field of Helicobacter species other than Helicobacter pylori. The initial part of the review covers new insights regarding the presence of gastric and enterohepatic non-H. pylori Helicobacter species (NHPH) in humans and animals, while the subsequent section focuses on the progress in our understanding of the pathogenicity and evolution of these species. Over the last year, relatively few cases of gastric NHPH infections in humans were published, with most NHPH infections being attributed to enterohepatic Helicobacters. A novel species, designated "Helicobacter caesarodunensis," was isolated from the blood of a febrile patient and numerous cases of human Helicobacter cinaedi infections underlined this species as a true emerging pathogen. With regard to NHPH in animals, canine/feline gastric NHPH cause little or no harm in their natural host; however they can become opportunistic when translocated to the hepatobiliary tract. The role of enterohepatic Helicobacter species in colorectal tumors in pets has also been highlighted. Several studies in rodent models have further elucidated the mechanisms underlying the development of NHPH-related disease, and the extra-gastric effects of a Helicobacter suis infection on brain homeostasis was also studied. Comparative genomics facilitated a breakthrough in the evolutionary history of Helicobacter in general and NHPH in particular. Investigation of the genome of Helicobacter apodemus revealed particular traits with regard to its virulence factors. A range of compounds including mulberries, dietary fiber, ginseng, and avian eggs which target the gut microbiota have also been shown to affect Helicobacter growth, with a potential therapeutic utilization and increase in survival.

Prevalence and role of Type six secretion system in pathogenesis of emerging zoonotic pathogen Helicobacter pullorum from retail poultry.

Helicobacter pullorum is an emerging zoonotic pathogen that causes gastroenteritis in chickens and inflammatory bowel disease in humans ingesting contaminated meat. However, the mechanism by which the bacterium causes disease is unclear. Type six secretion system (T6SS) plays a major role in bacterial pathogenesis and adaptation. Haemolysin coregulated protein (Hcp) plays a central role in the structure of the T6SS pilus and acts as effector protein in certain bacteria. In this study, H. pullorum isolated from 156 caecal samples of broiler chickens was screened for the presence of T6SS Hcp gene via PCR amplification. 30.7% of caecal and 18.3% of liver samples tested positive for presence of H. pullorum. From these positive samples, 29.7% possessed the T6SS gene. In bacterial co-culture experiments, significant loss of viability (81.6-39.1%) was observed for H. pullorum-infected hepatocytes and presence of Hcp did not contribute to the loss of cell viability. Nevertheless, infection of erythrocytes with Hcp-positive isolates was associated with greater haemolytic activity compared to infection with Hcp-negative isolates. Therefore, presence of T6SS could be indicative of virulent strains meriting further studies to characterize this virulence factor in H. pullorum infection.

Comparative genomics analysis to differentiate metabolic and virulence gene potential in gastric versus enterohepatic Helicobacter species.

BACKGROUND: The genus Helicobacter are gram-negative, microaerobic, flagellated, mucus-inhabiting bacteria associated with gastrointestinal inflammation and classified as gastric or enterohepatic Helicobacter species (EHS) according to host species and colonization niche. While there are over 30 official species, little is known about the physiology and pathogenic mechanisms of EHS, which account for most in the genus, as well as what genetic factors differentiate gastric versus EHS, given they inhabit different hosts and colonization niches. The objective of this study was to perform a whole-genus comparative analysis of over 100 gastric versus EHS genomes in order to identify genetic determinants that distinguish these Helicobacter species and provide insights about their evolution/adaptation to different hosts, colonization niches, and mechanisms of virulence. RESULTS: Whole-genome phylogeny organized Helicobacter species according to their presumed gastric or EHS classification. Analysis of orthologs revealed substantial heterogeneity in physiological and virulence-related genes between gastric and EHS genomes. Metabolic reconstruction predicted that unlike gastric species, EHS appear asaccharolytic and dependent on amino/organic acids to fuel metabolism. Additionally, gastric species lack de novo biosynthetic pathways for several amino acids and purines found in EHS and instead rely on environmental uptake/salvage pathways. Comparison of virulence factor genes between gastric and EHS genomes identified overlapping yet distinct profiles and included canonical cytotoxins, outer membrane proteins, secretion systems, and survival factors. CONCLUSIONS: The major differences in predicted metabolic function suggest gastric species and EHS may have evolved for survival in the nutrient-rich stomach versus the nutrient-devoid environments, respectively. Contrasting virulence factor gene profiles indicate gastric species and EHS may utilize different pathogenic mechanisms to chronically infect hosts and cause inflammation and tissue damage. The findings from this study provide new insights into the genetic differences underlying gastric versus EHS and support the need for future experimental studies to characterize these pathogens.

