1887

Abstract

Antimicrobial peptides are an important component of the innate immune defence. subsp. () is an organism that establishes contact with the respiratory and gastrointestinal mucosa as a necessary step for infection. is resistant to high concentrations of polymyxin B, a surrogate for antimicrobial peptides. To determine gene-encoding proteins that are associated with this resistance, we screened a transposon library of strain 104 for susceptibility to polymyxin B. Ten susceptible mutants were identified and the inactivated genes sequenced. The great majority of the genes were related to cell wall synthesis and permeability. The mutants were then examined for their ability to enter macrophages and to survive macrophage killing. Three clones among the mutants had impaired uptake by macrophages compared with the WT strain, and all ten clones were attenuated in macrophages. The mutants were also shown to be susceptible to cathelicidin (LL-37), in contrast to the WT bacterium. All but one of the mutants were significantly attenuated in mice. In conclusion, this study indicated that the envelope is the primary defence against host antimicrobial peptides.

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2014-07-01
2019-10-18
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References

  1. Alonso-Hearn M., Eckstein T. M., Sommer S., Bermudez L. E.. ( 2010;). A Mycobacterium avium subsp. paratuberculosis LuxR regulates cell envelope and virulence. . Innate Immun 16:, 235–247. [CrossRef][PubMed]
    [Google Scholar]
  2. Ashitani J., Mukae H., Hiratsuka T., Nakazato M., Kumamoto K., Matsukura S.. ( 2001;). Plasma and BAL fluid concentrations of antimicrobial peptides in patients with Mycobacterium avium-intracellulare infection. . Chest 119:, 1131–1137. [CrossRef][PubMed]
    [Google Scholar]
  3. Bals R.. ( 2000;). Epithelial antimicrobial peptides in host defense against infection. . Respir Res 1:, 141–150. [CrossRef][PubMed]
    [Google Scholar]
  4. Becknell B., Spencer J. D., Carpenter A. R., Chen X., Singh A., Ploeger S., Kline J., Ellsworth P., Li B.. & other authors ( 2013;). Expression and antimicrobial function of beta-defensin 1 in the lower urinary tract. . PLoS ONE 8:, e77714. [CrossRef][PubMed]
    [Google Scholar]
  5. Bermudez L. E., Young L. S., Gupta S.. ( 1990;). 1,25 Dihydroxyvitamin D3-dependent inhibition of growth or killing of Mycobacterium avium complex in human macrophages is mediated by TNF and GM-CSF. . Cell Immunol 127:, 432–441. [CrossRef][PubMed]
    [Google Scholar]
  6. Bevins C. L., Salzman N. H.. ( 2011;). Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. . Nat Rev Microbiol 9:, 356–368. [CrossRef][PubMed]
    [Google Scholar]
  7. Brogden K. A.. ( 2005;). Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria. ? Nat Rev Microbiol 3:, 238–250. [CrossRef][PubMed]
    [Google Scholar]
  8. Brogden K. A., Ackermann M., McCray P. B. Jr, Tack B. F.. ( 2003;). Antimicrobial peptides in animals and their role in host defences. . Int J Antimicrob Agents 22:, 465–478. [CrossRef][PubMed]
    [Google Scholar]
  9. Camacho L. R., Constant P., Raynaud C., Laneelle M. A., Triccas J. A., Gicquel B., Daffe M., Guilhot C.. ( 2001;). Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier. . J Biol Chem 276:, 19845–19854. [CrossRef][PubMed]
    [Google Scholar]
  10. Carroll J., Field D., O’Connor P. M., Cotter P. D., Coffey A., Hill C., Ross R. P., O’Mahony J.. ( 2010;). Gene encoded antimicrobial peptides, a template for the design of novel anti-mycobacterial drugs. . Bioeng Bugs 1:, 408–412. [CrossRef][PubMed]
