Publications by authors named "Markus Gerhard"

90 Publications

Phantosmia, Parosmia, and Dysgeusia Are Prolonged and Late-Onset Symptoms of COVID-19.

J Clin Med 2021 Nov 12;10(22). Epub 2021 Nov 12.

Helios Klinikum München West, Steinerweg 5, 81241 München, Germany.

Deficiencies in smell and taste are common symptoms of COVID-19. Quantitative losses are well surveyed. This study focuses on qualitative changes such as phantosmia (hallucination of smell), parosmia (alteration of smell), and dysgeusia (alteration of taste) and possible connections with the adaptive immune system. Subjective experience of deficiency in taste and smell was assessed by two different questionnaires after a median of 100 and 244 days after first positive RT-PCR test. SARS-CoV-2-specific antibody levels were measured with the iFlash-SARS-CoV-2 assay. After 100 days a psychophysical screening test for olfactory and gustatory dysfunction was administered. 30 of 44 (68.2%) participants reported a chemosensory dysfunction (14 quantitative, 6 qualitative, 10 quantitative, and qualitative) during COVID-19, eleven (25.0%) participants (1 quantitative, 7 qualitative, 3 quantitative, and quantity) after 100 days, and 14 (31.8%) participants (1 quantitative, 10 qualitative, 3 quantitative and qualitative) after 244 days. Four (9.1%) participants, who were symptom-free after 100 days reported now recently arisen qualitative changes. Serological and T-cell analysis showed no correlation with impairment of taste and smell. In conclusion, qualitative changes can persist for several months and occur as late-onset symptoms months after full recovery from COVID-19-induced quantitative losses in taste and smell.
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http://dx.doi.org/10.3390/jcm10225266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618742PMC
November 2021

Proteomic profiling identifies signatures associated with progression of precancerous gastric lesions and risk of early gastric cancer.

EBioMedicine 2021 Nov 21;74:103714. Epub 2021 Nov 21.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address:

Background: Molecular features underlining the multistage progression of gastric lesions and development of early gastric cancer (GC) are poorly understood, restricting the ability to GC prevention and management.

Methods: We portrayed proteomic landscape and explored proteomic signatures associated with progression of gastric lesions and risk of early GC. Tissue proteomic profiling was conducted for a total of 324 subjects. A case-control study was performed in the discovery stage (n=169) based on populations from Linqu, a known high-risk area for GC in China. We then conducted two-stage validation, including a cohort study from Linqu (n = 56), with prospective follow-up for progression of gastric lesions (280-473 days), and an independent case-control study from Beijing (n = 99).

Findings: There was a clear distinction in proteomic features for precancerous gastric lesions and GC. We derived four molecular subtypes of gastric lesions and identified subtype-S4 with the highest progression risk. We found 104 positively-associated and 113 inversely-associated proteins for early GC, with APOA1BP, PGC, HPX and DDT associated with the risk of gastric lesion progression. Integrating these proteomic signatures, the ability to predict progression of gastric lesions was significantly strengthened (areas-under-the-curve=0.88 (95%CI: 0.78-0.99) vs. 0.56 (0.36-0.76), Delong's P = 0.002). Immunohistochemistry assays and examination at mRNA level validated the findings for four proteins.

Interpretation: We defined proteomic signatures for progression of gastric lesions and risk of early GC, which may have translational significance for identifying particularly high-risk population and detecting GC at an early stage, improving potential for targeted GC prevention.

Funding: The funders are listed in the Acknowledgement.
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http://dx.doi.org/10.1016/j.ebiom.2021.103714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617343PMC
November 2021

Engagement of CEACAM1 by HopQ Is Important for the Activation of Non-Canonical NF-κB in Gastric Epithelial Cells.

Microorganisms 2021 Aug 16;9(8). Epub 2021 Aug 16.

Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany.

The gastric pathogen infects half of the world's population and is a major risk factor for gastric cancer development. In order to attach to human gastric epithelial cells and inject the oncoprotein CagA into host cells, utilizes the outer membrane protein HopQ that binds to the cell surface protein CEACAM, which can be expressed on the gastric mucosa. Once bound, activates a number of signaling pathways, including canonical and non-canonical NF-κB. We investigated whether HopQ-CEACAM interaction is involved in activating the non-canonical NF-κB signaling pathway. Different gastric cancer cells were infected with the wild type, or HopQ mutant strains, and the activation of non-canonical NF-κB was related to CEACAM expression levels. The correlation between CEACAM levels and the activation of non-canonical NF-κB was confirmed in human gastric tissue samples. Taken together, our findings show that the HopQ-CEACAM interaction is important for activation of the non-canonical NF-κB pathway in gastric epithelial cells.
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http://dx.doi.org/10.3390/microorganisms9081748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400456PMC
August 2021

Prolonged norovirus infections correlate to quasispecies evolution resulting in structural changes of surface-exposed epitopes.

iScience 2021 Jul 30;24(7):102802. Epub 2021 Jun 30.

Institute of Virology, Technische Universität/Helmholtz Zentrum München, 81675 Munich, Germany.

