View More View Less
  • 1 Charité — Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
  • | 2 Charité — University Medicine Berlin, CC5, Campus Benjamin Franklin, FEM, Garystr. 5, D-14195 Berlin, , Germany
Open access

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.

  • 1.

    Uematsu S , Akira S: Innate immune recognition of viral infection. Uirusu 56, 18 (2006)

  • 2.

    Akira S , Uematsu S, Takeuchi O: Pathogen recognition and innate immunity. Cell 124, 783801 (2006)

  • 3.

    King JD , Kocincova D, Westman EL, Lam JS: Review: lipopolysaccharide biosynthesis in Pseudomonas aeruginosa. Innate Immun 15, 261312 (2009)

    • Search Google Scholar
    • Export Citation
  • 4.

    Lam JS , Taylor VL, Islam ST, Hao Y, Kocincova D: Genetic and functional diversity of Pseudomonas aeruginosa lipopolysaccharide. Front Microbiol 2, 118 (2011)

    • Search Google Scholar
    • Export Citation
  • 5.

    Driscoll JA , Brody SL, Kollef MH: The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections. Drugs 67, 351368 (2007)

    • Search Google Scholar
    • Export Citation
  • 6.

    Gellatly, SL , Hancock, RE: Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathog Dis 67, 159173 (2013)

  • 7.

    Sievert DM , Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, Kallen A, Limbago B, Fridkin S, National Healthcare Safety Network T, Participating NF: Antimicrobial-resistant pathogens associated with healthcareassociated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2009–2010. Infect Control Hosp Epidemiol 34, 114 (2013)

    • Search Google Scholar
    • Export Citation
  • 8.

    Vincent JL : Nosocomial infections in adult intensive-care units. Lancet 361, 20682077 (2003)

  • 9.

    Lyczak JB , Cannon CL, Pier GB: Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. Microbes Infect 2, 10511060 (2000)

    • Search Google Scholar
    • Export Citation
  • 10.

    Potron A , Poirel L, Nordmann P: Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: mechanisms and epidemiology. Int J Antimicrob Agents 45, 568585 (2015)

    • Search Google Scholar
    • Export Citation
  • 11.

    Shooter RA , Walker KA, Williams VR, Horgan GM, Parker MT, Asheshov EH, Bullimore JF: Faecal carriage of Pseudomonas aeruginosa in hospital patients. Possible spread from patient to patient. Lancet 2, 13311334 (1966)

    • Search Google Scholar
    • Export Citation
  • 12.

    Cohen R , Babushkin F, Cohen S, Afraimov M, Shapiro M, Uda M, Khabra E, Adler A, Ben Ami R, Paikin S: A prospective survey of Pseudomonas aeruginosa colonization and infection in the intensive care unit. Antimicrob Resist Infect Control 6, 7 (2017)

    • Search Google Scholar
    • Export Citation
  • 13.

    Bereswill S , Fischer A, Plickert R, Haag LM, Otto B, Kühl AA, Dasti JI, Zautner AE, Munoz M, Loddenkemper C, Gross U, Göbel UB, Heimesaat MM: Novel murine infection models provide deep insights into the “ménage à trois” of Campylobacter jejuni, microbiota and host innate immunity. PLoS One 6, e20953 (2011)

    • Search Google Scholar
    • Export Citation
  • 14.

    Gomez-Zorrilla S , Camoez M, Tubau F, Canizares R, Periche E, Dominguez MA, Ariza J, Pena C: Prospective observational study of prior rectal colonization status as a predictor for subsequent development of Pseudomonas aeruginosa clinical infections. Antimicrob Agents Chemother 59, 52135219 (2015)

    • Search Google Scholar
    • Export Citation
  • 15.

    Livermore DM : Has the era of untreatable infections arrived? J Antimicrob Chemother 64(Suppl 1), i2936 (2009)

  • 16.

    Oliver A , Mulet X, Lopez-Causape C, Juan C: The increasing threat of Pseudomonas aeruginosa high-risk clones. Drug Resist Updat 21–22, 4159 (2015)

    • Search Google Scholar
    • Export Citation
  • 17.

    Tacconelli E , Magrini N: Global priority list of antibioticresistant bacteria to guide research discovery and development of new antibiotics. World Health Organisation (2017)

    • Search Google Scholar
    • Export Citation
  • 18.

    Kerckhoffs AP , Ben-Amor K, Samsom M, van der Rest ME, de Vogel J, Knol J, Akkermans LM: Molecular analysis of faecal and duodenal samples reveals significantly higher prevalence and numbers of Pseudomonas aeruginosa in irritable bowel syndrome. J Med Microbiol 60, 236245 (2011)

    • Search Google Scholar
    • Export Citation
  • 19.

    Wang M , Molin G, Ahrne S, Adawi D, Jeppsson B: High proportions of proinflammatory bacteria on the colonic mucosa in a young patient with ulcerative colitis as revealed by cloning and sequencing of 16s rrna genes. Dig Dis Sci 52, 620627 (2007)

    • Search Google Scholar
    • Export Citation
  • 20.

