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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  IFNβ . 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  IFNβ  was reduced in  nod2   −/−  macrophages during infection with either  L. monocytogenes  or  Mycobacterium tuberculosis . Combinatorial control of  IFNβ  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.

Distinct TLR- and NLR-Mediated Transcriptional Responses to an Intracellular Pathogen