In this study, we analyzed norovirus (NoV) evolution in sequential samples of six chronically infected patients. The capsid gene was amplified from stool samples, and deep sequencing was performed. The role of amino acid flexibility in structural changes and ligand binding was studied with molecular dynamics (MD) simulations. Concentrations of capsid-specific antibodies increased in sequential sera. Capsid sequences accumulated mutations during chronic infection, particularly in the surface-exposed antigenic epitopes A, D, and E. The number of quasispecies increased in infections lasting for >1 month. Interestingly, high genetic complexity and distances were followed by ongoing NoV replication, whereas lower genetic complexity and distances preceded cure. MD simulation revealed that surface-exposed amino acid substitutions of the P2 domain caused fluctuation of blockade epitopes. In conclusion, the capsid protein accumulates numerous mutations during chronic infection; however, only those on the protein surface change the protein structure substantially and may lead to immune escape.
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http://dx.doi.org/10.1016/j.isci.2021.102802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324856PMC
July 2021

Needs for an Integration of Specific Data Sources and Items - First Insights of a National Survey Within the German Center for Infection Research.

Stud Health Technol Inform 2021 May;278:237-244

German Center for Infection Research (DZIF), Braunschweig, Germany.

State-subsidized programs develop medical data integration centers in Germany. To get infection disease (ID) researchers involved in the process of data sharing, common interests and minimum data requirements were prioritized. In 06/2019 we have initiated the German Infectious Disease Data Exchange (iDEx) project. We have developed and performed an online survey to determine prioritization of requests for data integration and exchange in ID research. The survey was designed with three sub-surveys, including a ranking of 15 data categories and 184 specific data items and a query of available 51 data collecting systems. A total of 84 researchers from 17 fields of ID research participated in the survey (predominant research fields: gastrointestinal infections n=11, healthcare-associated and antibiotic-resistant infections n=10, hepatitis n=10). 48% (40/84) of participants had experience as medical doctor. The three top ranked data categories were microbiology and parasitology, experimental data, and medication (53%, 52%, and 47% of maximal points, respectively). The most relevant data items for these categories were bloodstream infections, availability of biomaterial, and medication (88%, 87%, and 94% of maximal points, respectively). The ranking of requests of data integration and exchange is diverse and depends on the chosen measure. However, there is need to promote discipline-related digitalization and data exchange.
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http://dx.doi.org/10.3233/SHTI210075DOI Listing
May 2021

Microbiota alteration at different stages in gastric lesion progression: a population-based study in Linqu, China.

Am J Cancer Res 2021 1;11(2):561-575. Epub 2021 Feb 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute Beijing, China.

In addition to Helicobacter pylori (H.pylori), gastric microbiota may be involved in carcinogenesis process. However, the longitudinal study to assess changes in the gastric microbiota associated with the development of gastric carcinogenesis is still limited. The aim of this study is to explore dynamic microbial alterations in gastric cancer (GC) development based on a 4-year endoscopic follow-up cohort in Linqu County, China. Microbial alterations were investigated by deep sequencing of the microbial 16S ribosomal RNA gene in 179 subjects with various gastric lesions, and validated in paired gastric biopsies prospectively collected before and after lesion progression and in non-progression controls. Significant differences were found in microbial diversity and community structure across various gastric lesions, with 62 candidate differential taxa between at least two lesion groups. Further validations identified Helicobacter, Bacillus, Capnocytophaga and Prevotella to be associated with lesion progression-to-dysplasia (DYS)/GC (all P < 0.05), especially for subjects progressing from intestinal metaplasia (IM) to DYS/GC. The combination of the four genera in a microbial dysbiosis index showed a significant difference after lesion progression-to-DYS/GC compared to controls (P = 0.027). The panel including the four genera identified subjects after progression-to-DYS/GC with an area under the receiver-operating curve (AUC) of 0.941. Predictive significance was found before lesion progression-to-DYS/GC with an AUC = 0.776 and an even better AUC (0.927) for subjects progressing from IM to DYS/GC. Microbiota may play different roles at different stages in gastric carcinogenesis. A panel of bacterial genera associated with gastric lesions may help to assess gastric microbial dysbiosis and show potential predictive values for lesion progression. Our findings provide new clues for the microbial mechanism of H.pylori-associated carcinogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868750PMC
February 2021

Loss of RNF43 Function Contributes to Gastric Carcinogenesis by Impairing DNA Damage Response.

Cell Mol Gastroenterol Hepatol 2021 11;11(4):1071-1094. Epub 2020 Nov 11.

Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address:

Background & Aims: RING finger protein 43 (RNF43) is a tumor suppressor that frequently is mutated in gastric tumors. The link between RNF43 and modulation of Wingless-related integration site (WNT) signaling has not been shown clearly in the stomach. Because mutations in RNF43 are highly enriched in microsatellite-unstable gastric tumors, which show defects in DNA damage response (DDR), we investigated whether RNF43 is involved in DDR in the stomach.

Methods: DDR activation and cell viability upon γ-radiation was analyzed in gastric cells where expression of RNF43 was depleted. Response to chemotherapeutic agents 5-fluorouracil and cisplatin was analyzed in gastric cancer cell lines and xenograft tumors. In addition, involvement of RNF43 in DDR activation was analyzed upon Helicobacter pylori infection in wild-type and Rnf43 mice. Furthermore, a cohort of human gastric biopsy specimens was analyzed for RNF43 expression and mutation status as well as for activation of DDR.

