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

PLoS Pathogens

Sridharan Raghavan¹  Jeffery S Cox¹  Nicole P Meyer-Morse²  Jess H Leber²  Gregory T Crimmins²  Daniel A Portnoy² 

[1] Department of Microbiology and Immunology, University of California, San Francisco, California, United States of America;Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America

关键词: Macrophages;    Listeria monocytogenes;    Immune receptor signaling;    DNA transcription;    Microarrays;    Intracellular pathogens;    Bacterial pathogens;    Immune response;   

DOI  :  10.1371/journal.ppat.0040006

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY