NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

Pandey, Amit; Yang, Yibin; Jiang, Zhaozhao; Fortune, Sarah M.; François, Clément; Behr, Marcel A.; Fitzgerald, Katherine A.; Sassetti, Christopher M.; Kelliher, Michelle A.

doi:10.1371/journal.ppat.1000500

Cited by 254 publications

(250 citation statements)

References 79 publications

Supporting

Mentioning

240

Contrasting

Unclassified

Order By: Relevance

“…The activation of IRF5 by S. aureus and TLR8 ligands was rapid and did not occur in bystander cells not infected by S. aureus, excluding the possibility that IRF5 is triggered via a secondary mediator. Mycobacterium tuberculosis induces IFN-b in mouse macrophages through a nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-receptor interacting protein 2 (RIP2)-TBK1-IRF5 pathway (45). Also, a NOD2-IRF5 mechanism of S. aureus-mediated IFN-b induction in mouse BMDCs was recently reported (46), and IRF5 was activated by TBK1/IKKi and RIP2 in overexpression studies (47,48).…”

Section: Discussionmentioning

confidence: 97%

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Bergstrøm

Aune

Awuh

et al. 2015

The Journal of Immunology

122

162

View full text Add to dashboard Cite

Staphylococcus aureus may cause serious infections and is one of the most lethal and common causes of sepsis. TLR2 has been described as the main pattern recognition receptor that senses S. aureus and elicits production of proinflammatory cytokines via MyD88–NF-κB signaling. S. aureus can also induce the production of IFN-β, a cytokine that requires IFN regulatory factors (IRFs) for its transcription, but the signaling mechanism for IFN-β induction by S. aureus are unclear. Surprisingly, we demonstrate that activation of TLR2 by lipoproteins does not contribute to IFN-β production but instead can suppress the induction of IFN-β in human primary monocytes and monocyte-derived macrophages. The production of IFN-β was induced by TLR8-mediated sensing of S. aureus RNA, which triggered IRF5 nuclear accumulation, and this could be antagonized by concomitant TLR2 signaling. The TLR8-mediated activation of IRF5 was dependent on TAK1 and IκB kinase (IKK)β, which thus reveals a physiological role of the recently described IRF5-activating function of IKKβ. TLR8–IRF5 signaling was necessary for induction of IFN-β and IL-12 by S. aureus, and it also contributed to the induction of TNF. In conclusion, our study demonstrates a physiological role of TLR8 in the sensing of entire S. aureus in human primary phagocytes, including the induction of IFN-β and IL-12 production via a TAK1–IKKβ–IRF5 pathway that can be inhibited by TLR2 signaling.

show abstract

Section: Discussionmentioning

confidence: 97%

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Bergstrøm

Aune

Awuh

et al. 2015

The Journal of Immunology

122

162

View full text Add to dashboard Cite

show abstract

“…5 B and C), and the same genetic variants are nominally associated with pulmonary TB in the GWAS data (Table S1). RIPK2 encodes an adapter protein of the NOD2-dependent signaling pathway, which is a key pathway involved in the regulation of host responses to MTB infection (44)(45)(46). ATP6V0A2 encodes a subunit of the vesicular proton-ATPase (v-ATPase) (47).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the genetic architecture of variation in the immune response toMycobacterium tuberculosisinfection

Barreiro

Tailleux²,

Pai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

243

263

View full text Add to dashboard Cite

Tuberculosis (TB) is a major public health problem. One-third of the world's population is estimated to be infected with Mycobacterium tuberculosis (MTB), the etiological agent causing TB, and active disease kills nearly 2 million individuals worldwide every year. Several lines of evidence indicate that interindividual variation in susceptibility to TB has a heritable component, yet we still know little about the underlying genetic architecture. To address this, we performed a genome-wide mapping study of loci that are associated with functional variation in immune response to MTB. Specifically, we characterized transcript and protein expression levels and mapped expression quantitative trait loci (eQTL) in primary dendritic cells (DCs) from 65 individuals, before and after infection with MTB. We found 198 response eQTL, namely loci that were associated with variation in gene expression levels in either untreated or MTB-infected DCs, but not both. These response eQTL are associated with natural regulatory variation that likely affects (directly or indirectly) host interaction with MTB. Indeed, when we integrated our data with results from a genome-wide association study (GWAS) for pulmonary TB, we found that the response eQTL were more likely to be genetically associated with the disease. We thus identified a number of candidate loci, including the MAPK phosphatase DUSP14 in particular, that are promising susceptibility genes to pulmonary TB.

show abstract

“…However, infection of mice with the intracellular bacterium Mycobacterium tuberculosis up-regulates the type I IFN system via conserved pattern recognition receptors (e.g. Tolllike and NOD-like receptors) and may play a role in priming or regulating the adaptive immune response (Pandey et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Pathological and immunological responses associated with differential survival of Chinook salmon following Renibacterium salmoninarum challenge

Metzger¹,

Elliott²,

Wargo³

et al. 2010

Dis. Aquat. Org.

View full text Add to dashboard Cite

Chinook salmon Oncorhynchus tshawytscha are highly susceptible to Renibacterium salmoninarum, the causative agent of bacterial kidney disease (BKD). Previously we demonstrated that introduced Chinook salmon from Lake Michigan, Wisconsin (WI), USA, have higher survival following R. salmoninarum challenge relative to the progenitor stock from Green River, Washington, USA. In the present study, we investigated the pathological and immunological responses that are associated with differential survival in the 2 Chinook salmon stocks following intra-peritoneal R. salmoninarum challenge of 2 different cohort years (2003 and 2005). Histological evaluation revealed delayed appearance of severe granulomatous lesions in the kidney and lower overall prevalence of membranous glomerulopathy in the higher surviving WI stock. The higher survival WI stock had a lower bacterial load at 28 d post-infection, as measured by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR). However, at all other time points, bacterial load levels were similar despite higher mortality in the more susceptible Green River stock, suggesting the possibility that the stocks may differ in their tolerance to infection by the bacterium. Interferon-γ, inducible nitric oxide synthase (iNOS), Mx-1, and transferrin gene expression were up-regulated in both stocks following challenge. A trend of higher iNOS gene expression at later time points (≥28 d post-infection) was observed in the lower surviving Green River stock, suggesting the possibility that higher iNOS expression may contribute to greater pathology in that stock.

show abstract

NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

Cited by 254 publications

References 79 publications

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Deciphering the genetic architecture of variation in the immune response toMycobacterium tuberculosisinfection

Pathological and immunological responses associated with differential survival of Chinook salmon following Renibacterium salmoninarum challenge

Contact Info

Product

Resources

About