Publications by authors named "Pierre Gosset"

49 Publications

The Toll-Like Receptor 5 agonist flagellin prevents Non-typeable Haemophilus influenzae-induced infection in cigarette smoke-exposed mice.

PLoS One 2021 30;16(3):e0236216. Epub 2021 Mar 30.

Univ. Lille, CNRS UMR9017, Inserm U1019, CHRU Lille, Institut Pasteur de Lille, CIIL-Center for Infection and Immunity of Lille, Lille, France.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. The major bacterial cause of COPD exacerbations is non-typeable Haemophilus influenzae (NTHi). 25 to over 80% of cases are associated with NTHi. This susceptibility to infection involves a defective production of interleukin (IL)-22 which plays an important role in mucosal defense. Prophylactic administration of flagellin, a Toll-like receptor 5 (TLR5) agonist, protects healthy mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might prevent COPD exacerbations. Mice chronically exposed to cigarette smoke (CS), which presented COPD symptoms, were infected with NTHi and intraperitoneally treated with recombinant flagellin following a prophylactic or therapeutic protocol. Compared with control, cigarette smoke-exposed mice treated with flagellin showed a lower bacterial load in the airways, the lungs and the blood. This protection was associated with an early neutrophilia, a lower production of pro-inflammatory cytokines and an increased IL-22 production. Flagellin treatment decreased the recruitment of inflammatory cells and the lung damages related to exacerbation. Morover, the protective effect of flagellin against NTHi was altered by treatment with anti-IL-22 blocking antibodies in cigarette smoke-exposed mice and in Il22-/- mice. The effect of flagellin treatment did not implicated the anti-bacterial peptides calgranulins and defensin-β2. This study shows that stimulation of innate immunity by a TLR5 ligand is a potent antibacterial treatment in CS-exposed mice, suggesting innovative therapeutic strategies against acute exacerbation in COPD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009382PMC
March 2021

Comparative study on gene expression profile in rat lung after repeated exposure to diesel and biodiesel exhausts upstream and downstream of a particle filter.

Environ Pollut 2020 Nov 26;266(Pt 2):115264. Epub 2020 Jul 26.

Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, 35000, Rennes, France.

Biodiesel is considered as a valuable and less toxic alternative to diesel. However, cellular and molecular effects of repeated exposure to biodiesel emissions from a recent engine equipped with a diesel particle filter (DPF) remain to be characterized. To gain insights about this point, the lung transcriptional signatures were analyzed for rats (n = 6 per group) exposed to filtered air, 30% rapeseed biodiesel (B30) blend or reference diesel (RF0), upstream and downstream a DPF, for 3 weeks (3 h/day, 5 days/week). Genomic analysis revealed a modest regulation of gene expression level (lower than a 2-fold) by both fuels and a higher number of genes regulated downstream the DPF than upstream, in response to either RF0 or to B30 exhaust emissions. The presence of DPF was found to notably impact the lung gene signature of rats exposed to B30. The number of genes regulated in common by both fuels was low, which is likely due to differences in concentrations of regulated pollutants in exhausts, notably for compound organic volatiles, polycyclic aromatic hydrocarbons, NO or NOx. Nevertheless, we have identified some pathways that were activated for both exhaust emissions, such as integrin-, IGF-1- and Rac-signaling pathways, likely reflecting the effects of gas phase products. By contrast, some canonical pathways relative to "oxidative phosphorylation" and "mitochondrial dysfunction" appear as specific to B30 exhaust emission; the repression of transcripts of mitochondrial respiratory chain in lung of rats exposed to B30 downstream of DPF supports the perturbation of mitochondria function. This study done with a recent diesel engine (compliant with the European IV emission standard) and commercially-available fuels reveals that the diesel blend composition and the presence of an after treatment system may modify lung gene signature of rats repeatedly exposed to exhaust emissions, however in a rather modest manner.
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http://dx.doi.org/10.1016/j.envpol.2020.115264DOI Listing
November 2020

A prospective pilot study of the T-lymphocyte response to fine particulate matter exposure.

J Appl Toxicol 2020 05 23;40(5):619-630. Epub 2020 Jan 23.

EA 4492 - UCEIV - Unité de Chimie Environnementale et Interactions sur le Vivant, Université du Littoral Côte d'Opale, SFR Condorcet FR CNRS 3417, Dunkerque, France.

Exposure to air pollution is associated with increased morbidity and mortality. Once the fine atmospheric particulate matter (FP) is inhaled, some of its compounds can pass through the lungs and reach the bloodstream where they can come into contact with immune cells. Exposure to FP particularly affects sensitive populations such as the elderly. Aging affects the immune system, making the elderly more vulnerable. The project aims to determine the effects of FP exposure on human T cells while looking for biomarkers associated with exposure. Blood samples from 95 healthy subjects in three different age groups (20-30, 45-55 and 70-85 years) were collected to determine a potential age effect. T lymphocytes were isolated to be exposed ex vivo for 72 hours to 45 μg/mL of FP collected in Dunkirk and chemically characterized. Overexpression of the CYP1A1, CYP1B1 and CYP2S1 genes was therefore measured after exposure of the T cells to FP. These genes code for enzymes known to be involved in the metabolic activation of organic compounds such as polycyclic aromatic hydrocarbons detected in the FP sample. T-cell profiling allowed us to suggest a mixed T-helper 1/2 profile caused by exposure to FP. With regard to the influence of age, we have observed differences in the expression of certain genes, as well as an increase in interleukin-4 and -13 concentrations in the elderly. These results showed that exposure of T lymphocytes to FP causes effects on both transcriptomic and cytokine secretion levels.
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http://dx.doi.org/10.1002/jat.3932DOI Listing
May 2020

Chemical characterization of fine and ultrafine PM, direct and indirect genotoxicity of PM and their organic extracts on pulmonary cells.

J Environ Sci (China) 2018 Sep 27;71:168-178. Epub 2018 Apr 27.

University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France.

