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 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.

Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection

“…Following phagocytosis and escape into the cytosol, it is sensed by NLRs, namely the Nod1, Ipaf, and Nalp3 inflammasomes (14,15). The concerted actions of these pathways translate into a robust sterilizing immunity and enhanced pathogen elimination (16).…”

Essential Role of Mitochondrial Antiviral Signaling, IFN Regulatory Factor (IRF)3, and IRF7 in Chlamydophila pneumoniae-Mediated IFN-β Response and Control of Bacterial Replication in Human Endothelial Cells

“…This has been demonstrated for Listeria monocytogenes as well as Shigella flexneri and L. pneumophila (39,40,58,59). The induction of IFN-b in Listeria-, Legionella-, or group B streptococci-infected macrophages was supposed to be mediated by the DNA-recognition pathway (35,37,40). The observation that the type IV secretion apparatus is required to initiate the type I IFN response in L. pneumophila and Brucella (39,40,60) suggests that the functionally analogous but evolutionary unrelated type III secretion apparatus of C. pneumoniae may be a crucial element in the IFN-b response.…”

“…However, the PRR(s) as well as the signaling pathway(s) activated in bacteria-infected host cells, which mediate IFN-b production remain incompletely understood. It has been suggested that DNA from intracellular bacteria or from bacteria that were engulfed by phagocytic cells is recognized by poorly characterized cytosolic PRRs (35)(36)(37)(38)(39)(40). Downstream of these PRRs, the Tankbinding kinase-1 and IRF3 are involved in the bacteria-stimulated IFN-b pathway (40)(41)(42)(43).…”

NKT Cells Are Required for Complete Freund’s Adjuvant-Mediated Protection from Autoimmune Diabetes

“…In these experiments, both wild-type and MyD88 2/2 DCs were equally capable of inducing DN32 cells to elevate CD69 and IL-2 expression. In addition to components activating TLR pathways, reports have described the peptidoglycan constituent muramyl dipeptide (MDP), recognized by the intracellular NOD2 receptor, as one of the major adjuvant activities of M. tuberculosis (50,51). As a consequence, we investigated whether MDP can activate NKT cells by incubating DN32 cells with treated BMDCs in vitro.…”