Results: RNF43 depletion conferred resistance to γ-radiation and chemotherapy by dampening the activation of DDR, thereby preventing apoptosis in gastric cells. Upon Helicobacter pylori infection, RNF43 loss of function reduced activation of DDR and apoptosis. Furthermore, RNF43 expression correlated with DDR activation in human gastric biopsy specimens, and RNF43 mutations found in gastric tumors conferred resistance to DNA damage. When exploring the molecular mechanisms behind these findings, a direct interaction between RNF43 and phosphorylated H2A histone family member X (γH2AX) was observed.

Conclusions: We identified a novel function for RNF43 in the stomach as a regulator of DDR. Loss of RNF43 function in gastric cells confers resistance to DNA damage-inducing radiotherapy and chemotherapy, suggesting RNF43 as a possible biomarker for therapy selection.
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http://dx.doi.org/10.1016/j.jcmgh.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898035PMC
November 2020

Fluorophore-conjugated Helicobacter pylori recombinant membrane protein (HopQ) labels primary colon cancer and metastases in orthotopic mouse models by binding CEA-related cell adhesion molecules.

Transl Oncol 2020 Dec 28;13(12):100857. Epub 2020 Aug 28.

Department of Surgery, University of California, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA. Electronic address:

HopQ is an outer-membrane protein of Helicobacter pylori that binds to human carcinoembryonic antigen-related cell-adhesion molecules (CEACAMs) with high specificity. We aimed to investigate fluorescence targeting of CEACAM-expressing colorectal tumors in patient-derived orthotopic xenograft (PDOX) models with fluorescently labeled recombinant HopQ (rHopQ). Western blotting, flow cytometry and ELISA were performed to determine the efficiency of rHopQ binding to CEACAMs. rHopQ was conjugated to IR800DyeCW (rHopQ-IR800). Nude mice received orthotopic implantation of colon cancer tumors. Three weeks later, mice were administered 25 μg or 50 μg HopQ-IR800 and imaged 24 or 48 h later. Intravital images were analyzed for tumor-to-background ratio (TBR). Flow cytometry and ELISA demonstrated binding of HopQ to CEACAM1, 3 and 5. Dose-response intravital imaging in PDOX models demonstrated optimal results 48 h after administration of 50 μg rHopQ-IR800 (TBR = 3.576) in our protocol. Orthotopic models demonstrated clear tumor margins of primary tumors and small regional metastases with a mean TBR = 3.678 (SD ± 1.027). rHopQ showed specific binding to various CEACAMs in PDOX models. rHopQ may be useful for CEACAM-positive tumor and metastasis detection for pre-surgical diagnosis, intra-operative imaging and fluorescence-guided surgery.
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http://dx.doi.org/10.1016/j.tranon.2020.100857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475271PMC
December 2020

Microbiota-associated Risk Factors for Clostridioides difficile Acquisition in Hospitalized Patients: A Prospective, Multicentric Study.

Clin Infect Dis 2021 11;73(9):e2625-e2634

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: Asymptomatic C. difficile colonization is believed to predispose to subsequent C. difficile infection (CDI). While emerging insights into the role of the commensal microbiota in mediating colonization resistance against C. difficile have associated CDI with specific microbial components, corresponding prospectively collected data on colonization with C. difficile are largely unavailable.

Methods: C. difficile status was assessed by GDH EIA and real-time PCR targeting the toxin A (tcdA) and B (tcdB) genes. 16S V3 and V4 gene sequencing results from fecal samples of patients tested positive for C. difficile were analyzed by assessing alpha and beta diversity, LefSe, and the Piphillin functional inference approach to estimate functional capacity.

Results: 1506 patients were recruited into a prospective observational study (DRKS00005335) upon admission into one of five academic hospitals. 936 of them provided fecal samples on admission and at discharge and were thus available for longitudinal analysis. Upon hospital admission, 5.5% (83/1506) and 3.7% (56/1506) of patients were colonized with toxigenic (TCD) and non-toxigenic C. difficile (NTCD), respectively. During hospitalization, 1.7% (16/936) acquired TCD. Risk factors for acquisition of TCD included pre-existing lung diseases, lower GI endoscopy and antibiotics. Species protecting against hospital-related C. difficile acquisition included Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococcus spp. Metagenomic pathway analysis identified steroid biosynthesis as the most underrepresented metabolic pathway in patients who later acquire C. difficile colonization.

Conclusions: Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococci were associated with a decreased risk of C. difficile acquisition.

Clinical Trials Registration: DRKS00005335.
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http://dx.doi.org/10.1093/cid/ciaa871DOI Listing
November 2021

Gut Microbiota-Derived Propionate Regulates the Expression of Reg3 Mucosal Lectins and Ameliorates Experimental Colitis in Mice.

J Crohns Colitis 2020 Oct;14(10):1462-1472

Klinik für Innere Medizin II, Klinikum rechts der Isar, Techn. Univ. Munich, Munich, Germany.

Background And Aims: Regenerating islet-derived protein type 3 [Reg3] lectins are antimicrobial peptides at mucosal surfaces of the gut, whose expression is regulated by pathogenic gut microbes via interleukin-22- or Toll-like receptor signalling. In addition to antimicrobial effects, tissue protection is hypothesized, but has been poorly investigated in the gut.