Particulate matter in ambient air constitutes a complex mixture of fine and ultrafine particles composed of various chemical compounds including metals, ions, and organics. A multidisciplinary approach was developed by studying physico-chemical characteristics and mechanisms involved in the toxicity of particulate atmospheric pollution. PM and PM including ultrafine particles were sampled in Dunkerque, a French industrialized seaside city. PM samples were characterized from a chemical and toxicological point of view. Physico-chemical characterization evidenced that PM comes from several sources: natural ones, such as soil resuspension and marine sea-salt emissions, as well as anthropogenic ones, such as shipping traffic, road traffic, and industrial activities. Human BEAS-2B lung cells were exposed to PM, or to the Extractable Organic Matter (EOM) of PM and PM. These exposures induced several mechanisms of action implied in the genotoxicity, such as oxidative DNA adducts and DNA Damage Response. The toxicity of PM-EOM was higher for the sample including the ultrafine fraction (PM) containing also higher concentrations of polycyclic aromatic hydrocarbons. These results evidenced the major role of organic compounds in the toxicity of PM.
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http://dx.doi.org/10.1016/j.jes.2018.04.022DOI Listing
September 2018

Influence of aging in the modulation of epigenetic biomarkers of carcinogenesis after exposure to air pollution.

Exp Gerontol 2018 09 31;110:125-132. Epub 2018 May 31.

Unité de Chimie Environnementale et Interactions sur le Vivant (EA4492), Université du Littoral Côte d'Opale, Dunkerque 59140, France.

Background: Classified as carcinogenic to humans by the IARC in 2013, fine air particulate matter (PM) can be inhaled and retained into the lung or reach the systemic circulation. This can cause or exacerbate numerous pathologies to which the elderly are often more sensitive.

Methods: In order to estimate the influence of age on the development of early cellular epigenetic alterations involved in carcinogenesis, peripheral blood mononuclear cells sampled from 90 patients from three age classes (25-30, 50-55 and 75-80 years old) were ex vivo exposed to urban PM.

Results: Particles exposure led to variations in telomerase activity and telomeres length in all age groups without any influence of age. Conversely, P16 gene expression increased significantly with age after exposure to PM. Age could enhance MGMT gene expression after exposure to particles, by decreasing the level of promoter methylation in the oldest people.

Conclusion: Hence, our results demonstrated several tendencies in cells modification depending on age, even if all epigenetic assays were carried out after a limited exposure time allowing only one or two cell cycles. Since lung cancer symptoms appear only at an advanced stage, our results underline the needs for further investigation on the studied biomarkers for early diagnosis of carcinogenesis to improve survival.
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http://dx.doi.org/10.1016/j.exger.2018.05.018DOI Listing
September 2018

Comparative study of diesel and biodiesel exhausts on lung oxidative stress and genotoxicity in rats.

Environ Pollut 2018 Apr 8;235:514-524. Epub 2018 Jan 8.

Normandie Univ, UNICAEN, UNIROUEN, ABTE, 14000 Caen et 76000, Rouen, France; Centre François Baclesse, Caen, France. Electronic address:

The contribution of diesel exhaust to atmospheric pollution is a major concern for public health, especially in terms of occurrence of lung cancers. The present study aimed at addressing the toxic effects of a repeated exposure to these emissions in an animal study performed under strictly controlled conditions. Rats were repeatedly exposed to the exhaust of diesel engine. Parameters such as the presence of a particle filter or the use of gasoil containing rapeseed methyl ester were investigated. Various biological parameters were monitored in the lungs to assess the toxic and genotoxic effects of the exposure. First, a transcriptomic analysis showed that some pathways related to DNA repair and cell cycle were affected to a limited extent by diesel but even less by biodiesel. In agreement with occurrence of a limited genotoxic stress in the lungs of diesel-exposed animals, small induction of γ-H2AX and acrolein adducts was observed but not of bulky adducts and 8-oxodGuo. Unexpected results were obtained in the study of the effect of the particle filter. Indeed, exhausts collected downstream of the particle filter led to a slightly higher induction of a series of genes than those collected upstream. This result was in agreement with the formation of acrolein adducts and γH2AX. On the contrary, induction of oxidative stress remained very limited since only SOD was found to be induced and only when rats were exposed to biodiesel exhaust collected upstream of the particle filter. Parameters related to telomeres were identical in all groups. In summary, our results point to a limited accumulation of damage in lungs following repeated exposure to diesel exhausts when modern engines and relevant fuels are used. Yet, a few significant effects are still observed, mostly after the particle filter, suggesting a remaining toxicity associated with the gaseous or nano-particular phases.
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http://dx.doi.org/10.1016/j.envpol.2017.12.077DOI Listing
April 2018

High association of Cryptosporidium spp. infection with colon adenocarcinoma in Lebanese patients.

PLoS One 2017 19;12(12):e0189422. Epub 2017 Dec 19.

Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille (CIIL), UMR CNRS 8204, INSERM U1019, Université de Lille, CHU de Lille, Biologie et Diversité des Pathogènes Eucaryotes Emergents (BDPEE), Lille, France.

Background: The association between Cryptosporidium and human colon cancer has been reported in different populations. However, this association has not been well studied. In order to add new strong arguments for a probable link between cryptosporidiosis and colon human cancer, the aim of this study was to determine prevalence and to identify species of Cryptosporidium among Lebanese patients.

Methodology And Principal Findings: Overall, 218 digestive biopsies were collected in Tripoli, Lebanon, from three groups of patients: (i) patients with recently diagnosed colon intraepithelial neoplasia/adenocarcinoma before any treatment (n = 72); (ii) patients with recently diagnosed stomach intraepithelial neoplasia/adenocarcinoma before any treatment (n = 21); and (iii) patients without digestive intraepithelial neoplasia/adenocarcinoma but with persistent digestive symptoms (n = 125). DNA extraction was performed from paraffin-embedded tissue. The presence of the parasite in tissues was confirmed by PCR, microscopic observation and immunofluorescence analysis. We identified a high rate (21%) of Cryptosporidium presence in biopsies from Lebanese patients with recently diagnosed colonic neoplasia/adenocarcinoma before any treatment. This prevalence was significantly higher compared to 7% of Cryptosporidium prevalence among patients without colon neoplasia but with persistent gastrointestinal symptoms (OR: 4, CI: 1.65-9.6, P = 0.001). When the comparison was done against normal biopsies, the risk of infection increased 11-fold in the group of patients with colon adenocarcinoma (OR: 11.315, CI: 1.44-89.02, P = 0.003).

Conclusions: This is the first study performed in Lebanon reporting the prevalence of Cryptosporidium among patients with digestive cancer. These results show that Cryptosporidium is strongly associated with human colon cancer being maybe a potential etiological agent of this disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189422PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736188PMC
January 2018

Three-dimensional (3D) culture of adult murine colon as an in vitro model of cryptosporidiosis: Proof of concept.

Sci Rep 2017 12 11;7(1):17288. Epub 2017 Dec 11.

Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, Lille, France.