Other Helicobacters and the gastric microbiome.

The current article is a review of the most important, accessible, and relevant literature published between April 2017 and March 2018 on other Helicobacters and the gastric microbiome. The first part of the review focuses on literature describing non-Helicobacter pylori-Helicobacter (NHPH) infections in humans and animals whilst the subsequent section focuses specifically on the human gastric microbiome. Novel diagnostic methods as well as new NHPHs species have been identified in recent studies. Furthermore, our knowledge about the pathogenesis of NHPH infections has been further enhanced by important fundamental studies in cell lines and animal models. Over the last year, additional insights over the prevalence and potential prevention strategies of NHPHs have also been reported. With regard to understanding the gastric microbiome, new information detailing the structure of the gastric microbiota at different stages of H. pylori infection, within different patient geographical locations, was documented. There was also a study detailing the impact of proton-pump inhibitor usage and the effect on the gastric microbiome. Newer analysis approaches including defining the active microbiome through analysis of RNA rather than DNA-based sequencing were also published allowing the first assessments of the functional capabilities of the gastric microbiome.

Evolution of Helicobacter: Acquisition by Gastric Species of Two Histidine-Rich Proteins Essential for Colonization.

Metal acquisition and intracellular trafficking are crucial for all cells and metal ions have been recognized as virulence determinants in bacterial pathogens. Virulence of the human gastric pathogen Helicobacter pylori is dependent on nickel, cofactor of two enzymes essential for in vivo colonization, urease and [NiFe] hydrogenase. We found that two small paralogous nickel-binding proteins with high content in Histidine (Hpn and Hpn-2) play a central role in maintaining non-toxic intracellular nickel content and in controlling its intracellular trafficking. Measurements of metal resistance, intracellular nickel contents, urease activities and interactomic analysis were performed. We observed that Hpn acts as a nickel-sequestration protein, while Hpn-2 is not. In vivo, Hpn and Hpn-2 form homo-multimers, interact with each other, Hpn interacts with the UreA urease subunit while Hpn and Hpn-2 interact with the HypAB hydrogenase maturation proteins. In addition, Hpn-2 is directly or indirectly restricting urease activity while Hpn is required for full urease activation. Based on these data, we present a model where Hpn and Hpn-2 participate in a common pathway of controlled nickel transfer to urease. Using bioinformatics and top-down proteomics to identify the predicted proteins, we established that Hpn-2 is only expressed by H. pylori and its closely related species Helicobacter acinonychis. Hpn was detected in every gastric Helicobacter species tested and is absent from the enterohepatic Helicobacter species. Our phylogenomic analysis revealed that Hpn acquisition was concomitant with the specialization of Helicobacter to colonization of the gastric environment and the duplication at the origin of hpn-2 occurred in the common ancestor of H. pylori and H. acinonychis. Finally, Hpn and Hpn-2 were found to be required for colonization of the mouse model by H. pylori. Our data show that during evolution of the Helicobacter genus, acquisition of Hpn and Hpn-2 by gastric Helicobacter species constituted a decisive evolutionary event to allow Helicobacter to colonize the hostile gastric environment, in which no other bacteria persistently thrives. This acquisition was key for the emergence of one of the most successful bacterial pathogens, H. pylori.

Individual differences in stress vulnerability: The role of gut pathobionts in stress-induced colitis.

Chronic subordinate colony housing (CSC), an established mouse model for chronic psychosocial stress, promotes a microbial signature of gut inflammation, characterized by expansion of Proteobacteria, specifically Helicobacter spp., in association with colitis development. However, whether the presence of Helicobacter spp. during CSC is critically required for colitis development is unknown. Notably, during previous CSC studies performed at Regensburg University (University 1), male specific-pathogen-free (SPF) CSC mice lived in continuous subordination to a physically present and Helicobacter spp.-positive resident. Therefore, it is likely that CSC mice were colonized, during the CSC procedure, with Helicobacter spp. originating from the dominant resident. In the present study we show that employing SPF CSC mice and Helicobacter spp.-free SPF residents at Ulm University (University 2), results in physiological responses that are typical of chronic psychosocial stress, including increased adrenal and decreased thymus weights, decreased adrenal in vitro adrenocorticotropic hormone (ACTH) responsiveness, and increased anxiety-related behavior. However, in contrast to previous studies that used Helicobacter spp.-positive resident mice, use of Helicobacter spp.-negative resident mice failed to induce spontaneous colitis in SPF CSC mice. Consistent with the hypothesis that the latter is due to a lack of Helicobacter spp. transmission from dominant residents to subordinate mice during the CSC procedure, colonization of SPF residents with Helicobacter typhlonius at University 2, prior to the start of the CSC model, rescued the colitis-inducing potential of CSC exposure. Furthermore, using SPF CSC mice and H. typhlonius-free SPF residents at University 1 prevented CSC-induced colitis. In summary, our data support the hypothesis that the presence or absence of exposure to certain pathobionts contributes to individual variability in susceptibility to stress-/trauma-associated pathologies and to reproducibility of stress-related outcomes between laboratories.