Methods: We applied antibiotic-induced microbiota perturbations, gnotobiotic approaches and a dextran-sodium sulfate [DSS] colitis model to assess microbial Reg3 regulation in the intestines and its role in colitis. We also used an intestinal organoid model to investigate this axis in vitro.

Results: First, we studied whether gut commensals are involved in Reg3 expression in mice, and found that antibiotic-mediated reduction of Clostridia downregulated intestinal Reg3B. A loss in Clostridia was accompanied by a significant reduction of short-chain fatty acids [SCFAs], and knock-out [KO] mice for SCFA receptors GPR43 and GPR109 expressed less intestinal Reg3B/-G. Propionate was found to induce Reg3 in intestinal organoids and in gnotobiotic mice colonized with a defined, SCFA-producing microbiota. Investigating the role of Reg3B as a protective factor in colitis, we found that Reg3B-KO mice display increased inflammation and less crypt proliferation in the DSS colitis model. Propionate decreased colitis and increased proliferation. Treatment of organoids exposed to DSS with Reg3B or propionate reversed the chemical injury with a loss of expression of the stem-cell marker Lgr5 and Olfm4.

Conclusions: Our results suggest that Clostridia can regulate Reg3-associated epithelial homeostasis through propionate signalling. We also provide evidence that the Reg3-propionate axis may be an important mediator of gut epithelial regeneration in colitis.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa065DOI Listing
October 2020

Cysteine Residues in Adhesin HopQ are Required for CEACAM-HopQ Interaction and Subsequent CagA Translocation.

Microorganisms 2020 Mar 25;8(4). Epub 2020 Mar 25.

Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany.

Attachment to the host gastric mucosa is a key step in infection. Recently, a novel adhesin, HopQ, was shown to bind distinct host CEACAM proteins-an interaction that was found to be essential for the translocation of CagA, a key virulence factor of The HopQ-CEACAM1 co-crystal structure revealed a binding mode dependent on loops in HopQ that are clasped by disulfide bonds. In this study, we investigated the importance of these cysteine residues for CEACAM1 engagement by . We observed a loss of CEACAM1 binding and CagA translocation upon disruption of the disulfide bond in loop CL1 (connecting C103 to C132 in HopQ). Deletion of the Dsb-like oxidoreductase HP0231 did not affect cell surface expression of HopQ or alter the interaction of with target cells. Although HP0231 deletion was previously described to impede CagA translocation, our results indicate that this occurs through a HopQ-independent mechanism. Together, our results open up new avenues to therapeutically target the HopQ-CEACAM1 interaction and reduce the burden of pathogenic .
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http://dx.doi.org/10.3390/microorganisms8040465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232459PMC
March 2020

Effect of on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer.

Gut 2020 09 19;69(9):1598-1607. Epub 2019 Dec 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China

Objective: Gastrointestinal microbiota may be involved in associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from infection.

Design: Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti- treatment, relative to 49 negative subjects.

Results: In positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between and , , , , were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased after successful eradication and more upregulated drug-resistant functional orthologs after failed treatment.

Conclusion: infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
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http://dx.doi.org/10.1136/gutjnl-2019-319696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456744PMC
September 2020

A mass spectrometry guided approach for the identification of novel vaccine candidates in gram-negative pathogens.

Sci Rep 2019 11 22;9(1):17401. Epub 2019 Nov 22.

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.

Vaccination is the most effective method to prevent infectious diseases. However, approaches to identify novel vaccine candidates are commonly laborious and protracted. While surface proteins are suitable vaccine candidates and can elicit antibacterial antibody responses, systematic approaches to define surfomes from gram-negatives have rarely been successful. Here we developed a combined discovery-driven mass spectrometry and computational strategy to identify bacterial vaccine candidates and validate their immunogenicity using a highly prevalent gram-negative pathogen, Helicobacter pylori, as a model organism. We efficiently isolated surface antigens by enzymatic cleavage, with a design of experiment based strategy to experimentally dissect cell surface-exposed from cytosolic proteins. From a total of 1,153 quantified bacterial proteins, we thereby identified 72 surface exposed antigens and further prioritized candidates by computational homology inference within and across species. We next tested candidate-specific immune responses. All candidates were recognized in sera from infected patients, and readily induced antibody responses after vaccination of mice. The candidate jhp_0775 induced specific B and T cell responses and significantly reduced colonization levels in mouse therapeutic vaccination studies. In infected humans, we further show that jhp_0775 is immunogenic and activates IFNγ secretion from peripheral CD4 and CD8 T cells. Our strategy provides a generic preclinical screening, selection and validation process for novel vaccine candidates against gram-negative bacteria, which could be employed to other gram-negative pathogens.
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http://dx.doi.org/10.1038/s41598-019-53493-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874673PMC
November 2019

Quantitation of norovirus-specific IgG before and after infection in immunocompromised patients.

Braz J Microbiol 2020 Mar 26;51(1):183-187. Epub 2019 Oct 26.

Institute of Virology, Technische Universität und Helmholtz Zentrum München, Munich, Germany.

