title: Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen.
abstract: How the innate immune system tailors specific responses to diverse microbial infections is not well understood. Cells use a limited number of host receptors and signaling pathways to both discriminate among extracellular and intracellular microbes, and also to generate responses commensurate to each threat. Here, we have addressed these questions by using DNA microarrays to monitor the macrophage transcriptional response to the intracellular bacterial pathogen Listeria monocytogenes. By utilizing combinations of host and bacterial mutants, we have defined the host transcriptional responses to vacuolar and cytosolic bacteria. These compartment-specific host responses induced significantly different sets of target genes, despite activating similar transcription factors. Vacuolar signaling was entirely MyD88-dependent, and induced the transcription of pro-inflammatory cytokines. The IRF3-dependent cytosolic response induced a distinct set of target genes, including IFNbeta. Many of these cytosolic response genes were induced by secreted cytokines, so we further identified those host genes induced independent of secondary signaling. The host response to cytosolic bacteria was reconstituted by the cytosolic delivery of L. monocytogenes genomic DNA, but we observed an amplification of this response by NOD2 signaling in response to MDP. Correspondingly, the induction of IFNbeta was reduced in nod2-/- macrophages during infection with either L. monocytogenes or Mycobacterium tuberculosis. Combinatorial control of IFNbeta induction by recognition of both DNA and MDP may highlight a mechanism by which the innate immune system integrates the responses to multiple ligands presented in the cytosol by intracellular pathogens.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
authors.forename: Jess H
authors.initials: JH
authors.lastname: Leber
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Crimmins
authors.forename: Sridharan
authors.initials: S
authors.lastname: Raghavan
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Meyer-Morse
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Portnoy
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing; D007111:Immunity, Cellular / Q000235:genetics*; D008089:Listeria monocytogenes / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D051193:Toll-Like Receptors