Cryptosporidium parvum is a major cause of diarrheal illness and was recently potentially associated with digestive carcinogenesis. Despite its impact on human health, Cryptosporidium pathogenesis remains poorly known, mainly due to the lack of a long-term culture method for this parasite. Thus, the aim of the present study was to develop a three-dimensional (3D) culture model from adult murine colon allowing biological investigations of the host-parasite interactions in an in vivo-like environment and, in particular, the development of parasite-induced neoplasia. Colonic explants were cultured and preserved ex vivo for 35 days and co-culturing was performed with C. parvum. Strikingly, the resulting system allowed the reproduction of neoplastic lesions in vitro at 27 days post-infection (PI), providing new evidence of the role of the parasite in the induction of carcinogenesis. This promising model could facilitate the study of host-pathogen interactions and the investigation of the process involved in Cryptosporidium-induced cell transformation.
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http://dx.doi.org/10.1038/s41598-017-17304-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725449PMC
December 2017

A one-step immune-chromatographic Helicobacter pylori stool antigen test for children was quick, consistent, reliable and specific.

Acta Paediatr 2017 Dec 25;106(12):2025-2030. Epub 2017 Jul 25.

Service de Bactériologie, Hôpital Cochin, Université Paris Descartes, Paris, France.

Aim: This French study assessed a quick, noninvasive, immuno-chromatographic, Helicobacter pylori (H. pylori) stool antigen test for detecting infections in children.

Methods: We enrolled 158 children, with a median age of 8.5 years (range eight months to 17 years), with digestive symptoms suggesting upper gastrointestinal tract disease. Upper digestive endoscopy was performed with gastric biopsy specimens for histology, a rapid urease test, culture test and quantitative real-time polymerase chain reaction. The H. pylori stool antigen test was performed twice for each child and the results were compared to the reference method.

Results: The reference methods showed that 23 (14.6%) of the 158 children tested were H. pylori positive. The H. pylori stool antigen test showed 91.3% sensitivity, with a 95% confidence interval (95% CI) of 86.9-95.6 and 97% specificity (95% CI 94.3-99.6), 30.84 positive likelihood ratio and 0.09 negative likelihood ratio. The test accuracy was 96.2% (95% CI 93.2-99.1). The two blinded independent observers produced identical H. pylori stool antigen test results and the Kappa coefficient for the H. pylori stool antigen test was one.

Conclusion: The H. pylori stool antigen test was found to be a consistent, reliable, quick and specific test for detecting the H. pylori infection in children.
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http://dx.doi.org/10.1111/apa.13968DOI Listing
December 2017

How do they stick together? Bacterial adhesins implicated in the binding of bacteria to the human gastrointestinal mucins.

Biochem Soc Trans 2017 04;45(2):389-399

CNRS, UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université Lille, F-59000 Lille, France

The gastrointestinal mucosal surface is the primary interface between internal host tissues and the vast microbiota. Mucins, key components of mucus, are high-molecular-weight glycoproteins characterized by the presence of many -linked oligosaccharides to the core polypeptide. They play many biological functions, helping to maintain cellular homeostasis and to establish symbiotic relationships with complex microbiota. Mucin -glycans exhibit a huge variety of peripheral sequences implicated in the binding of bacteria to the mucosal tissues, thereby playing a key role in the selection of specific species and in the tissue tropism displayed by commensal and pathogenic bacteria. Bacteria have evolved numerous strategies to colonize host mucosae, and among these are modulation of expression of cell surface adhesins which allow bacteria to bind to mucins. However, despite well structurally characterized adhesins and lectins, information on the nature and structure of oligosaccharides recognized by bacteria is still disparate. This review summarizes the current knowledge on the structure of epithelial mucin -glycans and the interaction between host and commensal or pathogenic bacteria mediated by mucins.
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http://dx.doi.org/10.1042/BST20160167DOI Listing
April 2017

Urothelial Tumors and Dual-Band Imaging: A New Concept in Confocal Laser Endomicroscopy.

J Endourol 2017 05 22;31(5):538-544. Epub 2017 Mar 22.

1 Department of Urology, Groupe Hospitalier de l'Institut Catholique Lillois , Faculté Libre de Médecine, Lille, France .

Objectives: Confocal laser endomicroscopy (CLE) uses a low-energy laser light source to obtain microscopic histology images of bladder tissue exposed to a fluorescent dye. To evaluate the feasibility of using CLE with two fluorophores: fluorescein (FLUO) and hexylaminolevulinate (HAL) to determine histologic and cytologic bladder cancer criteria.

Methods: Patients eligible for HAL-photodynamic diagnosis-assisted transurethral resection of bladder tumor were included. The procedures were performed with the patient under regional or general anesthesia (60-90 minutes) after bladder instillation of HAL (50 mL, 8 mmol/L; Hexvix; Ipsen, France). Resected tissue was examined ex vivo using CLE either with Cellvizio system (CVI) single laser (488 nm) or with Cellvizio Dual system (CVII) double laser (488, 660 nm).

Results: Twenty-one patients were included, 12 examined by CVI and 9 by CVII. Sample examination on CVI after HAL-CLE-only histologic analysis was not possible because HAL is mostly cytoplasmic and gives poor details on cellular architecture. On the contrary, FLUO-CLE gives good extracellular architecture and not clear information of nucleocytoplasmic abnormality. Samples on CVII for seven out of nine patients clearly showed cytoplasm of suspect cells and nuclei. In real time, fluorescence observed on bandwidth (673-800 nm) with HAL and FLUO was associated with the presence of cancer, with a sensibility and specificity of 80% and 100%, respectively.

Conclusions: Real-time cytodetection was feasible using two fluorophores (FLUO and HAL) and the new system of CVII. This technology was useful to observe cytoplasm, nuclei, and nucleocytoplasmic abnormality, but an improved system is necessary (to overcome the overlapping of fluorescence) to increase the specificity.
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http://dx.doi.org/10.1089/end.2016.0892DOI Listing
May 2017

Activation of mutated TRPA1 ion channel by resveratrol in human prostate cancer associated fibroblasts (CAF).

Mol Carcinog 2017 08 22;56(8):1851-1867. Epub 2017 May 22.

Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.