Noroviruses (NoV) cause the majority of non-bacterial gastroenteritis cases worldwide, with genotype II.4 being the most common. The aim of our study was to quantitate norovirus-specific IgG in immunocompromised patients before and after laboratory-confirmed norovirus infection. A quantitative ELISA was developed by coating ELISA plates with recombinantly expressed P domain of GII.1 capsid protein. After testing mouse sera drawn before and after immunization with GII.1- and GII.4 P domain, sera from GII.1- and GII.4 infected patients were tested. The assay reliably detected preexisting NoV-specific IgG antibodies. Sera drawn after infection showed increased antibody concentrations. Antibodies elicited by GII.1- and GII.4 infections could be detected with coated GII.1 capsid protein. IgG levels remained constant during the first week and then increased in the second week after laboratory diagnosis. The results show that immunocompromised patients elicited IgG responses to NoV infections that could be reliably detected with our quantitative ELISA.
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http://dx.doi.org/10.1007/s42770-019-00176-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058766PMC
March 2020

Exploits the NLRC4 Inflammasome to Dampen Host Defenses.

J Immunol 2019 10 11;203(8):2183-2193. Epub 2019 Sep 11.

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Fakultät für Medizin, Technische Universität München, 81675 Munich, Germany; and

colonizes the stomach of around 50% of humans. This chronic infection can lead to gastric pathologic conditions such as gastric ulcers and gastric adenocarcinomas. The strong inflammatory response elicited by is characterized by the induction of the expression of several cytokines. Among those, IL-18 is found highly upregulated in infected individuals, and its expression correlates with the severity of gastric inflammation. IL-18 is produced as inactive proform and has to be cleaved by the multiprotein complex inflammasome to be active. In immune cells, the NLRC4 inflammasome, which is activated by flagellin or bacterial secretion systems, was shown to be dispensable for -induced inflammasome activation. However, apart from immune cells, gastric epithelial cells can also produce IL-18. In this study, we analyzed the role of the NLRC4 inflammasome during infection. Our results indicate that NLRC4 and a functional type IV secretion system are crucial for the production of IL-18 from human and murine gastric epithelial cells. In vivo, mice failed to produce gastric IL-18 upon infection. Compared with wild type mice, mice controlled better without showing strong inflammation. Moreover, -induced IL-18 inhibits β-defensin 1 expression in a NF-κB-dependent manner, resulting in higher bacterial colonization. At the same time, inflammasome activation enhances neutrophil infiltration, resulting in inflammation. Thus, NLRC4 inflammasome activation and subsequent IL-18 production favors bacterial persistence by inhibiting antimicrobial peptide production and, at the same time, contributes to gastric inflammation.
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http://dx.doi.org/10.4049/jimmunol.1900351DOI Listing
October 2019

Concomitant Infection of S. mansoni and H. pylori Promotes Promiscuity of Antigen-Experienced Cells and Primes the Liver for a Lower Fibrotic Response.

Cell Rep 2019 07;28(1):231-244.e5

Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany. Electronic address:

Helicobacter pylori chronically colonizes the stomach and is strongly associated with gastric cancer. Its concomitant occurrence with helminths such as schistosomes has been linked to reduced cancer incidence, presumably due to suppression of H. pylori-associated pro-inflammatory responses. However, experimental evidence in support of such a causal link or the mutual interaction of both pathogens is lacking. We investigated the effects of co-infection during the different immune phases of S. mansoni infection. Surprisingly, co-infected mice had increased H. pylori gastric colonization during the interferon gamma (IFNγ) phase of schistosome infection but reduced infiltration of T cells in the stomach due to misdirection of antigen-experienced CXCR3 T cells to the liver. Unexpectedly, H. pylori co-infection resulted in partial protection from schistosome-induced liver damage. Here, we demonstrate that an increase in fibrosis-protective IL-13Ra2 is associated with H. pylori infection. Thus, our study strongly points to an immunological interaction of anatomically isolated pathogens, eventually resulting in altered disease pathology.
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http://dx.doi.org/10.1016/j.celrep.2019.05.108DOI Listing
July 2019

Increased LIGHT expression and activation of non-canonical NF-κB are observed in gastric lesions of MyD88-deficient mice upon Helicobacter felis infection.

Sci Rep 2019 05 7;9(1):7030. Epub 2019 May 7.

Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA.

Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis. Among those, NF-κB signaling plays a pivotal role during infection and malignant transformation of the gastric epithelium. However, deficiency of the adaptor molecule myeloid differentiation primary response 88 (MyD88), which signals through NF-κB, led to an accelerated development of gastric pathology upon H. felis infection, but the mechanisms leading to this phenotype remained elusive. Non-canonical NF-κB signaling was shown to aggravate H. pylori-induced gastric inflammation via activation of the lymphotoxin β receptor (LTβR). In the present study, we explored whether the exacerbated pathology observed in MyD88-deficient (Myd88) mice was associated with aberrant activation of non-canonical NF-κB. Our results indicate that, in the absence of MyD88, H. felis infection enhances the activation of non-canonical NF-κB that is associated with increase in Cxcl9 and Icam1 gene expression and CD3 lymphocyte recruitment. In addition, activation of signal transducer and activator of transcription 3 (STAT3) signaling was higher in Myd88 compared to wild type (WT) mice, indicating a link between MyD88 deficiency and STAT3 activation in response to H. felis infection. Thereby, MyD88 deficiency results in accelerated and aggravated gastric pathology induced by Helicobacter through activation of non-canonical NF-κB.
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http://dx.doi.org/10.1038/s41598-019-43417-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504916PMC
May 2019

The HopQ outermembrane protein inhibits immune cell activities.

