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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 19 March 2013, Vol.110(12), pp.4458-63
    Description: The Gram-negative enteroinvasive bacterium Shigella flexneri is responsible for the endemic form of bacillary dysentery, an acute rectocolitis in humans. S. flexneri uses a type III secretion system to inject effector proteins into host cells, thus diverting cellular functions to its own benefit. Protective immunity to reinfection requires several rounds of infection to be elicited and is short-lasting, suggesting that S. flexneri interferes with the priming of specific immunity. Considering the key role played by T-lymphocyte trafficking in priming of adaptive immunity, we investigated the impact of S. flexneri on T-cell dynamics in vivo. By using two-photon microscopy to visualize bacterium-T-cell cross-talks in the lymph nodes, where the adaptive immunity is initiated, we provide evidence that S. flexneri, via its type III secretion system, impairs the migration pattern of CD4(+) T cells independently of cognate recognition of bacterial antigens. We show that bacterial invasion of CD4(+) T lymphocytes occurs in vivo, and results in cell migration arrest. In the absence of invasion, CD4(+) T-cell migration parameters are also dramatically altered. Signals resulting from S. flexneri interactions with subcapsular sinus macrophages and dendritic cells, and recruitment of polymorphonuclear cells are likely to contribute to this phenomenon. These findings indicate that S. flexneri targets T lymphocytes in vivo and highlight the role of type III effector secretion in modulating host adaptive immune responses.
    Keywords: Adaptive Immunity ; Antigens, Bacterial -- Immunology ; Cd4-Positive T-Lymphocytes -- Immunology ; Cell Movement -- Immunology ; Dysentery, Bacillary -- Immunology ; Host-Pathogen Interactions -- Immunology ; Shigella Flexneri -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 19 March 2013, Vol.110(12), pp.4437-4437
    Description: As a young resident doctor at France’s Hôpitaux de Paris in the 1970s, Philippe Sansonetti saw a lot of patients with infectious diseases, such as typhoid, whooping cough, and leprosy. Sansonetti and his colleagues treated those patients with antibiotics. By that point, however, the first signs of antibiotic resistance were beginning to emerge. Sansonetti realized that treating infectious diseases might require alternative therapies, the development of which requires knowledge of how infectious microbes make people sick. Therefore, after completing his residency and training in molecular genetics at the Institut Pasteur, Sansonetti accepted a postdoctoral fellowship with Samuel B. Formal at the Walter Reed Army Institute of Research, then located in Washington, DC, to isolate the genes that let microbes invade host cells. Sansonetti’s model pathogen was Shigella, which causes febrile bloody diarrhea and can be lethal in infants. The disease Shigellosis primarily afflicts individuals in developing countries who lack access to basic hygiene. Over the years, Sansonetti, now the Chair of Microbiology and Infectious Disease at the Collège de France and Professor at Institut Pasteur, has used Shigella to ask questions about microbial mechanics: What genes allow a microbe to penetrate a cell? How does it move once inside the host? How does it kill the cell? Elected as a foreign member to the National Academy of Sciences in 2012, Sansonetti is seen as a founding member of the field of cellular microbiology. For his work, Sansonetti has received numerous awards, including the Prix Jacques Monod for excellence in molecular biology in 1983, the Louis-Jeantet Prize of Medicine in 1994, and the Robert Koch Prize in 1997. He has been a Howard Hughes Medical Institute foreign scholar since 2000. In his Inaugural Article, Sansonetti provides an explanation for why individuals must go through several painful bouts of Shigellosis before developing immunity to the disease (1). His findings could help efforts to develop a Shigellosis vaccine.