Previous studies showed the effects of resveratrol (RES) on several cancer cells, including prostate cancer (PCa) cell apoptosis without taking into consideration the impact of the tumor microenvironment (TME). The TME is composed of cancer cells, endothelial cells, blood cells, and cancer-associated fibroblasts (CAF), the main source of growth factors. The latter cells might modify in the TME the impact of RES on tumor cells via secreted factors. Recent data clearly show the impact of CAF on cancer cells apoptosis resistance via secreted factors. However, the effects of RES on PCa CAF have not been studied so far. We have investigated here for the first time the effects of RES on the physiology of PCa CAF in the context of TME. Using a prostate cancer CAF cell line and primary cultures of CAF from prostate cancers, we show that RES activates the N-terminal mutated Transient Receptor Potential Ankyrin 1 (TRPA1) channel leading to an increase in intracellular calcium concentration and the expression and secretion of growth factors (HGF and VEGF) without inducing apoptosis in these cells. Interestingly, in the present work, we also show that when the prostate cancer cells were co-cultured with CAF, the RES-induced cancer cell apoptosis was reduced by 40%, an apoptosis reduction canceled in the presence of the TRPA1 channel inhibitors. The present work highlights CAF TRPA1 ion channels as a target for RES and the importance of the channel in the epithelial-stromal crosstalk in the TME leading to resistance to the RES-induced apoptosis.
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http://dx.doi.org/10.1002/mc.22642DOI Listing
August 2017

Activation of TRPA1 Channel by Antibacterial Agent Triclosan Induces VEGF Secretion in Human Prostate Cancer Stromal Cells.

Cancer Prev Res (Phila) 2017 Mar 17;10(3):177-187. Epub 2017 Jan 17.

Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, F-59000 Lille, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, France; Laboratory of Excellence, Ion Channels Science and Therapeutics; Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.

Accruing evidence indicates that exposure to environmental compounds may adversely affect human health and promote carcinogenesis. Triclosan (TCS), an antimicrobial agent widely used as a preservative in personal care products, has been shown to act as an endocrine disruptor in hormone-dependent tissues. Here, we demonstrate a new molecular mechanism by which TCS stimulates the secretion by human prostate cancer stromal cells of vascular endothelial growth factor (VEGF), a factor known to promote tumor growth. This mechanism involves an increase in intracellular calcium levels due to the direct activation of a membrane ion channel. Using calcium imaging and electrophysiology techniques, we show for the first time that environmentally relevant concentrations of TCS activate a cation channel of the TRP family, TRPA1 (Transient Receptor Potential Ankirin 1), in primary cultured human prostate cancer stromal cells. The TCS-induced TRPA1 activation increased basal calcium in stromal cells and stimulated the secretion of VEGF and epithelial cells proliferation. Interestingly, immunofluorescence labeling performed on formalin-fixed paraffin-embedded prostate tissues showed an exclusive expression of the TRPA1 channel in prostate cancer stromal cells. Our data demonstrate an impact of the environmental factor TCS on the tumor microenvironment interactions, by activating a tumor stroma-specific TRPA1 ion channel. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0257DOI Listing
March 2017

Smoker extracellular vesicles influence status of human bronchial epithelial cells.

Int J Hyg Environ Health 2017 04 30;220(2 Pt B):445-454. Epub 2016 Dec 30.

Unité de Chimie Environnementale et Interactions sur le Vivant (UCEIV), EA4492, Université du Littoral Côte d'Opale (ULCO), Dunkerque, France. Electronic address:

Cigarette smoking is a habit that has spread all over the world and is a significant risk factor for many diseases including cardiovascular disease, chronic obstructive pulmonary disease (COPD), asthma and lung cancer. Evaluation and understanding of tobacco health effects are of major interest worldwide and answer to important societal concerns. Identification of new biomarkers of exposure to tobacco smoke potentially implicated in COPD or lung carcinogenesis would allow a better observation of tobacco exposed population, thanks to screening establishment at reversible stages of pathological processes. In this study, we questioned whether cigarette smoking alters miRNA profiles of Extracellular Vesicles (EVs) present in human Broncho Alveolar Lavages (BALs), which could affect surrounding normal bronchial epithelial cells status. To this aim, BALs were carried out on 10 Smokers and 10 Non-Smokers, and EVs were isolated from the supernatants and characterized. We then compared the amount of 10 microRNAs (miRNAs) present in Smokers versus Non-Smokers BAL EVs and performed statistical analysis to discuss the biological significance by the smoking status and to evaluate BAL EV miRNAs as potential biomarkers of tobacco exposure. Finally, we tested the effects of smokers versus non-smokers EVs on human bronchial epithelial cells (BEAS-2B) to compare their influence on the cells status. Our study shows for the first time in human samples that smoking can alter lung EV profile that can influence surrounding bronchial epithelial cells.
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http://dx.doi.org/10.1016/j.ijheh.2016.12.010DOI Listing
April 2017

Flagellin-Mediated Protection against Intestinal Yersinia pseudotuberculosis Infection Does Not Require Interleukin-22.

Infect Immun 2017 02 26;85(2). Epub 2017 Jan 26.

Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204, CIIL-Center for Infection and Immunity of Lille, Lille, France

Signaling through Toll-like receptors (TLRs), the main receptors in innate immunity, is essential for the defense of mucosal surfaces. It was previously shown that systemic TLR5 stimulation by bacterial flagellin induces an immediate, transient interleukin-22 (IL-22)-dependent antimicrobial response to bacterial or viral infections of the mucosa. This process was dependent on the activation of type 3 innate lymphoid cells (ILCs). The objective of the present study was to analyze the effects of flagellin treatment in a murine model of oral infection with Yersinia pseudotuberculosis (an invasive, Gram-negative, enteropathogenic bacterium that targets the small intestine). We found that systemic administration of flagellin significantly increased the survival rate after intestinal infection (but not systemic infection) by Y. pseudotuberculosis This protection was associated with a low bacterial count in the gut and the spleen. In contrast, no protection was afforded by administration of the TLR4 agonist lipopolysaccharide, suggesting the presence of a flagellin-specific effect. Lastly, we found that TLR5- and MyD88-mediated signaling was required for the protective effects of flagellin, whereas neither lymphoid cells nor IL-22 was involved.
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http://dx.doi.org/10.1128/IAI.00806-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278166PMC
February 2017

Identification of Plasmodium falciparum Translation Initiation eIF2β Subunit: Direct Interaction with Protein Phosphatase Type 1.

Front Microbiol 2016 26;7:777. Epub 2016 May 26.

Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - Centre d'Infection et d'Immunité de Lille, Université de Lille Lille, France.