Genomic and clinical evidence uncovers the enterohepatic species Helicobacter valdiviensis as a potential human intestinal pathogen.

BACKGROUND: Helicobacter valdiviensis is a recently described enterohepatic species isolated from wild bird's fecal samples. Currently, its pathogenic potential and clinical significance are unknown mainly due to the lack of whole-genome sequences to compare with other helicobacters and the absence of specific screenings to determine its prevalence in humans. MATERIALS AND METHODS: The species type strain (WBE14T ) was whole-genome-sequenced, and comparative analyses were carried out including the genomes from other Helicobacter species to determine the exact phylogenetic position of H. valdiviensis and to study the presence and evolution of virulence determinants. In parallel, stools from diarrheic patients and healthy individuals were screened by PCR to assess the clinical incidence of H. valdiviensis. RESULTS: Helicobacter valdiviensis belongs to a monophyletic clade conformed by H. canadensis, H. pullorum, H. winghamensis, H. rodentium, and H. apodemus. Its predicted genome size is 2 176 246 bp., with 30% of G+C content and 2064 annotated protein-coding genes. The patterns of virulence factors in H. valdiviensis were similar to other enterohepatic species, but evidence of horizontal gene transfer from Campylobacter species was detected for key genes like those coding for the CDT subunits. Positive PCR results confirmed the presence of H. valdiviensis in 2 of 254 (0.78%) stools of patients with acute diarrhea while not a single sample was positive in healthy individuals. CONCLUSIONS: Horizontal gene transfer has contributed to shape the gene repertory of H. valdiviensis, which codes for virulence factors conserved in other pathogens that are well-known human pathogens. Additionally, the detection of H. valdiviensisDNA in diarrheic patients supports its role as a potential emergent intestinal pathogen. Further, sampling efforts are needed to uncover the clinical relevance of this species, which should be accomplished by the isolation of H. valdiviensis from ill humans and the obtention of whole genomes from clinical isolates.

Unusual manifestation of Helicobacter cinaedi infection: a case report of intracranial subdural empyema and bacteremia.

BACKGROUND: There have been various reports concerning Helicobacter cinaedi infections. However, few reports have examined central nervous system infections. CASE PRESENTATION: A 52-year-old man was transferred from the local hospital because of a persistent headache and suspected intracranial subdural empyema. Neurosurgical drainage was performed via burr holes. Gram staining and results from abscess cultures were negative. The blood culture yielded H. cinaedi. He was given an antibiotic regimen consisting of 2 g of ceftriaxone twice a day, but the size of the abscess was not reduced in size at all after 3 weeks of treatment. Neurosurgical drainage was performed again, and the antimicrobial regimen was switched to 2 g of meropenem 3 times a day. The size of the abscess was reduced after 2 weeks of the second drainage and antimicrobial drug change to meropenem. After 4 weeks treatment with meropenem, the patient was discharged, and his symptoms had completely resolved. CONCLUSIONS: H. cinaedi infection should be considered in the differential diagnosis of subdural empyema cases for which Gram staining and abscess culture results are negative. Meropenem can be a first-line drug of choice or an effective alternative treatment for H. cinaedi central nervous system infections.

The Cytolethal Distending Toxin Subunit CdtB of Helicobacter Induces a Th17-related and Antimicrobial Signature in Intestinal and Hepatic Cells In Vitro.

Enterohepatic Helicobacter species are associated with several digestive diseases. Helicobacter pullorum is an emerging human foodborne pathogen, and Helicobacter hepaticus is a mouse pathogen; both species are associated with intestinal and/or hepatic diseases. They possess virulence factors, such as cytolethal distending toxin (CDT). Data indicate that CDT may be involved in chronic inflammatory responses, via its active subunit, CdtB. The proinflammatory properties of the CdtB of H. pullorum and H. hepaticus were assessed on human intestinal and hepatic epithelial cells in vitro. Interleukin 8 expression was evaluated by using wild-type strains and their corresponding CdtB isogenic mutants and by delivering CdtB directly into the cells. Nuclear factor κB nuclear translocation and transcriptomic characteristics in response to CdtB were also evaluated. The CdtB of these Helicobacter species induced nuclear factor κB nuclear translocation and exhibited proinflammatory properties, mainly the expression of T-helper type 17-related genes and genes encoding antimicrobial products also involved in cancer. The Histidine residue in position 265 of the CdtB catalytic site appeared to play a role in the regulation of most of these genes. As for flagellin or lipopolysaccharides, CdtB also induced expression of inflammation-associated genes related to antimicrobial activity.