    Keywords: Biological sciences -- Biology -- Microbiology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Biological sciences -- Biology -- Microbiology -- Lymphocytes ; Biological sciences -- Biology -- Cytology -- Lymphocytes ; Health sciences -- Medical conditions -- Diseases -- Lymphocytes ; Health sciences -- Medical treatment -- Biological therapy -- Lymphocytes ; Biological sciences -- Biology -- Microbiology -- Lymphocytes ; Health sciences -- Medical conditions -- Diseases -- Lymphocytes ; Behavioral sciences -- Anthropology -- Applied anthropology -- Lymphocytes ; Biological sciences -- Biology -- Genetics -- Lymphocytes
    ISSN: 00278424
    E-ISSN: 10916490
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  • 3
    In: PLoS ONE, 2015, Vol.10(3)
    Description: Shigella spp. are responsible for bacillary dysentery in humans. The acquisition or the modification of the virulence plasmid encoding factors promoting entry of bacteria into and dissemination within epithelial cells was a critical step in the evolution of these bacteria from their Escherichia coli ancestor(s). Incorporation of genomic islands (GI) and gene inactivation also shaped interactions between these pathogens and their human host. Sequence analysis of the GI inserted next to the leuX tRNA gene in S . boydii , S . dysenteriae , S . flexneri , S . sonnei and enteroinvasive E . coli (EIEC) suggests that this region initially carried the fec , yjhATS and fim gene clusters. The fim cluster encoding type I fimbriae is systematically inactivated in both reference strains and clinical isolates and distinct mutations are responsible for this inactivation in at least three phylogenetic groups. To investigate consequences of the presence of fimbriae on the outcome of the interaction of Shigella with host cells, we used a S . flexneri strain harboring a plasmid encoding the E . coli fim operon. Production of fimbriae by this recombinant strain increased the ability of bacteria to adhere to and enter into epithelial cells and had no effect on their ability to disseminate from cell to cell. The observations that production of type I fimbriae increases invasion of epithelial cells and that independent mutations abolish fimbriae production in Shigella suggest that these mutations correspond to pathoadaptive events.
    Keywords: Research Article
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Current Biology, 08 September 2014, Vol.24(17), pp.R784-R791
    Description: The type III secretion system (T3SS) is a membrane-embedded nanomachine found in several Gram-negative bacteria. Upon contact between bacteria and host cells, the syringe-like T3SS ( ) transfers proteins termed effectors from the bacterial cytosol to the cytoplasm or the plasma membrane of a single target cell. This is a major difference from secretion systems that merely release molecules into the extracellular milieu, where they act on potentially distant target cells expressing the relevant surface receptors. The syringe architecture is conserved at the structural and functional level and supports injection into a great variety of hosts and tissues. However, the pool of effectors is species specific and determines the outcome of the interaction, via modulation of target-cell function. The type III secretion system (T3SS) creates a channel through bacterial and host membranes, allowing for the injection of bacterial effector proteins directly into the host cell. Puhar and Sansonetti discuss the structure and evolution of the T3SS, the functions of the effectors, and the immune response in plants and animals to effector injection.
    Keywords: Biology
    ISSN: 0960-9822
    E-ISSN: 1879-0445
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  • 5
    Language: English
    In: PLoS ONE, 2012, Vol.7(6), p.e36446
    Description: Quantitative reverse transcription PCR analysis is an important tool to monitor changes in gene expression in animal models. The rabbit is a widely accepted and commonly used animal model in the study of human diseases and infections by viral, fungal, bacterial and protozoan pathogens. Only a limited number of rabbit genes have, however, been analyzed by this method as the rabbit genome sequence remains unfinished. Recently, increasing coverage of the genome has permitted the prediction of a growing number of genes that are relevant in the context of the immune response. We hereby report the design of twenty-four quantitative PCR primer pairs covering common cytokines, chemoattractants, antimicrobials and enzymes for a rapid, sensitive and quantitative analysis of the rabbit immune response. Importantly, all primer pairs were designed to be used under identical experimental conditions, thereby enabling the simultaneous analysis of all genes in a high-throughput format. This tool was used to analyze the rabbit innate immune response to infection with the human gastrointestinal pathogen Shigella flexneri . Beyond the known inflammatory mediators, we identified IL-22, IL-17A and IL-17F as highly upregulated cytokines and as first responders to infection during the innate phase of the host immune response. This set of qPCR primers also provides a convenient tool for monitoring the rabbit immune response during infection with other pathogens and other inflammatory conditions.
