Mycobacteria counteract a TLR-mediated nitrosative defense mechanism in a zebrafish infection model

PLoS One. 2014 Jun 26;9(6):e100928. doi: 10.1371/journal.pone.0100928. eCollection 2014.

Abstract

Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Interleukin-8 / metabolism
  • Mycobacterium / physiology*
  • Mycobacterium Infections / immunology
  • Mycobacterium Infections / metabolism*
  • Mycobacterium Infections / microbiology*
  • Myeloid Differentiation Factor 88 / metabolism
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Peroxidase / metabolism
  • Reactive Nitrogen Species / metabolism*
  • Receptors, Interleukin-1 / metabolism
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction
  • Toll-Like Receptors / metabolism*
  • Tyrosine / metabolism
  • Zebrafish

Substances

  • Interleukin-8
  • Myeloid Differentiation Factor 88
  • Reactive Nitrogen Species
  • Receptors, Interleukin-1
  • Receptors, Interleukin-8B
  • Toll-Like Receptors
  • Tyrosine
  • Peroxidase

Grant support

P.M.E. is the recipient of a European Respiratory Society Fellowship (LTRF fellowship n°176-2011). P.M.E. is further funded by a University of Sheffield Vice-Chancellor’s Fellowship. The identification of the mpx-/- spotless mutant used in this study was supported by the European Commission through a FP6 Integrated Project ZF-MODELS grant (LSHG-CT-2003-503496) to P. Herbomel (Institut Pasteur, Paris). A.H.M, M.vdV., and H.P.S. are funded by the Smart Mix Program of the Netherlands Ministry of Economic Affairs and the Ministry of Education, Culture and Science. This work is further supported by the European Commission 7th framework project ZF-HEALTH (HEALTH-F4-2010-242048), and by the Leiden University Fund (LUF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.