    [Google Scholar]
  11. Danelishvili L., Wu M., Stang B., Harriff M., Cirillo S. L., Cirillo J. D., Bildfell R., Arbogast B., Bermudez L. E.. ( 2007;). Identification of Mycobacterium avium pathogenicity island important for macrophage and amoeba infection. . Proc Natl Acad Sci U S A 104:, 11038–11043. [CrossRef][PubMed]
    [Google Scholar]
  12. Duplantier A. J., van Hoek M. L.. ( 2013;). The human cathelicidin antimicrobial peptide LL-37 as a potential treatment for polymicrobial infected wounds. . Front Immunol 4:, 143. [CrossRef][PubMed]
    [Google Scholar]
  13. Gao L. Y., Laval F., Lawson E. H., Groger R. K., Woodruff A., Morisaki J. H., Cox J. S., Daffe M., Brown E. J.. ( 2003;). Requirement for kasB in Mycobacterium mycolic acid biosynthesis, cell wall impermeability and intracellular survival: implications for therapy. . Mol Microbiol 49:, 1547–1563. [CrossRef][PubMed]
    [Google Scholar]
  14. Gutierrez M. G., Master S. S., Singh S. B., Taylor G. A., Colombo M. I., Deretic V.. ( 2004;). Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. . Cell 119:, 753–766. [CrossRef][PubMed]
    [Google Scholar]
  15. Hansdottir S., Monick M. M., Hinde S. L., Lovan N., Look D. C., Hunninghake G. W.. ( 2008;). Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. . J Immunol 181:, 7090–7099. [CrossRef][PubMed]
    [Google Scholar]
  16. Inderlied C. B., Kemper C. A., Bermudez L. E.. ( 1993;). The Mycobacterium avium complex. . Clin Microbiol Rev 6:, 266–310.[PubMed]
    [Google Scholar]
  17. Johansson M. E., Phillipson M., Petersson J., Velcich A., Holm L., Hansson G. C.. ( 2008;). The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. . Proc Natl Acad Sci U S A 105:, 15064–15069. [CrossRef][PubMed]
    [Google Scholar]
  18. Johansson M. E., Larsson J. M., Hansson G. C.. ( 2011;). The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. . Proc Natl Acad Sci U S A 108: (Suppl. 1), 4659–4665. [CrossRef][PubMed]
    [Google Scholar]
  19. Li Y. J., Danelishvili L., Wagner D., Petrofsky M., Bermudez L. E.. ( 2010;). Identification of virulence determinants of Mycobacterium avium that impact on the ability to resist host killing mechanisms. . J Med Microbiol 59:, 8–16. [CrossRef][PubMed]
    [Google Scholar]
  20. Liu P. T., Stenger S., Li H., Wenzel L., Tan B. H., Krutzik S. R., Ochoa M. T., Schauber J., Wu K.. & other authors ( 2006;). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. . Science 311:, 1770–1773. [CrossRef][PubMed]
    [Google Scholar]
  21. Maloney E., Stankowska D., Zhang J., Fol M., Cheng Q. J., Lun S., Bishai W. R., Rajagopalan M., Chatterjee D., Madiraju M. V.. ( 2009;). The two-domain LysX protein of Mycobacterium tuberculosis is required for production of lysinylated phosphatidylglycerol and resistance to cationic antimicrobial peptides. . PLoS Pathog 5:, e1000534. [CrossRef][PubMed]
    [Google Scholar]
  22. Marras T. K., Daley C. L.. ( 2002;). Epidemiology of human pulmonary infection with mycobacteria nontuberculous. . Clin Chest Med 23:, 553–567. [CrossRef][PubMed]
    [Google Scholar]
  23. Mikusová K., Slayden R. A., Besra G. S., Brennan P. J.. ( 1995;). Biogenesis of the mycobacterial cell wall and the site of action of ethambutol. . Antimicrob Agents Chemother 39:, 2484–2489. [CrossRef][PubMed]
    [Google Scholar]