    Heimesaat MM , Bereswill S, Fischer A, Fuchs D, Struck D, Niebergall J, Jahn HK, Dunay IR, Moter A, Gescher DM, Schumann RR, Göbel UB, Liesenfeld O: Gram-negative bacteria aggravate murine small intestinal th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol 177, 87858795 (2006)

    • Search Google Scholar
    • Export Citation
  • 21.

    Ekmekciu I , von Klitzing E, Fiebiger U, Escher U, Neumann C, Bacher P, Scheffold A, Kühl AA, Bereswill S, Heimesaat MM: Immune responses to broad-spectrum antibiotic treatment and fecal microbiota transplantation in mice. Front Immunol 8, 397 (2017)

    • Search Google Scholar
    • Export Citation
  • 22.

    von Klitzing E , Ekmekciu I, Bereswill S, Heimesaat MM: Acute ileitis facilitates infection with multidrug resistant Pseudomonas aeruginosa in human microbiota-associated mice. Gut Pathog 9, 4 (2017)

    • Search Google Scholar
    • Export Citation
  • 23.

    Haag LM , Fischer A, Otto B, Plickert R, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM: Campylobacter jejuni induces acute enterocolitis in gnotobiotic IL-10−/− mice via toll-like-receptor-2 and -4 signaling. PLoS One 7, e40761 (2012)

    • Search Google Scholar
    • Export Citation
  • 24.

    Alutis ME , Grundmann U, Fischer A, Hagen U, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM: The role of gelatinases in Campylobacter jejuni infection of gnotobiotic mice. Eur J Microbiol Immunol (Bp) 5, 256267 (2015)

    • Search Google Scholar
    • Export Citation
  • 25.

    Alutis ME , Grundmann U, Hagen U, Fischer A, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM: Matrix metalloproteinase-2 mediates intestinal immunopathogenesis in Campylobacter jejuni-infected infant mice. Eur J Microbiol Immunol (Bp) 5, 188198 (2015)

    • Search Google Scholar
    • Export Citation
  • 26.

    Heimesaat MM , Nogai A, Bereswill S, Plickert R, Fischer A, Loddenkemper C, Steinhoff U, Tchaptchet S, Thiel E, Freudenberg MA, Göbel UB, Uharek L: Myd88/tlr9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 59, 10791087 (2010)

    • Search Google Scholar
    • Export Citation
  • 27.

    Masanta WO , Heimesaat MM, Bereswill S, Tareen AM, Lugert R, Gross U, Zautner AE: Modification of intestinal microbiota and its consequences for innate immune response in the pathogenesis of campylobacteriosis. Clin Dev Immunol 2013, 526860 (2013)

    • Search Google Scholar
    • Export Citation
  • 28.

    Fiebiger U , Bereswill S, Heimesaat MM: Dissecting the interplay between intestinal microbiota and host immunity in health and disease: Lessons learned from germfree and gnotobiotic animal models. Eur J Microbiol Immunol (Bp) 6, 253271 (2016)

    • Search Google Scholar
    • Export Citation
  • 29.

    Wohlgemuth S , Keller S, Kertscher R, Stadion M, Haller D, Kisling S, Jahreis G, Blaut M, Loh G: Intestinal steroid profiles and microbiota composition in colitic mice. Gut Microbes 2, 159166 (2011)

    • Search Google Scholar
    • Export Citation
  • 30.

    Heimesaat MM , Grundmann U, Alutis ME, Fischer A, Bereswill S: Absence of nucleotide-oligomerizationdomain-2 is associated with less distinct disease in Campylobacter jejuni infected secondary abiotic IL-10 deficient mice. Front Cell Infect Microbiol 7, 322 (2017)

    • Search Google Scholar
    • Export Citation
  • 31.

    Korneev KV , Arbatsky NP, Molinaro A, Palmigiano A, Shaikhutdinova RZ, Shneider MM, Pier GB, Kondakova AN, Sviriaeva EN, Sturiale L, Garozzo D, Kruglov AA, Nedospasov SA, Drutskaya MS, Knirel YA Kuprash DV: Structural relationship of the lipid a acyl groups to activation of murine toll-like receptor 4 by lipopolysaccharides from pathogenic strains of Burkholderia mallei, Acinetobacter baumannii, and Pseudomonas aeruginosa. Front Immunol 6, 595 (2015)

    • Search Google Scholar
    • Export Citation
  • 32.

    Ouyang W , Rutz S, Crellin NK, Valdez PA, Hymowitz SG: Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29, 71109 (2011)

    • Search Google Scholar
    • Export Citation
  • 33.

    Eidenschenk C , Rutz S, Liesenfeld O, Ouyang W: Role of IL-22 in microbial host defense. Curr Top Microbiol Immunol 380, 213236 (2014)

  • 34.

    Heimesaat MM , Grundmann U, Alutis ME, Fischer A, Göbel UB, Bereswill S: The IL-23/IL-22/IL-18 axis in murine Campylobacter jejuni infection. Gut Pathog 8, 21 (2016)

    • Search Google Scholar
    • Export Citation
  • 35.