Protein phosphatase 1 (PP1c) is one of the main phosphatases whose function is shaped by many regulators to confer a specific location and a selective function for this enzyme. Here, we report that eukaryotic initiation factor 2β of Plasmodium falciparum (PfeIF2β) is an interactor of PfPP1c. Sequence analysis of PfeIF2β revealed a deletion of 111 amino acids when compared to its human counterpart and the presence of two potential binding motifs to PfPP1 ((29)FGEKKK(34), (103)KVAW(106)). As expected, we showed that PfeIF2β binds PfeIF2γ and PfeIF5, confirming its canonical interaction with partners of the translation complex. Studies of the PfeIF2β-PfPP1 interaction using wild-type, single and double mutated versions of PfeIF2β revealed that both binding motifs are critical. We next showed that PfeIF2β is able to induce Germinal Vesicle Break Down (GVBD) when expressed in Xenopus oocytes, an indicator of its capacity to regulate PP1. Only combined mutations of both binding motifs abolished the interaction with PP1 and the induction of GVBD. In P. falciparum, although the locus is accessible for genetic manipulation, PfeIF2β seems to play an essential role in intraerythrocytic cycle as no viable knockout parasites were detectable. Interestingly, as for PfPP1, the subcellular fractionation of P. falciparum localized PfeIF2β in cytoplasm and nuclear extracts, suggesting a potential effect on PfPP1 in both compartments and raising the question of a non-canonical function of PfeIf2β in the nucleus. Hence, the role played by PfeIF2β in blood stage parasites could occur at multiple levels involving the binding to proteins of the translational complex and to PfPP1.
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http://dx.doi.org/10.3389/fmicb.2016.00777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881399PMC
June 2016

Interleukin-22 protects against non-typeable Haemophilus influenzae infection: alteration during chronic obstructive pulmonary disease.

Mucosal Immunol 2017 01 4;10(1):139-149. Epub 2016 May 4.

Université Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, Lille, France.

Chronic obstructive pulmonary disease is a major health problem becoming a leading cause of morbidity and mortality worldwide. A large part of these disorders is associated with acute exacerbations resulting from infection by bacteria, such as non-typeable Haemophilus influenzae (NTHi). Our understanding of the pathogenesis of these exacerbations is still elusive. We demonstrate herein that NTHi infection of mice chronically exposed to cigarette smoke (CS), an experimental model of chronic obstructive pulmonary disease (COPD), not only causes acute pulmonary inflammation but also impairs the production of interleukin (IL)-22, a cytokine with potential anti-bacterial activities. We also report that mice lacking IL-22, as well as mice exposed to CS, have a delayed clearance of NTHi bacteria and display enhanced alveolar wall thickening and airway remodeling compared with controls. Supplementation with IL-22 not only boosted bacterial clearance and the production of anti-microbial peptides but also limited lung damages induced by infection both in IL-22 and CS-exposed mice. In vitro exposure to CS extract altered the NTHi-induced IL-22 production by spleen cells. This study shows for the first time that a defect in IL-22 is involved in the acute exacerbation induced by NTHi infection during experimental COPD and opens the way to innovative therapeutic strategies.
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http://dx.doi.org/10.1038/mi.2016.40DOI Listing
January 2017

In vitro short-term exposure to air pollution PM2.5-0.3 induced cell cycle alterations and genetic instability in a human lung cell coculture model.

Environ Res 2016 May 11;147:146-58. Epub 2016 Feb 11.

Université de Lille, Lille, France; EA4492-UCEIV, Université du Littoral-Côte d'Opale, Dunkerque, France; EA4483-IMPECS, Université de Lille 2, Lille, France. Electronic address:

Although its adverse health effects of air pollution particulate matter (PM2.5) are well-documented and often related to oxidative stress and pro-inflammatory response, recent evidence support the role of the remodeling of the airway epithelium involving the regulation of cell death processes. Hence, the overarching goals of the present study were to use an in vitro coculture model, based on human AM and L132 cells to study the possible alteration of TP53-RB gene signaling pathways (i.e. cell cycle phases, gene expression of TP53, BCL2, BAX, P21, CCND1, and RB, and protein concentrations of their active forms), and genetic instability (i.e. LOH and/or MSI) in the PM2.5-0.3-exposed coculture model. PM2.5-0.3 exposure of human AM from the coculture model induced marked cell cycle alterations after 24h, as shown by increased numbers of L132 cells in subG1 and S+G2 cell cycle phases, indicating apoptosis and proliferation. Accordingly, activation of the TP53-RB gene signaling pathways after the coculture model exposure to PM2.5-0.3 was reported in the L132 cells. Exposure of human AM from the coculture model to PM2.5-0.3 resulted in MS alterations in 3p chromosome multiple critical regions in L132 cell population. Hence, in vitro short-term exposure of the coculture model to PM2.5-0.3 induced cell cycle alterations relying on the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation and genetic instability.
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http://dx.doi.org/10.1016/j.envres.2016.01.041DOI Listing
May 2016

IL-22 Defect During Streptococcus pneumoniae Infection Triggers Exacerbation of Chronic Obstructive Pulmonary Disease.

EBioMedicine 2015 Nov 26;2(11):1686-96. Epub 2015 Sep 26.

Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59021 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France.

Progression of chronic obstructive pulmonary disease (COPD) is linked to episodes of exacerbations caused by bacterial infections due to Streptococcus pneumoniae. Our objective was to identify during COPD, factors of susceptibility to bacterial infections among cytokine network and their role in COPD exacerbations. S. pneumoniae was used to sub-lethally challenge mice chronically exposed to air or cigarette smoke (CS) and to stimulate peripheral blood mononuclear cells (PBMC) from non-smokers, smokers and COPD patients. The immune response and the cytokine production were evaluated. Delayed clearance of the bacteria and stronger lung inflammation observed in infected CS-exposed mice were associated with an altered production of IL-17 and IL-22 by innate immune cells. This defect was related to a reduced production of IL-1β and IL-23 by antigen presenting cells. Importantly, supplementation with recombinant IL-22 restored bacterial clearance in CS-exposed mice and limited lung alteration. In contrast with non-smokers, blood NK and NKT cells from COPD patients failed to increase IL-17 and IL-22 levels in response to S. pneumoniae, in association with a defect in IL-1β and IL-23 secretion. This study identified IL-17 and IL-22 as susceptibility factors in COPD exacerbation. Therefore targeting such cytokines could represent a potent strategy to control COPD exacerbation.
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http://dx.doi.org/10.1016/j.ebiom.2015.09.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740310PMC
November 2015

Early detection of colonic dysplasia by magnetic resonance molecular imaging with a contrast agent raised against the colon cancer marker MUC5AC.