Novel Helicobacter species H.japonicum isolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10-/- mice.

A novel Helicobacter species Helicobacter japonicum was isolated from the stomach and intestines of clinically normal mice received from three institutes from Japan. The novel Helicobacter sp. was microaerobic, grew at 37°C and 42°C, was catalase and oxidase positive, but urease negative. It is most closely related to the 16S rRNA gene of H.muridarum (98.6%); to the 23S rRNA gene of H.hepaticus (97.9%); to the hsp60 gene of H.typhlonius (87%). The novel Helicobacter sp. has in vitro cytolethal distending toxin (CDT) activity; its cdtB gene sequence has 83.8% identity with that of H.hepaticus The whole genome sequence of H.japonicum MIT 01-6451 has a 2.06-Mb genome length with a 37.5% G + C content. When the organism was inoculated into C57BL/129 IL10-/- mice, it was cultured from the stomach, colon and cecum of infected mice at 6 and 10 weeks post-infection. The cecum had the highest H.japonicum colonization levels by quantitative PCR. The histopathology of the lower bowel was characterized by moderate to severe inflammation, mild edema, epithelial defects, mild to severe hyperplasia, dysplasia and carcinoma. Inflammatory cytokines IFNγ, TNFα and IL17a, as well as iNOS were significantly upregulated in the cecal tissue of infected mice. These results demonstrate that the novel H.japonicum can induce inflammatory bowel disease and carcinoma in IL10-/- mice and highlights the importance of identifying novel Helicobacter spp. especially when they are introduced from outside mouse colonies from different geographic locations.

Male Syrian Hamsters Experimentally Infected with Helicobacter spp. of the H. bilis Cluster Develop MALT-Associated Gastrointestinal Lymphomas.

BACKGROUND: Aged hamsters naturally infected with novel Helicobacter spp. classified in the H. bilis cluster develop hepatobiliary lesions and typhlocolitis. METHODS: To determine whether enterohepatic H. spp. contribute to disease, Helicobacter-free hamsters were experimentally infected with H. spp. after suppression of intestinal bacteria by tetracycline treatment of dams and pups. After antibiotic withdrawal, weanlings were gavaged with four H. bilis-like Helicobacter spp. isolated from hamsters or H. bilis ATCC 43879 isolated from human feces and compared to controls (n = 7 per group). RESULTS: Helicobacter bilis 43879-dosed hamsters were necropsied at 33 weeks postinfection (WPI) due to the lack of detectable infection by fecal PCR; at necropsy, 5 of 7 were weakly PCR positive but lacked intestinal lesions. The remaining hamsters were maintained for ~95 WPI; chronic H. spp. infection in hamsters (6/7) was confirmed by PCR, bacterial culture, fluorescent in situ hybridization, and ELISA. Hamsters had mild-to-moderate typhlitis, and three of the male H. spp.-infected hamsters developed small intestinal lymphoma, in contrast to one control. Of the three lymphomas in H. spp.-infected hamsters, one was a focal ileal mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, while the other two were multicentric small intestinal large B-cell lymphomas involving both the MALT and extra-MALT mucosal sites with lymphoepithelial lesions. The lymphoma in the control hamster was a diffuse small intestinal lymphoma with a mixed population of T and B cells. CONCLUSIONS: Results suggest persistent H. spp. infection may augment risk for gastrointestinal MALT origin lymphomas. This model is consistent with H. pylori/heilmannii-associated MALT lymphoma in humans and could be further utilized to investigate the mechanisms of intestinal lymphoma development.

Helicobacter pullorum isolated from fresh chicken meat: antibiotic resistance and genomic traits of an emerging foodborne pathogen.

Meat and meat products are important sources of human intestinal infections. We report the isolation of Helicobacter pullorum strains from chicken meat. Bacteria were isolated from 4 of the 17 analyzed fresh chicken meat samples, using a membrane filter method. MIC determination revealed that the four strains showed acquired resistance to ciprofloxacin; one was also resistant to erythromycin, and another one was resistant to tetracycline. Whole-genome sequencing of the four strains and comparative genomics revealed important genetic traits within the H. pullorum species, such as 18 highly polymorphic genes (including a putative new cytotoxin gene), plasmids, prophages, and a complete type VI secretion system (T6SS). The T6SS was found in three out of the four isolates, suggesting that it may play a role in H. pullorum pathogenicity and diversity. This study suggests that the emerging pathogen H. pullorum can be transmitted to humans by chicken meat consumption/contact and constitutes an important contribution toward a better knowledge of the genetic diversity within the H. pullorum species. In addition, some genetic traits found in the four strains provide relevant clues to how this species may promote adaptation and virulence.