    Keywords: Research Article ; Biology ; Immunology ; Microbiology ; Molecular Biology
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 29 July 2014, Vol.111(30), pp.E3101-9
    Description: Although the composition of the gut microbiota and its symbiotic contribution to key host physiological functions are well established, little is known as yet about the bacterial factors that account for this symbiosis. We selected Lactobacillus casei as a model microorganism to proceed to genomewide identification of the functions required for a symbiont to establish colonization in the gut. As a result of our recent development of a transposon-mutagenesis tool that overcomes the barrier that had prevented L. casei random mutagenesis, we developed a signature-tagged mutagenesis approach combining whole-genome reverse genetics using a set of tagged transposons and in vivo screening using the rabbit ligated ileal loop model. After sequencing transposon insertion sites in 9,250 random mutants, we assembled a library of 1,110 independent mutants, all disrupted in a different gene, that provides a representative view of the L. casei genome. By determining the relative quantity of each of the 1,110 mutants before and after the in vivo challenge, we identified a core of 47 L. casei genes necessary for its establishment in the gut. They are involved in housekeeping functions, metabolism (sugar, amino acids), cell wall biogenesis, and adaptation to environment. Hence we provide what is, to our knowledge, the first global functional genomics analysis of L. casei symbiosis.
    Keywords: Lactic Acid Bacteria ; Commensalism ; Lactobacillus Casei ; Mutation ; Ileum -- Microbiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 16 October 2018, Vol.115(42), pp.E9869-E9878
    Description: Antimicrobial peptides (AMPs) are mucosal defense effectors of the human innate immune response. In the intestine, AMPs are produced and secreted by epithelial cells to protect the host against pathogens and to support homeostasis with commensals. The inducible nature of AMPs suggests that potent inducers could be used to increase their endogenous expression for the prevention or treatment of diseases. Here we aimed at identifying molecules from the natural pharmacopoeia that induce expression of human β-defensin-3 (HBD3), one of the most efficient AMPs, without modifying the production of proinflammatory cytokines. By screening, we identified three molecules isolated from medicinal plants, andrographolide, oridonin, and isoliquiritigenin, which induced HBD3 production in human colonic epithelial cells. This effect was observed without activation of the NF-κB pathway or the expression of associated proinflammatory cytokines. We identified the EGF receptor as the target of these compounds and characterized the downstream-activated MAPK pathways. At the chromatin level, molecules increased phosphorylation of histone H3 on serine S10 and recruitment of the c-Fos, c-Jun, and Elk1 or c-Myc transcription factors at the HBD3 promoter. Interestingly, stimulating cells with a combination of andrographolide and isoliquiritigenin synergistically enhanced HBD3 induction 10-fold more than observed with each molecule alone. Finally, we investigated the molecular basis governing the synergistic effect, confirmed our findings in human colonic primary cells, and demonstrated that synergism increased cellular antimicrobial activity. This work shows the capability of small molecules to achieve induction of epithelial antimicrobial defenses while simultaneously avoiding the deleterious risks of an inflammatory response.
    Keywords: Epithelial Cell ; Gene Regulation ; Natural Inducer ; Synergistic Effect ; Β-Defensin ; Anti-Infective Agents -- Pharmacology ; Bacteria -- Drug Effects ; Biological Products -- Pharmacology ; Colon -- Metabolism ; Gene Expression Regulation -- Drug Effects ; Immunity, Innate -- Drug Effects ; Beta-Defensins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 8
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e32862
    Description: Activation of the type III secretion apparatus (T3SA) of Shigella flexneri , upon contact of the bacteria with host cells, and its deregulation, as in ipaB mutants, specifically increases transcription of a set of effector-encoding genes controlled by MxiE, an activator of the AraC family, and IpgC, the chaperone of the IpaB and IpaC translocators. Thirteen genes carried by the virulence plasmid ( ospB , ospC1 , ospD2 , ospD3 , ospE1 , ospE2 , ospF , ospG , virA , ipaH1.4 , ipaH4.5 , ipaH7.8 and ipaH9.8 ) and five genes carried by the chromosome ( ipaHa-e ) are regulated by the T3SA activity. A conserved 17-bp MxiE box is present 5′ of most of these genes. To characterize the promoter activity of these MxiE box-containing regions, similar ∼67-bp DNA fragments encompassing the MxiE box of 14 MxiE-regulated genes were cloned 5′ of lacZ in a promoter probe plasmid; β-galactosidase activity detected in wild-type and ipaB strains harboring these plasmids indicated that most MxiE box-carrying regions contain a promoter regulated by the T3SA activity and that the relative strengths of these promoters cover an eight-fold range. The various MxiE boxes exhibiting up to three differences as compared to the MxiE box consensus sequence were introduced into the ipaH9.8 promoter without affecting its activity, suggesting that they are equally efficient in promoter activation. In contrast, all nucleotides conserved among MxiE boxes were found to be involved in MxiE-dependent promoter activity. In addition, we present evidence that the 5′ UTRs of four MxiE-regulated genes enhance expression of the downstream gene, presumably by preventing degradation of the mRNA, and the 5′ UTRs of two other genes carry an ancillary promoter.
