Inflammation Research

, Volume 67, Issue 5, pp 435–443 | Cite as

The host control of a clinical isolate strain of P. aeruginosa infection is independent of Nod-1 but depends on MyD88

  • Fabiane Sônego
  • Fernanda V. S. Castanheira
  • Catarina V. Horta
  • Alexandre Kanashiro
  • Paula G. Czaikoski
  • Dario S. Zamboni
  • José Carlos Alves-Filho
  • Fernando Q. Cunha
Original Research Paper


Objective and design

The objective of this study was to investigate the role of Nod1 in the recruitment of neutrophils into the infection site and in the establishment of the inflammatory response elicited by a clinical isolate strain of P. aeruginosa in vivo, while comparing it to the well-established role of MyD88 in this process.


Wild-type, Nod1−/− and MyD88−/− mice, all with a C57Bl/6 background.


Mice were intranasally infected with Pseudomonas aeruginosa DZ605. Bronchoalveolar lavage and blood were harvested 6 or 20 h post-infection for evaluating bacterial load, chemokine levels and neutrophil migration. Survival post-infection was also observed.


We show here that wild-type and Nod1−/− mice induce similar lung chemokine levels, neutrophil recruitment, and bacterial load, thus leading to equal survival rates upon P. aeruginosa pulmonary infection. Furthermore, we confirmed the essential role of MyD88-dependent signalling in recruiting neutrophils and controlling P. aeruginosa-induced pulmonary infection.


The results suggest that in contrast to MyD88, under our experimental conditions, the absence of Nod1 does not impair the recruitment of neutrophils in response to P. aeruginosa DZ605.


Nod1 MyD88 Pseudomonas aeruginosa Pneumonia Neutrophil migration Chemokines 



The authors would like to thank Agnes Afrodite S Albuquerque, Ieda Regina dos Santos, Ana Kátia dos Santos, Giuliana Bertozi and Marco Antônio Silva for their technical assistance. This work was supported by São Paulo Research Foundation (FAPESP), grants #2008/11593-4 and #2011/19670-0, CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and European Community’s Seventh Framework Programme [FP7-2007-2013] under grant agreement number HEALTH-F4-2011-281608. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Compliance with ethical standards

Conflict of interest

The authors declares that there is no conflicts of interest.

Supplementary material

11_2018_1135_MOESM1_ESM.doc (91 kb)
Supplementary material 1 (DOC 91 KB)