Oncoimmunology 2019;8(4):e1553487. Epub 2019 Jan 29.

The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel.

We previously showed that the colorectal cancer colonizing bacterium protects tumors from immune cell attack via binding of the fusbacterial Fap2 outer-membrane protein to TIGIT, a checkpoint inhibitory receptor expressed on T cells and NK cells. , the causative agent for peptic ulcer disease, is associated with the development of gastric adenocarcinoma and MALT lymphoma. The HopQ outer-membrane adhesin of was recently shown to bind carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) including CEACAM1, an inhibitory receptor expressed mainly by activated T and NK cells. Here we investigated the possibility that similar to Fap2, HopQ can also inhibit immune cell activities by interacting with CEACAM1. We used several approaches to confirm that HopQ indeed interacts with CEACAM1, and show that CEACAM1-mediated activation by HopQ, may inhibit NK and T cell functions.
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http://dx.doi.org/10.1080/2162402X.2018.1553487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422397PMC
January 2019

Mutated Aggravates -Induced Gastric Pathology.

Cancers (Basel) 2019 Mar 16;11(3). Epub 2019 Mar 16.

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany.

The E3 ubiquitin ligase ring finger protein 43 (RNF43) is frequently mutated in gastric tumors and loss of RNF43 expression was suggested to be one of the key events during the transition from adenoma to gastric carcinoma. Functional studies on RNF43 have shown that it acts as a tumor suppressor by negatively regulating Wnt signaling. Interestingly, we observed that RNF43 mice bearing two point mutations in the ring domain displayed thickening of the mucosa at early age but did not develop neoplasia. In this study, we infected these mice for 6 months with , which has been described as one of the major risk factors for gastric cancer. Mice bearing mutant RNF43 showed higher gastritis scores upon infection compared to wild-type mice, accompanied by increased lymphocyte infiltration and levels. Furthermore, infected mutant mice developed atrophy, hyperplasia and MUC2 expressing metaplasia and displayed higher levels of the gastric stem cell marker CD44 and canonical NF-κB signaling. In summary, our results show that transactivating mutations in the tumor suppressor can worsen induced pathology.
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http://dx.doi.org/10.3390/cancers11030372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468876PMC
March 2019

Loss of endogenous RNF43 function enhances proliferation and tumour growth of intestinal and gastric cells.

Carcinogenesis 2019 06;40(4):551-559

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.

Ring finger protein 43 (RNF43) is an E3 ubiquitin ligase that has been described to be frequently mutated in gastrointestinal cancers. RNF43 downregulation was associated with distant metastasis, TNM stage and poorer survival in patients with gastric and colorectal cancers. Functional analysis has shown that overexpressed RNF43 negatively regulates Wnt signalling by ubiquitinating Frizzled receptors and targeting them for degradation and by sequestering T-cell factor 4 (TCF4) to the nuclear membrane, thereby inhibiting Wnt-mediated transcription. In the stomach, RNF43 overexpression was shown to impair stem-like properties and to be negatively correlated with expression of Wnt-target genes. In this study, we show that RNF43 knockdown enhances the tumourigenic potential of gastric and colorectal cancer cell lines in vitro and in vivo. Thus, loss of RNF43 leads to increased proliferation and anchorage-independent growth as well as increased invasive capacity. In a xenograft model, RNF43 depletion enhanced tumour growth. Furthermore, we established two mouse models in which mutations in the RING domain of RNF43 were introduced. In the intestine and colon, loss of Rnf43 did not induce changes in epithelial architecture or proliferation. In contrast, in the stomach, thickening of the mucosa, hyperplasia and cellular atypia were observed in these mice. Notably, this was independent of elevated Wnt signalling. Together, our results show that RNF43 plays a tumour suppressive role in gastric and colorectal cancer cells and that the loss of its function alters gastric tissue homeostasis in vivo.
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http://dx.doi.org/10.1093/carcin/bgy152DOI Listing
June 2019

Association Between Gut Microbiota and -Related Gastric Lesions in a High-Risk Population of Gastric Cancer.

Front Cell Infect Microbiol 2018 19;8:202. Epub 2018 Jun 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

Eradication of has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and -related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were , and with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current infection compared with negative subjects. As for the differential bacteria, the average relative abundance of was found to significantly decrease from negative (66.16%) to past infection group (33.01%, = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, = 0.027). For and , the average relative abundances showed elevated trends in the past infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of and , may be involved in the process of -related gastric lesion progression and provide hints for future evaluation of microbial changes after eradication.
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http://dx.doi.org/10.3389/fcimb.2018.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018392PMC
July 2019

adhesin HopQ disrupts dimerization in human CEACAMs.

EMBO J 2018 07 1;37(13). Epub 2018 Jun 1.

Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Brussels, Belgium

The human gastric pathogen 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 specificity toward human CEACAM receptors. Both HopQ alleles target the β-strands G, F, and C of C1ND, which form the 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 a route to influence CEACAM-mediated cell adherence and signaling events.
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http://dx.doi.org/10.15252/embj.201798665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028033PMC
July 2018

Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori.