    Keywords: Research Article ; Biology ; Genetics And Genomics ; Microbiology ; Molecular Biology
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 24 January 2017, Vol.114(4), pp.E506-E513
    Description: The intestinal epithelium is continuously renewed by intestinal epithelial stem cells (IESCs) positioned at the base of each crypt. Mesenchymal-derived factors are essential to maintain IESCs; however, the cellular composition and development of such mesenchymal niche remains unclear. Here, we identify pericryptal CD34 Gp38 αSMA mesenchymal cells closely associated with Lgr5 IESCs. We demonstrate that CD34 Gp38 cells are the major intestinal producers of the niche factors Wnt2b, Gremlin1, and R-spondin1, and are sufficient to promote maintenance of Lgr5 IESCs in intestinal organoids, an effect mainly mediated by Gremlin1. CD34 Gp38 cells develop after birth in the intestinal submucosa and expand around the crypts during the third week of life in mice, independently of the microbiota. We further show that pericryptal CD34gp38 cells are rapidly activated by intestinal injury, up-regulating niche factors Gremlin1 and R-spondin1 as well as chemokines, proinflammatory cytokines, and growth factors with key roles in gut immunity and tissue repair, including IL-7, Ccl2, Ptgs2, and Amphiregulin. Our results indicate that CD34 Gp38 mesenchymal cells are programmed to develop in the intestine after birth to constitute a specialized microenvironment that maintains IESCs at homeostasis and contribute to intestinal inflammation and repair after injury.
    Keywords: Cd34 ; Inflammation ; Intestinal Stem Cells ; Mesenchymal Niche ; Stem Cell Niche ; Antigens, Cd34 -- Metabolism ; Mesenchymal Stem Cells -- Cytology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 24 May 2016, Vol.113(21), pp.E2993-3001
    Description: Antimicrobial peptides (AMP) are defense effectors of the innate immunity playing a crucial role in the intestinal homeostasis with commensals and protection against pathogens. Herein we aimed to investigate AMP gene regulation by deciphering specific characteristics allowing their enhanced expression among innate immune genes, particularly those encoding proinflammatory mediators. Our emphasis was on epigenetic regulation of the gene encoding the AMP β-defensin 2 (HBD2), taken as a model of possibly specific induction, upon challenge with a commensal bacterium, compared with the proinflammatory cytokine IL-8. Using an in vitro model of colonic epithelial cells challenged with Escherichia coli K12, we showed that inhibition of histone deacetylases (HDAC) by trichostatin A dramatically enhanced induction of HBD2 expression, without affecting expression of IL-8. This mechanism was supported by an increased phosphorylation of histone H3 on serine S10, preferentially at the HBD2 promoter. This process occurred through activation of the IκB kinase complex, which also led to activation of NF-κB. Moreover, we demonstrated that NF-κB was modified by acetylation upon HDAC inhibition, partly by the histone acetyltransferase p300, and that both NF-κB and p300 supported enhanced induction of HBD2 expression. Furthermore, we identified additional genes belonging to antimicrobial defense and epithelial restitution pathways that showed a similar pattern of epigenetic control. Finally, we confirmed our finding in human colonic primary cells using an ex vivo organoid model. This work opens the way to use epigenetic pharmacology to achieve induction of epithelial antimicrobial defenses, while limiting the deleterious risk of an inflammatory response.
    Keywords: Acetylation ; Antimicrobial Peptides ; Colonic Mucosa ; Epigenetic ; Epithelial Cells ; E1a-Associated P300 Protein -- Antagonists & Inhibitors ; Epigenesis, Genetic -- Drug Effects ; Escherichia Coli K12 -- Immunology ; Histone Deacetylase Inhibitors -- Pharmacology ; Interleukin-8 -- Immunology ; Beta-Defensins -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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