  1. 1.
    Fraimow H, Nahra R. Resistant gram-negative infections. Crit Care Clin. 2013;29(4):895–921. Scholar
  2. 2.
    Tommasi R, Brown DG, Walkup GK, Manchester JI, Miller AA. ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Disc. 2015;14(8):529–542. Scholar
  3. 3.
    Pendleton JN, Gorman SP, Gilmore BF. Clinical relevance of the ESKAPE pathogens. Expert Rev Anti-infective Ther. 2013;11(3):297–308. Scholar
  4. 4.
    Segal AW. How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197–223. Scholar
  5. 5.
    Robertson CM, Perrone EE, McConnell KW, Dunne WM, Boody B, Brahmbhatt T, et al. Neutrophil depletion causes a fatal defect in murine pulmonary Staphylococcus aureus clearance. J Surg Res. 2008;150(2):278–285. Scholar
  6. 6.
    Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM. Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5. Infecti Immun. 2005;73(11):7151–7160. Scholar
  7. 7.
    Skerrett SJ, Wilson CB, Liggitt HD, Hajjar AM. Redundant Toll-like receptor signaling in the pulmonary host response to Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2007;292(1):L312-22. Scholar
  8. 8.
    Morris AE, Liggitt HD, Hawn TR, Skerrett SJ. Role of Toll-like receptor 5 in the innate immune response to acute P. aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol. 2009;297(6):L1112–L1119. Scholar
  9. 9.
    Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4(7):702–7. Scholar
  10. 10.
    Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003;300(5625):1584–7. Scholar
  11. 11.
    Watanabe T, Asano N, Kitani A, Fuss IJ, Chiba T, Strober W. NOD1-mediated mucosal host defense against Helicobacter pylori. Int J Inflamm. 2010;2010:476482. Scholar
  12. 12.
    Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR, et al. CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2001;2(8):736–742. Scholar
  13. 13.
    Frutuoso MS, Hori JI, Pereira MS, Junior DS, Sonego F, Kobayashi KS, et al. The pattern recognition receptors Nod1 and Nod2 account for neutrophil recruitment to the lungs of mice infected with Legionella pneumophila. Microbes Inf Institut Pasteur. 2010;12(11):819–827. Scholar
  14. 14.
    Masumoto J, Yang K, Varambally S, Hasegawa M, Tomlins SA, Qiu S, et al. Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo. J Exp Med. 2006;203(1):203–213. Scholar
  15. 15.
    Travassos LH, Carneiro LA, Girardin SE, Boneca IG, Lemos R, Bozza MT, et al. Nod1 participates in the innate immune response to Pseudomonas aeruginosa. J Biol Chem. 2005;280(44):36714–3678. Scholar
  16. 16.
    Power MR, Peng Y, Maydanski E, Marshall JS, Lin TJ. The development of early host response to Pseudomonas aeruginosa lung infection is critically dependent on myeloid differentiation factor 88 in mice. J Biol Chem. 2004;279(47):49315–493122. Scholar
  17. 17.
    Sabharwal N, Dhall S, Chhibber S, Harjai K. Molecular detection of virulence genes as markers in Pseudomonas aeruginosa isolated from urinary tract infections. Int J Mol Epidemiol Genet. 2014;5(3):125–134.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Benjamim CF, Ferreira SH, Cunha FQ. Role of nitric oxide in the failure of neutrophil migration in sepsis. J Infect Dis. 2000;182(1):214–223. Scholar
  19. 19.
    Czaikoski PG, Nascimento DC, Sonego F, de Freitas A, Turato WM, de Carvalho MA, et al. Heme oxygenase inhibition enhances neutrophil migration into the bronchoalveolar spaces and improves the outcome of murine pneumonia-induced sepsis. Shock. 2013;39(4):389–396. Scholar
  20. 20.
    Koh AY, Priebe GP, Ray C, Van Rooijen N, Pier GB. Inescapable need for neutrophils as mediators of cellular innate immunity to acute Pseudomonas aeruginosa pneumonia. Infect Immun. 2009;77(12):5300–5310. Scholar
  21. 21.
    Moreira LO, Zamboni DS. NOD1 and NOD2 Signaling in Infection and Inflammation. Front Immunol. 2012;3:328. Scholar
  22. 22.
    Cigana C, Curcuru L, Leone MR, Ierano T, Lore NI, Bianconi I, et al. Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection. PloS One. 2009;4(12):e8439. Scholar
  23. 23.
    Sonego F, Castanheira FV, Czaikoski PG, Kanashiro A, Souto FO, Franca RO, et al. MyD88-, but not Nod1- and/or Nod2-deficient mice, show increased susceptibility to polymicrobial sepsis due to impaired local inflammatory response. PloS One. 2014;9(8):e103734. Scholar
  24. 24.
    Skerrett SJ, Liggitt HD, Hajjar AM, Wilson CB. Cutting edge: myeloid differentiation factor 88 is essential for pulmonary host defense against Pseudomonas aeruginosa but not Staphylococcus aureus. J Immunol. 2004;172(6):3377–3381.CrossRefPubMedGoogle Scholar
  25. 25.
    McIsaac SM, Stadnyk AW, Lin TJ. Toll-like receptors in the host defense against Pseudomonas aeruginosa respiratory infection and cystic fibrosis. J Leukoc Biolgy. 2012;92(5):977–985. Scholar
  26. 26.
    Mijares LA, Wangdi T, Sokol C, Homer R, Medzhitov R, Kazmierczak BI. Airway epithelial MyD88 restores control of Pseudomonas aeruginosa murine infection via an IL-1-dependent pathway. J Immunol. 2011;186(12):7080–7088. Scholar
  27. 27.
    Miao EA, Ernst RK, Dors M, Mao DP, Aderem A. Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci USA. 2008;105(7):2562–2567. Scholar
  28. 28.
    Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003;301(5633):640–643. Scholar
  29. 29.
    Power MR, Li B, Yamamoto M, Akira S, Lin TJ. A role of Toll-IL-1 receptor domain-containing adaptor-inducing IFN-beta in the host response to Pseudomonas aeruginosa lung infection in mice. J Immunol. 2007;178(5):3170–3176.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Fabiane Sônego
    • 1
  • Fernanda V. S. Castanheira
    • 1
  • Catarina V. Horta
    • 2
  • Alexandre Kanashiro
    • 1
  • Paula G. Czaikoski
    • 1
  • Dario S. Zamboni
    • 2
  • José Carlos Alves-Filho
    • 1
  • Fernando Q. Cunha
    • 1
  1. 1.Departamento de FarmacologiaFaculdade de Medicina de Ribeirão PretoRibeirão PretoBrazil
  2. 2.Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil

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