Contrast Media Mol Imaging 2016 05 14;11(3):211-21. Epub 2016 Jan 14.

University of Lille Nord de France, F-59000, Lille, France.

Human gastric mucin MUC5AC is secreted in the colonic mucus of cancer patients and is a specific marker of precancerous lesions called aberrant crypt foci. Using MUC5AC as a specific marker can improve sensitivity in the detection of early colorectal cancer. Here we demonstrated that the accumulation of MUC5AC in xenograft and mouse stomach can be detected by magnetic resonance imaging (MRI). We used ultrasmall particles of iron oxide (USPIOs) conjugated with disulfide constrained heptapeptide that were identified using a screening phage display. To accomplish this, we employed positive selection of the phage display library on MUC5AC purified from fresh human colonic adenomas in combination with negative selection of the phage library on purified human MUC2, which is predominantly found in normal colorectal tissues. This conjugate was tested on human colorectal cancer cell lines that were either able or unable to secrete MUC5AC, both in vitro and in vivo. MUC5AC-USPIO contrast agent and USPIOs alone were not detected in cell lines unable to secrete MUC5AC. A combination of MRI and microscopy studies was performed to detect a specific accumulation of the contrast agent in vivo. Thus, the MUC5AC contrast agent enabled non-invasive detection of precancerous lesions and colorectal cancer, highlighting its potential use in diagnostics, in the early detection of colorectal cancer recurrences after treatment and in mechanistic studies implicating MUC5AC. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/cmmi.1682DOI Listing
May 2016

Structural Characterization of Mucin O-Glycosylation May Provide Important Information to Help Prevent Colorectal Tumor Recurrence.

Front Oncol 2015 8;5:217. Epub 2015 Oct 8.

Structural and Functional Glycobiology Unit, UMR CNRS 8576, University of Lille , Villeneuve d'Ascq , France.

Although colorectal cancer is a preventable and curable disease if early stage tumors are removed, it still represents the second cause of cancer-related death worldwide. Surgical resection is the only curative treatment but once operated the patient is either subjected to adjuvant chemotherapy or not, depending on the invasiveness of the cancer and risks of recurrence. In this context, we investigated, by mass spectrometry (MS), alterations in the repertoire of glycosylation of mucins from colorectal tumors of various stages, grades, and recurrence status. Tumors were also compared with their counterparts in resection margins from the same patients and with healthy controls. The obtained data showed an important decrease in the level of expression of sialylated core 3-based O-glycans in tumors correlated with an increase in sialylated core 1 structures. No correlation was established between stages of the tumor samples and mucin O-glycosylation. However, with the notable exception of sialyl Tn antigens, tumors with recurrence presented a milder alteration of glycosylation profile than tumors without recurrence. These results suggest that mucin O-glycans from tumors with recurrence might mimic a healthier physiological situation, hence deceiving the immune defense system.
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http://dx.doi.org/10.3389/fonc.2015.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597131PMC
October 2015

Claudin 3, 4, and 15 expression in solid tumors of lung adenocarcinoma versus malignant pleural mesothelioma.

Ann Diagn Pathol 2015 Aug 14;19(4):193-7. Epub 2015 Apr 14.

Department of Pathology, Hospital of St Vincent, GHICL, Lille, France.

Epithelioid malignant pleural mesothelioma (MPM) can easily be confused with lung adenocarcinomas (ACAs). In serous effusion, claudin (cldn) 3 is shown to be useful in the diagnosis of mesothelioma vs ACAs. Cldn15 is reported to be overexpressed in epithelioid mesothelioma and absent in human airway epithelium. The aim was to assess the value of cldn3 and cldn4 compared to that of BerEp4 and thyroid transcription factor-1 (TTF1) in differentiating lung ACA from epithelioid MPM and to examine the expression of cldn15 in these tumors. The expression of cldn3, cldn4, cldn15, BerEp4, and TTF1 was examined by immunohistochemistry in a total of 62 human specimen including 28 epithelioid MPMs and 34 ACAs of the lung. In lung ACA, cldn4 was strongly expressed in all 34 (100%) specimens followed by cldn3 in 33 (97%) of 34. BerEp4 was expressed in 32 (94.1%) of 34. TTF1 reacted for only 20 (58.82%) of 34 cases of lung ACA. In MPM specimens, the expression of cldn3 and4 as well as that of TTF1 was completely absent. In contrast, BerEp4 was focally expressed in 5 (17.85%) of 28 cases of epithelioid MPM. Cldn15 was strongly expressed in 53% pf epithelioid MPMs but also in 50% of lung ACAs. Its expression was moderate in normal pleura and limited in normal lung. Cldn3 and cldn4 appear to be the best performing carcinoma markers in discriminating lung ACA from mesothelioma compared with BerEp4 and TTF1. There is no differential expression of cldn15 between the 2 pathologies. However, the limited cldn15 expression in normal tissues and high expression in tumors make it an attractive candidate for cancer therapy.
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http://dx.doi.org/10.1016/j.anndiagpath.2015.03.007DOI Listing
August 2015

Usefulness of Gastric Biopsy-Based Real-Time Polymerase Chain Reaction for the Diagnosis of Helicobacter pylori Infection in Children.

J Pediatr Gastroenterol Nutr 2015 Sep;61(3):307-12

*Clinique Pédiatrique St Antoine †Département d'Anatomopathologie, Hôpital St Vincent de Paul ‡Département de Microbiologie, Hôpital St Philibert, Groupement des Hôpitaux de l'Institut Catholique de Lille, Lille §Service de Gastroentérologie Pédiatrique, Hôpital Necker-Enfants-malades, AP-HP ||Service de Microbiologie, Hôpital Cochin, Université Paris V-René Descartes, Paris, France.

Objectives: The aim of the study was to assess the usefulness of gastric biopsy-based quantitative real-time polymerase chain reaction (qPCR) for the detection of Helicobacter pylori infection and the identification of clarithromycin-resistant strains in children.

Methods: A gastric biopsy-based qPCR for the detection of H pylori infection and the identification of clarithromycin-resistant strains in children was evaluated in 62 children with infection and 341 children without infection. H pylori infection was considered by the "reference method" when culture was positive for both histology and rapid urease test (RUT). Results were compared with those obtained using the qPCR.