    Bereswill S , Grundmann U, Alutis ME, Fischer A, Kühl AA, Heimesaat MM: Immune responses upon Campylobacter jejuni infection of secondary abiotic mice lacking nucleotide-oligomerization-domain-2. Gut Pathog 9, 33 (2017)

    • Search Google Scholar
    • Export Citation
  • 36.

    Munoz M , Heimesaat MM, Danker K, Struck D, Lohmann U, Plickert R, Bereswill S, Fischer A, Dunay IR, Wolk K, Loddenkemper C, Krell HW, Libert C, Lund LR, Frey O, Holscher C, Iwakura Y, Ghilardi N, Ouyang W, Kamradt T, Sabat R, Liesenfeld O: Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of Il-17. J Exp Med 206, 30473059 (2009)

    • Search Google Scholar
    • Export Citation
  • 37.

    Munoz M , Liesenfeld O, Heimesaat MM: Immunology of Toxoplasma gondii. Immunol Rev 240, 269285 (2011)

  • 38.

    Munoz M , Eidenschenk C, Ota N, Wong K, Lohmann U, Kühl AA, Wang X, Manzanillo P, Li Y, Rutz S, Zheng Y, Diehl L, Kayagaki N, van Lookeren-Campagne M, Liesenfeld O, Heimesaat M, Ouyang W: Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42, 321331 (2015)

    • Search Google Scholar
    • Export Citation
The author instruction is available in PDF.
Please, download the file from HERE.

Senior editors

Editor(s)-in-Chief: Dunay, Ildiko Rita

Editor(s)-in-Chief: Heimesaat, Markus M.

Vice Editor(s)-in-Chief: Fuchs, Anja

Editorial Board

Chair of the Editorial Board:
Jeffrey S. Buguliskis (Thomas Jefferson University, USA)

  • Jörn Albring (University of Münster, Germany)
  • Stefan Bereswill (Charité - University Medicine Berlin, Germany)
  • Dunja Bruder (University of Megdeburg, Germany)
  • Jan Buer (University of Duisburg, Germany)
  • Jeff Buguliskis (Thomas Jefferson University, USA)
  • Edit Buzas (Semmelweis University, Hungary)
  • Charles Collyer (University of Sydney, Australia)
  • Renato Damatta (UENF, Brazil)
  • Ivelina Damjanova (Semmelweis University, Hungary)
  • Maria Deli (Biological Research Center, HAS, Hungary)
  • Olgica Djurković-Djaković (University of Belgrade, Serbia)
  • Jean-Dennis Docquier (University of Siena, Italy)
  • Anna Erdei (Eötvös Loránd University, Hungary)
  • Zsuzsanna Fabry (University of Washington, USA)
  • Beniam Ghebremedhin (Witten/Herdecke University, Germany)
  • Nancy Guillen (Institute Pasteur, France)
  • Georgina L. Hold (University of Aberdeen, United Kingdom)
  • Ralf Ignatius (Charité - University Medicine Berlin, Germany)
  • Zsuzsanna Izsvak (MDC-Berlin, Germany)
  • Achim Kaasch (University of Cologne, Germany)
  • Tamás Laskay (University of Lübeck, Germany)
  • Oliver Liesenfeld (Roche, USA)
  • Shreemanta Parida (Vaccine Grand Challenge Program, India)
  • Matyas Sandor (University of Wisconsin, USA)
  • Ulrich Steinhoff (University of Marburg, Germany)
  • Michal Toborek (University of Miami, USA)
  • Mary Jo Wick (University of Gothenburg, Sweden)
  • Susanne A. Wolf (MDC-Berlin, Germany)


Dr. Dunay, Ildiko Rita
Magdeburg, Germany

Indexing and Abstracting Services:

  • PubMed Central
  • Scopus
  • ESCI
  • CABI


CrossRef Documents 23
WoS Cites 708
Wos H-index 27
Days from submission to acceptance 219
Days from acceptance to publication 176
Acceptance Rate 70%



European Journal of Microbiology and Immunology
Publication Model Gold Open Access
Submission Fee none
Article Processing Charge 928 EUR/article
Regional discounts on country of the funding agency World Bank Lower-middle-income economies: 50%
World Bank Low-income economies: 100%
Further Discounts Editorial Board / Advisory Board members: 50%
Corresponding authors, affiliated to an EISZ member institution subscribing to the journal package of Akadémiai Kiadó: 100%
Subscription Information Gold Open Access
Purchase per Title  

European Journal of Microbiology and Immunology
Language English
Size A4
Year of
per Year
per Year
Founder Akadémiai Kiadó
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Publisher Akadémiai Kiadó
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Chief Executive Officer, Akadémiai Kiadó
ISSN 2062-509X (Print)
ISSN 2062-8633 (Online)

Monthly Content Usage

Abstract Views Full Text Views PDF Downloads
Aug 2021 0 5 0
Sep 2021 0 1 1
Oct 2021 0 5 1
Nov 2021 0 4 3
Dec 2021 0 5 2
Jan 2022 0 1 1
Feb 2022 0 0 0