High Throughput 2017 Oct 30;6(4). Epub 2017 Oct 30.

NMI Natural and Medical Sciences Institute at the University of Tuebingen, 72770 Reutlingen, Germany.

The spread of infectious diseases and vaccination history are common subjects of epidemiological and immunological research studies. Multiplexed serological assays are useful tools for assessing both current and previous infections as well as vaccination efficacy. We developed a serological multi-pathogen assay for hepatitis A, B and C virus, cytomegalovirus (CMV), , and using a bead-based multiplex assay format. The multi-pathogen assay consisting of 15 antigens was utilized for the analysis of the serological response in elderly individuals of an influenza vaccination study ( = 34). The technical assay validation revealed a mean intra-assay precision of coefficient of variation (CV) = 3.2 ± 1.5% and a mean inter-assay precision of CV = 8.2 ± 5.3% across all 15 antigens and all tested samples, indicating a robust test system. Furthermore, the assay shows high sensitivities (ranging between 94% and 100%) and specificities (ranging between 93% and 100%) for the different pathogens. The highest seroprevalence rates in our cohort were observed for hepatitis A virus (HAV; 73.5%), followed by CMV (70.6%), (67.6%) and (32.4%). Seroprevalences for hepatitis B virus (HBV, 8.8%) and hepatitis C virus (HCV, 0%) were low. The seroprevalences observed in our study were similar to those from other population-based studies in Germany. In summary, we conclude that our multiplex serological assay represents a suitable tool for epidemiological studies.
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http://dx.doi.org/10.3390/ht6040014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748593PMC
October 2017

BaiCD gene cluster abundance is negatively correlated with Clostridium difficile infection.

PLoS One 2018 8;13(5):e0196977. Epub 2018 May 8.

Hannover Medical School, Institute of Medical Microbiology and Hospital Epidemiology, Hannover, Germany.

Background: Clostridium difficile infection (CDI) is a major cause of hospital-acquired diarrhea. Secondary bile acids were shown to confer resistance to colonization by C. difficile. 7α-dehydroxylation is a key step in transformation of primary to secondary bile acids and required genes have been located in a single bile acid-inducible (bai) operon in C. scindens as well as in C. hiranonis, two Clostridium sp. recently reported to protect against C. difficile colonization.

Aim: To analyze baiCD gene abundance in C. difficile positive and negative fecal samples.

Material & Methods: A species-specific qPCR for detecting baiCD genes was established. Fecal samples of patients with CDI, asymptomatic toxigenic C. difficile colonization (TCD), non-toxigenic C. difficile colonization (NTCD), of C. difficile negative (NC) patients, and of two patients before and after fecal microbiota transplantation (FMT) for recurrent CDI (rCDI) were tested for the presence of the baiCD genes.

Results: The prevalence of the baiCD gene cluster was significantly higher in C. difficile negative fecal samples than in samples of patients diagnosed with CDI (72.5% (100/138) vs. 35.9% (23/64; p<0.0001). No differences in baiCD gene cluster prevalence were seen between NC and NTCD or NC and TCD samples. Both rCDI patients were baiCD-negative at baseline, but one of the two patients turned positive after successful FMT from a baiCD-positive donor.

Conclusion: Fecal samples of CDI patients are less frequently baiCD-positive than samples from asymptomatic carriers or C. difficile-negative individuals. Furthermore, we present a case of baiCD positivity observed after successful FMT for rCDI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940204PMC
August 2018

Evidence suggests that germline mutations are a rare cause of serrated polyposis.

Gut 2018 12 12;67(12):2230-2232. Epub 2018 Jan 12.

Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.

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http://dx.doi.org/10.1136/gutjnl-2017-315733DOI Listing
December 2018

Helicobacter pylori γ-glutamyl transferase contributes to colonization and differential recruitment of T cells during persistence.

Sci Rep 2017 10 20;7(1):13636. Epub 2017 Oct 20.

Institut für medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675, Munich, Germany.

Helicobacter pylori γ-glutamyl transferase (gGT) is a key bacterial virulence factor that is not only important for bacterial gastric colonization but also related to the development of gastric pathology. Despite accumulating evidence for pathogenic and immunologic functions of H. pylori gGT, it is still unclear how it supports gastric colonization and how its specific effects on the host's innate and adaptive immune responses contribute to colonization and pathology. We have compared mice showing similar bacterial load after infection with gGT-proficient or gGT-deficient H. pylori to analyse the specific role of the enzyme during infection. Our data indicate that H. pylori gGT supports initial colonization. Nevertheless, bacteria lacking gGT can still colonize and persist. We observed that the presence of gGT during infection favoured a proinflammatory innate and adaptive immune response. Notably, H. pylori gGT activity was linked to increased levels of IFNγ, which were attributed to a differential recruitment of CD8 T cells to the stomach. Our data support an essential role for H. pylori gGT in gastric colonization and further suggest that gGT favours infiltration of CD8 cells to the gastric mucosa, which might play an important and yet overlooked role in the pathogenesis of H. pylori.
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http://dx.doi.org/10.1038/s41598-017-14028-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651840PMC
October 2017

Performance of a Multiplex Serological Helicobacter pylori Assay on a Novel Microfluidic Assay Platform.

Proteomes 2017 Oct 3;5(4). Epub 2017 Oct 3.