Results: The reference method versus H pylori qPCR positivity showed 95% confidence interval sensitivity 100% versus 100%, specificity 93.2% (86.9-99.4) versus 100%, positive predictive value 59.7% (47.4-71.9) versus 100%, negative predictive value 100% versus 100%, and, finally, test accuracy of 59.6% (47.3-71.8) versus 100%. Sixty-two children were found to be H pylori positive, based on the qPCR results. Among those, 31 children had both positive qPCR and culture with concordant antimicrobial susceptibility testing results, whereas 31 children had negative culture and positive qPCR. The qPCR showed a bacterial load ≥10 copies per milliliter when culture, histology, and RUT were all positive (29/31 children) versus <10 copies per milliliter when culture, histology, and RUT were all negative (25/31 children). Grades 2 and 3 histological gastritis were associated with a bacterial load ≥10 copies per milliliter for 28/35 of children versus 27/27 of grade 0 to 1 <10 copies per milliliter.

Conclusions: H pylori qPCR positivity is a more precise test than the routine culture, histology, RUT alone and allows detecting low bacterial loads.
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http://dx.doi.org/10.1097/MPG.0000000000000787DOI Listing
September 2015

Alteration or adaptation, the two roads for human gastric mucin glycosylation infected by Helicobacter pylori.

Glycobiology 2015 Jun 16;25(6):617-31. Epub 2015 Jan 16.

Univ Lille Nord de France, Lille F-59000, France USTL, UGSF, IFR 147, Villeneuve d'Ascq F-59650, France CNRS, UMR 8576, Villeneuve d'Ascq F-59650, France

Helicobacter pylori is a Gram-negative bacterium that colonizes the mucus niche of the gastric mucosa and infects more than half of the world's human population. Chronic infection may cause gastritis, duodenal ulcer, intestinal metaplasia or gastric cancer. In the stomach, H. pylori interacts with O-glycans of gastric mucins but the mechanism by which the bacteria succeed in altering the mucosa remains mainly unknown. To better understand the physiopathology of the infection, inhibitory adhesion assays were performed with various O-glycans expressed by human gastric mucins, and topographic expression of gastric mucins MUC5AC and MUC6 was analyzed for healthy uninfected individuals, for infected asymptomatic individuals and for patients infected by H. pylori and having the incomplete type of intestinal metaplasia. The glycosylation of the gastric mucosa of asymptomatic individuals infected by H. pylori was determined and compared with the glycosylation pattern found for patients with the incomplete type of intestinal metaplasia. Results show that H. pylori manages to modulate host's glycosylation during the course of infection in order to create a favorable niche, whereas asymptomatic infected individuals seem to counteract further steps of infection development by adapting their mucus glycosylation.
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http://dx.doi.org/10.1093/glycob/cwv004DOI Listing
June 2015

Overexpression of chemokine receptor CXCR2 and ligand CXCL7 in liver metastases from colon cancer is correlated to shorter disease-free and overall survival.

Cancer Sci 2015 Mar 5;106(3):262-9. Epub 2015 Mar 5.

Inserm, U837, Team-5 (Mucins, Epithelial Differentiation, and Carcinogenesis), Jean-Pierre Aubert Research Centre, Université Lille, France; Department of Digestive and Visceral Surgery, GHICL, Saint-Vincent de Paul Hospital, Lille, France.

Our aim was to analyze the potential role of chemokine receptors CXCR2 and CXCR4 signalling pathways in liver metastatic colorectal cancer (CRC) relapse. CXCR2, CXCR4, and their chemokine ligands were evaluated in liver metastases of colorectal cancer in order to study their correlation with overall and disease-free survival of patients having received, or not received, a neoadjuvant chemotherapy regimen. Quantitative RT-PCR and CXCR2 immunohistochemical staining were carried out using CRC liver metastasis samples. Expression levels of CXCR2, CXCR4, and their ligands were statistically analyzed according to treatment with neoadjuvant chemotherapy and patients' outcome. CXCR2 and CXCL7 overexpression are correlated to shorter overall and disease-free survival. By multivariate analysis, CXCR2 and CXCL7 expressions are independent factors of overall and disease-free survival. Neoadjuvant chemotherapy increases significantly the expression of CXCR2: treated group 1.89 (0.02-50.92) vs 0.55 (0.07-3.22), P = 0.016. CXCL7 was overexpressed close to significance, 0.40 (0.00-7.85) vs 0.15 (0.01-7.88), P = 0.12. We show the involvement of CXCL7/CXCR2 signalling pathways as a predictive factor of poor outcome in metastatic CRC. 5-Fluorouracil-based chemotherapy regimens increase the expression of these genes in liver metastasis, providing one explanation for aggressiveness of relapsed drug-resistant tumors. Selective blockage of CXCR2/CXCL7 signalling pathways could provide new potential therapeutic opportunities.
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http://dx.doi.org/10.1111/cas.12603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376434PMC
March 2015

TRPV6 calcium channel translocates to the plasma membrane via Orai1-mediated mechanism and controls cancer cell survival.

Proc Natl Acad Sci U S A 2014 Sep 29;111(37):E3870-9. Epub 2014 Aug 29.

Institut National de la Santé et de la Recherche Médicale U1003, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Laboratory of Excellence Ion Channel Science and Therapeutics, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq, France;

Transient receptor potential vanilloid subfamily member 6 (TRPV6) is a highly selective calcium channel that has been considered as a part of store-operated calcium entry (SOCE). Despite its first discovery in the early 2000s, the role of this channel in prostate cancer (PCa) remained, until now, obscure. Here we show that TRPV6 mediates calcium entry, which is highly increased in PCa due to the remodeling mechanism involving the translocation of the TRPV6 channel to the plasma membrane via the Orai1/TRPC1-mediated Ca(2+)/Annexin I/S100A11 pathway, partially contributing to SOCE. The TRPV6 calcium channel is expressed de novo by the PCa cell to increase its survival by enhancing proliferation and conferring apoptosis resistance. Xenografts in nude mice and bone metastasis models confirmed the remarkable aggressiveness of TRPV6-overexpressing tumors. Immunohistochemical analysis of these demonstrated the increased expression of clinical markers such as Ki-67, prostate specific antigen, synaptophysin, CD31, and CD56, which are strongly associated with a poor prognosis. Thus, the TRPV6 channel acquires its oncogenic potential in PCa due to the remodeling mechanism via the Orai1-mediated Ca(2+)/Annexin I/S100A11 pathway.
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http://dx.doi.org/10.1073/pnas.1413409111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169956PMC
September 2014

The lacdiNAc-specific adhesin LabA mediates adhesion of Helicobacter pylori to human gastric mucosa.