  24. Miyakawa Y., Ratnakar P., Rao A. G., Costello M. L., Mathieu-Costello O., Lehrer R. I., Catanzaro A.. ( 1996;). In vitro activity of the antimicrobial peptides human and rabbit defensins and porcine leukocyte protegrin against Mycobacterium tuberculosis. . Infect Immun 64:, 926–932.[PubMed]
    [Google Scholar]
  25. Ogata K., Linzer B. A., Zuberi R. I., Ganz T., Lehrer R. I., Catanzaro A.. ( 1992;). Activity of defensins from human neutrophilic granulocytes against Mycobacterium avium-Mycobacterium intracellulare. . Infect Immun 60:, 4720–4725.[PubMed]
    [Google Scholar]
  26. Ouellette A. J.. ( 1999;). IV. Paneth cell antimicrobial peptides and the biology of the mucosal barrier. . Am J Physiol 277:, G257–G261.[PubMed]
    [Google Scholar]
  27. Rivas-Santiago B., Sada E., Tsutsumi V., Aguilar-Leon D., Contreras J. L., Hernandez-Pando R.. ( 2006;). β-Defensin gene expression during the course of experimental tuberculosis infection. . J Infect Dis 194:, 697–701. [CrossRef][PubMed]
    [Google Scholar]
  28. Rivas-Santiago B., Hernandez-Pando R., Carranza C., Juarez E., Contreras J. L., Aguilar-Leon D., Torres M., Sada E.. ( 2008;). Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells. . Infect Immun 76:, 935–941. [CrossRef][PubMed]
    [Google Scholar]
  29. Ryndak M., Wang S., Smith I.. ( 2008;). PhoP, a key player in Mycobacterium tuberculosis virulence. . Trends Microbiol 16:, 528–534. [CrossRef][PubMed]
    [Google Scholar]
  30. Shin D. M., Jo E. K.. ( 2011;). Antimicrobial peptides in innate immunity against mycobacteria. . Immune Netw 11:, 245–252. [CrossRef][PubMed]
    [Google Scholar]
  31. Sonawane A., Santos J. C., Mishra B. B., Jena P., Progida C., Sorensen O. E., Gallo R., Appelberg R., Griffiths G.. ( 2011;). Cathelicidin is involved in the intracellular killing of mycobacteria in macrophages. . Cell Microbiol 13:, 1601–1617. [CrossRef][PubMed]
    [Google Scholar]
  32. Sørensen O. E., Borregaard N., Cole A. M.. ( 2008;). Antimicrobial peptides in innate immune responses. . Contrib Microbiol 15:, 61–77. [CrossRef][PubMed]
    [Google Scholar]
  33. Sow F. B., Nandakumar S., Velu V., Kellar K. L., Schlesinger L. S., Amara R. R., Lafuse W. P., Shinnick T. M., Sable S. B.. ( 2011;). Mycobacterium tuberculosis components stimulate production of the antimicrobial peptide hepcidin. . Tuberculosis (Edinb) 91:, 314–321. [CrossRef][PubMed]
    [Google Scholar]
  34. Sturgill-Koszycki S., Schlesinger P. H., Chakraborty P., Haddix P. L., Collins H. L., Fok A. K., Allen R. D., Gluck S. L., Heuser J., Russell D. G.. ( 1994;). Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. . Science 263:, 678–681. [CrossRef][PubMed]
    [Google Scholar]
  35. van der Does A. M., Bergman P., Agerberth B., Lindbom L.. ( 2012;). Induction of the human cathelicidin LL-37 as a novel treatment against bacterial infections. . J Leukoc Biol 92:, 735–742. [CrossRef][PubMed]
    [Google Scholar]
  36. Yuk J. M., Shin D. M., Lee H. M., Yang C. S., Jin H. S., Kim K. K., Lee Z. W., Lee S. H., Kim J. M., Jo E. K.. ( 2009;). Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. . Cell Host Microbe 6:, 231–243. [CrossRef][PubMed]
    [Google Scholar]
  37. Zaragoza O., González-Párraga P., Pedreño Y., Alvarez-Peral F. J., Argüelles J.-C.. ( 2003;). Trehalose accumulation induced during the oxidative stress response is independent of TPS1 mRNA levels in Candida albicans. . Int Microbiol 6:, 121–125. [CrossRef][PubMed]
    [Google Scholar]
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