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      Toll-Like Receptor-4 Dependent Inflammatory Responses Following Intestinal Colonization of Secondary Abiotic IL10-Deficient Mice with Multidrug-Resistant Pseudomonas Aeruginosa

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          Abstract

          The rising incidences of infections with multidrug-resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have gained increasing attention in medicine, but also in the general public and global health politics. The mechanisms underlying opportunistic pathogen–host interactions are unclear, however. To address this, we challenged secondary abiotic IL10 –/– mice deficient for Toll-like receptor-4 (TLR4 –/– × IL10 –/–), the main receptor of the Gram-negative cell wall constituent lipopolysaccharide, with a clinical MDR PA isolate. Despite higher intestinal colonization densities, apoptotic colonic epithelial cell numbers were lower in TLR4 –/– × IL10 –/– mice as compared to IL10 –/– controls at day 14 postinfection (p.i.), whereas proliferating/regenerating cells had increased in the latter only. Furthermore, PA-colonized TLR4 –/– × IL10 –/– mice displayed less distinct innate and adaptive immune cell responses in the colon as compared to IL10 –/– counterparts that were accompanied by lower nitric oxide concentrations in mesenteric lymph nodes in the former at day 14 p.i. Conversely, splenic NO levels were higher in both naive and PA-colonized TLR4-deficient IL10 –/– mice versus IL10 –/– controls. Remarkably, intestinal MDR PA was able to translocate to extra-intestinal including systemic compartments of TLR4 –/– × IL10 –/– mice only. Hence, MDR PA-induced intestinal and systemic immune responses observed in secondary abiotic IL10 –/– mice are TLR4-dependent.

          Most cited references40

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          Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist.

          Pseudomonas aeruginosa is an ubiquitous pathogen capable of infecting virtually all tissues. A large variety of virulence factors contribute to its importance in burn wounds, lung infection and eye infection. Prominent factors include pili, flagella, lipopolysaccharide, proteases, quorum sensing, exotoxin A and exoenzymes secreted by the type III secretion system.
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            Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii.

            Oral infection of susceptible mice with Toxoplasma gondii results in Th1-type immunopathology in the ileum. We investigated gut flora changes during ileitis and determined contributions of gut bacteria to intestinal inflammation. Analysis of the intestinal microflora revealed that ileitis was accompanied by increasing bacterial load, decreasing species diversity, and bacterial translocation. Gram-negative bacteria identified as Escherichia coli and Bacteroides/Prevotella spp. accumulated in inflamed ileum at high concentrations. Prophylactic or therapeutic administration of ciprofloxacin and/or metronidazole ameliorated ileal immunopathology and reduced intestinal NO and IFN-gamma levels. Most strikingly, gnotobiotic mice in which cultivable gut bacteria were removed by quintuple antibiotic treatment did not develop ileitis after Toxoplasma gondii infection. A reduction in total numbers of lymphocytes was observed in the lamina propria of specific pathogen-free (SPF), but not gnotobiotic, mice upon development of ileitis. Relative numbers of CD4(+) T cells did not differ in naive vs infected gnotobiotic or SPF mice, but infected SPF mice showed a significant increase in the frequencies of activated CD4(+) T cells compared with gnotobiotic mice. Furthermore, recolonization with total gut flora, E. coli, or Bacteroides/Prevotella spp., but not Lactobacillus johnsonii, induced immunopathology in gnotobiotic mice. Animals recolonized with E. coli and/or total gut flora, but not L. johnsonii, showed elevated ileal NO and/or IFN-gamma levels. In conclusion, Gram-negative bacteria, i.e., E. coli, aggravate pathogen-induced intestinal Th1-type immunopathology. Thus, pathogen-induced acute ileitis may prove useful to study bacteria-host interactions in small intestinal inflammation and to test novel therapies based on modulation of gut flora.
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              The increasing threat of Pseudomonas aeruginosa high-risk clones.

              The increasing prevalence of chronic and hospital-acquired infections produced by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa strains is associated with significant morbidity and mortality. This growing threat results from the extraordinary capacity of this pathogen for developing resistance through chromosomal mutations and from the increasing prevalence of transferable resistance determinants, particularly those encoding carbapenemases or extended-spectrum β-lactamases (ESBLs). P. aeruginosa has a nonclonal epidemic population structure, composed of a limited number of widespread clones which are selected from a background of a large quantity of rare and unrelated genotypes that are recombining at high frequency. Indeed, recent concerning reports have provided evidence of the existence of MDR/XDR global clones, denominated high-risk clones, disseminated in hospitals worldwide; ST235, ST111, and ST175 are likely those more widespread. Noteworthy, the vast majority of infections by MDR, and specially XDR, strains are produced by these and few other clones worldwide. Moreover, the association of high-risk clones, particularly ST235, with transferable resistance is overwhelming; nearly 100 different horizontally-acquired resistance elements and up to 39 different acquired β-lactamases have been reported so far among ST235 isolates. Likewise, MDR internationally-disseminated epidemic strains, such as the Liverpool Epidemic Strain (LES, ST146), have been noted as well among cystic fibrosis patients. Here we review the population structure, epidemiology, antimicrobial resistance mechanisms and virulence of the P. aeruginosa high-risk clones. The phenotypic and genetic factors potentially driving the success of high-risk clones, the aspects related to their detection in the clinical microbiology laboratory and the implications for infection control and public health are also discussed.

                Author and article information

                Journal
                Eur J Microbiol Immunol (Bp)
                Eur J Microbiol Immunol (Bp)
                EUJMI
                European Journal of Microbiology & Immunology
                Akadémiai Kiadó (Budapest )
                2062-509X
                2062-8633
                11 September 2017
                September 2017
                : 7
                : 3
                : 210-219
                Affiliations
                Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health , Department of Microbiology and Hygiene, Berlin, Germany
                Author notes
                * Department of Microbiology and Hygiene, Charité – University Medicine Berlin, CC5, Campus Benjamin Franklin, FEM, Garystr. 5, D-14195 Berlin, Germany; +49-30-450524318; markus.heimesaat@ 123456charite.de
                Article
                10.1556/1886.2017.00023
                5632748
                8b7bb8b1-41c9-46ec-9b52-234c3243aafb
                © 2017, The Author(s)

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and reproduction in any medium for non-commercial purposes, provided the original author and source are credited, a link to the CC License is provided, and changes – if any – are indicated.

                History
                : 10 August 2017
                : 23 August 2017
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 38, Pages: 10
                Categories
                Original Article

                pseudomonas aeruginosa,multidrug-resistant gram-negative bacteria,colonization resistance,susceptibility to infection,gut microbiota shifts,secondary abiotic (gnotobiotic) il10-deficient mice,pro-inflammatory immune responses,bacterial translocation,toll-like receptor-4,lipopolysaccharide

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