J Infect Dis 2014 Oct 21;210(8):1286-95. Epub 2014 Apr 21.

Univ Lille Nord de France USTL, UGSF, IFR 147 CNRS, UMR 8576.

Adhesion of Helicobacter pylori to the gastric mucosa is a necessary prerequisite for the pathogenesis of H. pylori-related diseases. In this study, we investigated the GalNAcβ1-4GlcNAc motif (also known as N,N'-diacetyllactosediamine [lacdiNAc]) carried by MUC5AC gastric mucins as the target for bacterial binding to the human gastric mucosa. The expression of LacdiNAc carried by gastric mucins was correlated with H. pylori localization, and all strains tested adhered significantly to this motif. Proteomic analysis and mutant construction allowed the identification of a yet uncharacterized bacterial adhesin, LabA, which specifically recognizes lacdiNAc. These findings unravel a target of adhesion for H. pylori in addition to moieties recognized by the well-characterized adhesins BabA and SabA. Localization of the LabA target, restricted to the gastric mucosa, suggests a plausible explanation for the tissue tropism of these bacteria. These results pave the way for the development of alternative strategies against H. pylori infection, using adherence inhibitors.
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http://dx.doi.org/10.1093/infdis/jiu239DOI Listing
October 2014

Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection.

J Virol 2013 Jun 17;87(12):6911-24. Epub 2013 Apr 17.

Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France.

Interleukin-22 (IL-22) has redundant, protective, or pathogenic functions during autoimmune, inflammatory, and infectious diseases. Here, we addressed the potential role of IL-22 in host defense and pathogenesis during lethal and sublethal respiratory H3N2 influenza A virus (IAV) infection. We show that IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection. Our data indicate that retinoic acid receptor-related orphan receptor-γt (RORγt)-positive αβ and γδ T cells, as well as innate lymphoid cells, expressed enhanced Il22 transcripts as early as 2 days postinfection. During lethal or sublethal IAV infections, endogenous IL-22 played no role in the control of IAV replication and in the development of the IAV-specific CD8(+) T cell response. During lethal infection, where wild-type (WT) mice succumbed to severe pneumonia, the lack of IL-22 did not accelerate or delay IAV-associated pathogenesis and animal death. In stark contrast, during sublethal IAV infection, IL-22-deficient animals had enhanced lung injuries and showed a lower airway epithelial integrity relative to WT littermates. Of importance, the protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection. Indeed, after challenge with Streptococcus pneumoniae, IAV-experienced Il22(-/-) animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs. Together, IL-22 plays no major role during lethal influenza but is beneficial during sublethal H3N2 IAV infection, where it limits lung inflammation and subsequent bacterial superinfections.
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http://dx.doi.org/10.1128/JVI.02943-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676141PMC
June 2013

Bisphenol A stimulates human prostate cancer cell migration via remodelling of calcium signalling.

Springerplus 2013 Dec 15;2(1):54. Epub 2013 Feb 15.

Inserm, U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, France ; Laboratory of Excellence, Ion Channels Science and Therapeutics; Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.

Bisphenol A (BPA), the principal constituent of reusable water bottles, metal cans, and plastic food containers, has been shown to be involved in human prostate cancer (PCa) cell proliferation. The aim of the present study was to explore the effect of BPA on PCa cell migration and the pathways involved in these processes. Using the transwell technique, we clearly show for the first time that the pre-treatment of the cells with BPA (1-10 nM) induces human PCa cell migration. Using a calcium imaging technique, we show that BPA pre-treatment induces an amplification of Store-Operated Calcium Entry (SOCE) in LNCaP cells. RT-PCR and Western blot experiments allowed the identification of the ion channel proteins which are up-regulated by BPA pre-treatments. These include the Orai1 protein, which is known as an important SOCE actor in various cell systems, including human PCa cells. Using a siRNA strategy, we observed that BPA-induced amplification of SOCE was Orai1-dependent. Interestingly, the BPA-induced PCa cell migration was suppressed when the calcium entry was impaired by the use of SOCE inhibitors (SKF96365, BTP2), or when the extracellular calcium was chelated. Taken together, the results presented here show that BPA induces PCa cells migration via a modulation of the ion channel protein expression involved in calcium entry and in cancer cell migration. The present data provide novel insights into the molecular mechanisms involved in the effects of an environmental factor on cancer cells and suggest both the necessity of preventive measures and the possibility of targeting ion channels in the treatment of PCa cell metastasis.
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http://dx.doi.org/10.1186/2193-1801-2-54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581770PMC
December 2013

Cryptosporidium parvum infection in SCID mice infected with only one oocyst: qPCR assessment of parasite replication in tissues and development of digestive cancer.

PLoS One 2012 13;7(12):e51232. Epub 2012 Dec 13.

Laboratoire Environnement & Santé, Faculté Libre des Sciences et Technologies de Lille, Université Lille Nord de France, Lille, France.

Dexamethasone (Dex) treated Severe Combined Immunodeficiency (SCID) mice were previously described as developing digestive adenocarcinoma after massive infection with Cryptosporidium parvum as soon as 45 days post-infection (P.I.). We aimed to determine the minimum number of oocysts capable of inducing infection and thereby gastrointestinal tumors in this model. Mice were challenged with calibrated oocyst suspensions containing intended doses of: 1, 10, 100 or 10(5) oocysts of C. parvum Iowa strain. All administered doses were infective for animals but increasing the oocyst challenge lead to an increase in mice infectivity (P = 0.01). Oocyst shedding was detected at 7 days P.I. after inoculation with more than 10 oocysts, and after 15 days in mice challenged with one oocyst. In groups challenged with lower inocula, parasite growth phase was significantly higher (P = 0.005) compared to mice inoculated with higher doses. After 45 days P.I. all groups of mice had a mean of oocyst shedding superior to 10,000 oocyst/g of feces. The most impressive observation of this study was the demonstration that C. parvum-induced digestive adenocarcinoma could be caused by infection with low doses of Cryptosporidium, even with only one oocyst: in mice inoculated with low doses, neoplastic lesions were detected as early as 45 days P.I. both in the stomach and ileo-caecal region, and these lesions could evolve in an invasive adenocarcinoma. These findings show a great amplification effect of parasites in mouse tissues after challenge with low doses as confirmed by quantitative PCR. The ability of C. parvum to infect mice with one oocyst and to develop digestive adenocarcinoma suggests that other mammalian species including humans could be also susceptible to this process, especially when they are severely immunocompromised.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051232PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521773PMC
June 2013