NMI Natural and Medical Sciences Institute at the University of Tuebingen, Markwiesenstr 55, 72770 Reutlingen, Germany.

Infection with () occurs in 50% of the world population, and is associated with the development of ulcer and gastric cancer. Serological diagnostic tests indicate an infection by detecting antibodies directed against proteins. In addition to line blots, multiplex assay platforms provide smart solutions for the simultaneous analysis of antibody responses towards several proteins. We used seven proteins (FliD, gGT, GroEL, HpaA, CagA, VacA, and HP0231) and an lysate for the development of a multiplex serological assay on a novel microfluidic platform. The reaction limited binding regime in the microfluidic channels allows for a short incubation time of 35 min. The developed assay showed very high sensitivity (99%) and specificity (100%). Besides sensitivity and specificity, the technical validation (intra-assay CV = 3.7 ± 1.2% and inter-assay CV = 5.5 ± 1.2%) demonstrates that our assay is also a robust tool for the analysis of the -specific antibody response. The integration of the virulence factors CagA and VacA allow for the assessment of the risk for gastric cancer development. The short assay time and the performance of the platform shows the potential for implementation of such assays in a clinical setting.
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http://dx.doi.org/10.3390/proteomes5040024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748559PMC
October 2017

Validation of a Novel Immunoline Assay for Patient Stratification according to Virulence of the Infecting Strain and Eradication Status.

J Immunol Res 2017 30;2017:8394593. Epub 2017 May 30.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.

infection shows a worldwide prevalence of around 50%. However, only a minority of infected individuals develop clinical symptoms or diseases. The presence of virulence factors, such as CagA and VacA, has been associated with disease development, but assessment of virulence factor presence requires gastric biopsies. Here, we evaluate the Line test for risk stratification of infected patients by comparing the test score and immune recognition of type I or type II strains defined by the virulence factors CagA, VacA, GroEL, UreA, HcpC, and gGT with patient's disease status according to histology. Moreover, the immune responses of eradicated individuals from two different populations were analysed. Their immune response frequencies and intensities against all antigens except CagA declined below the detection limit. CagA was particularly long lasting in both independent populations. An isolated CagA band often represents past eradication with a likelihood of 88.7%. In addition, a high Line score was significantly associated with high-grade gastritis, atrophy, intestinal metaplasia, and gastric cancer. Thus, the Line is a sensitive and specific noninvasive test for detecting serum responses against in actively infected and eradicated individuals. Moreover, it allows stratifying patients according to their disease state.
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http://dx.doi.org/10.1155/2017/8394593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468576PMC
April 2018

Cut-off optimization for C-urea breath test in a community-based trial by mathematic, histology and serology approach.

Sci Rep 2017 05 18;7(1):2072. Epub 2017 May 18.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, China.

The performance of diagnostic tests in intervention trials of Helicobacter pylori (H.pylori) eradication is crucial, since even minor inaccuracies can have major impact. To determine the cut-off point for C-urea breath test (C-UBT) and to assess if it can be further optimized by serologic testing, mathematic modeling, histopathology and serologic validation were applied. A finite mixture model (FMM) was developed in 21,857 subjects, and an independent validation by modified Giemsa staining was conducted in 300 selected subjects. H.pylori status was determined using recomLine H.pylori assay in 2,113 subjects with a borderline C-UBT results. The delta over baseline-value (DOB) of 3.8 was an optimal cut-off point by a FMM in modelling dataset, which was further validated as the most appropriate cut-off point by Giemsa staining (sensitivity = 94.53%, specificity = 92.93%). In the borderline population, 1,468 subjects were determined as H.pylori positive by recomLine (69.5%). A significant correlation between the number of positive H.pylori serum responses and DOB value was found (r = 0.217, P < 0.001). A mathematical approach such as FMM might be an alternative measure in optimizing the cut-off point for C-UBT in community-based studies, and a second method to determine H.pylori status for subjects with borderline value of C-UBT was necessary and recommended.
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http://dx.doi.org/10.1038/s41598-017-02180-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437005PMC
May 2017

Immune Evasion Strategies and Persistence of Helicobacter pylori.

Curr Top Microbiol Immunol 2017;400:53-71

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.

Helicobacter pylori infection is commonly acquired during childhood, can persist lifelong if not treated, and can cause different gastric pathologies, including chronic gastritis, peptic ulcer disease, and eventually gastric cancer. H. pylori has developed a number of strategies in order to cope with the hostile conditions found in the human stomach as well as successful mechanisms to evade the strong innate and adaptive immune responses elicited upon infection. Thus, by manipulating innate immune receptors and related signaling pathways, inducing tolerogenic dendritic cells and inhibiting effector T cell responses, H. pylori ensures low recognition by the host immune system as well as its persistence in the gastric epithelium. Bacterial virulence factors such as cytotoxin-associated gene A, vacuolating cytotoxin A, or gamma-glutamyltranspeptidase have been extensively studied in the context of bacterial immune escape and persistence. Further, the bacterium possesses other factors that contribute to immune evasion. In this chapter, we discuss in detail the main evasion and persistence strategies evolved by the bacterium as well as the specific bacterial virulence factors involved.
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http://dx.doi.org/10.1007/978-3-319-50520-6_3DOI Listing
June 2017
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