A rare case of axillobifemoral bypass graft infection caused by Helicobacter cinaedi.

Helicobacter cinaedi infection is rarely encountered in nonimmunocompromised patients. We report the case of an 85-year-old man who presented with axillobifemoral bypass graft infection caused by Helicobacter cinaedi. The patient was not immunocompromised. We successfully treated him by iliac stenting of the native iliac artery, with near-total removal of the infected graft. At present, 48 months later, the patient is doing well at home, with no evidence of infection. To the best of our knowledge, this is the first report of infection of a prosthetic graft caused by Helicobacter cinaedi.

Helicobacter cinaedi induced typhlocolitis in Rag-2-deficient mice.

BACKGROUND: Helicobacter cinaedi, an enterohepatic helicobacter species (EHS), is an important human pathogen and is associated with a wide range of diseases, especially in immunocompromised patients. It has been convincingly demonstrated that innate immune response to certain pathogenic enteric bacteria is sufficient to initiate colitis and colon carcinogenesis in recombinase-activating gene (Rag)-2-deficient mice model. To better understand the mechanisms of human IBD and its association with development of colon cancer, we investigated whether H. cinaedi could induce pathological changes noted with murine enterohepatic helicobacter infections in the Rag2(-/-) mouse model. MATERIALS AND METHODS: Sixty 129SvEv Rag2(-/-) mice mouse were experimentally or sham infected orally with H. cinaedi strain CCUG 18818. Gastrointestinal pathology and immune responses in infected and control mice were analyzed at 3, 6 and 9 months postinfection (MPI). H. cinaedi colonized the cecum, colon, and stomach in infected mice. RESULTS: H. cinaedi induced typhlocolitis in Rag2(-/-) mice by 3 MPI and intestinal lesions became more severe by 9 MPI. H. cinaedi was also associated with the elevation of proinflammatory cytokines, interferon-γ, tumor-necrosis factor-α, IL-1ß, IL-10; iNOS mRNA levels were also upregulated in the cecum of infected mice. However, changes in IL-4, IL-6, Cox-2, and c-myc mRNA expressions were not detected. CONCLUSIONS: Our results indicated that the Rag2(-/-) mouse model will be useful to continue investigating the pathogenicity of H. cinaedi, and to study the association of host immune responses in IBD caused by EHS.

Helicobacter pullorum cytolethal distending toxin targets vinculin and cortactin and triggers formation of lamellipodia in intestinal epithelial cells.

Helicobacter pullorum, a bacterium initially isolated from poultry, has been associated with human digestive disorders. However, the factor responsible for its cytopathogenic effects on epithelial cells has not been formally identified. The cytopathogenic alterations induced by several human and avian H. pullorum strains were investigated on human intestinal epithelial cell lines. Moreover, the effects of the cytolethal distending toxin (CDT) were evaluated first by using a wild-type strain and its corresponding cdtB isogenic mutant and second by delivering the active CdtB subunit of the CDT directly into the cells. All of the H. pullorum strains induced cellular distending phenotype, actin cytoskeleton remodeling, and G2/M cell cycle arrest. These effects were dependent on the CDT, as they were (1) not observed in response to a cdtB isogenic mutant strain and (2) present in cells expressing CdtB. CdtB also induced an atypical delocalization of vinculin from focal adhesions to the perinuclear region, formation of cortical actin-rich large lamellipodia with an upregulation of cortactin, and decreased cellular adherence. In conclusion, the CDT of H. pullorum is responsible for major cytopathogenic effects in vitro, confirming its role as a main virulence factor of this emerging human pathogen.

[Role of animal gastric Helicobacter species in human gastric pathology].

Animal Helicobacter species other than Helicobacter pylori are also able to cause human gastritis, gastric ulcers, and MALT lymphomas. Animal Helicobacter species are presented with typical spiral fastidious microorganisms colonizing the gastric mucosa of different animals. Bacteria initially received their provisional name Helicobacter heilmannii, and out of them at least five species colonizing the gastric mucosa of pigs, cats, and dogs were isolated later on. A high proportion of these diseases are shown to be zoonotic. Transmission of pathogens occurs by contact. The factors of bacterial pathogenicity remain little studied.