title: Mycobacteria counteract a TLR-mediated nitrosative defense mechanism in a zebrafish infection model.
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.
authors: Institute of Biology, Leiden University, Leiden, South Holland, The Netherlands; The Bateson Centre, University of Sheffield, Sheffield, South Yorkshire, United Kingdom; Department of Infection and Immunity, University of Sheffield, Sheffield, South Yorkshire, United Kingdom.
authors: Philip M
authors: PM
authors: Elks
authors: Institute of Biology, Leiden University, Leiden, South Holland, The Netherlands.
authors: Michiel
authors: M
authors: van der Vaart
authors: Institute of Biology, Leiden University, Leiden, South Holland, The Netherlands.
authors: Vincent
authors: V
authors: van Hensbergen
authors: Institute of Biology, Leiden University, Leiden, South Holland, The Netherlands.
authors: Esther
authors: E
authors: Schutz
authors: Department of Oncological Sciences, University Of Utah, Salt Lake City, Utah, United States of America.
authors: Michael J
authors: MJ
authors: Redd
authors: Unité Macrophages et Développement de l'Immunité, Institut Pasteur, Paris, France; Centre National de la Recherche Scientifique-Unité de Recherche Associée 2578, Institut Pasteur, Paris, France.
authors: Emi
authors: E
authors: Murayama
authors: Institute of Biology, Leiden University, Leiden, South Holland, The Netherlands.
authors: Herman P
authors: HP
authors: Spaink
authors: Institute of Biology, Leiden University, Leiden, South Holland, The Netherlands.
authors: Annemarie H
authors: AH
authors: Meijer
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D016209:Interleukin-8 / Q000378:metabolism; D009161:Mycobacterium / Q000502:physiology*; D009164:Mycobacterium Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D015027:Zebrafish
chemical_list: D016209:Interleukin-8; D053594:Myeloid Differentiation Factor 88; D026361:Reactive Nitrogen Species; D017472:Receptors, Interleukin-1; D023063:Receptors, Interleukin-8B; D051193:Toll-Like Receptors; D014443:Tyrosine; D009195:Peroxidase