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HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.

Lai RP, Meintjes G, Wilkinson KA, Graham CM, Marais S, Van der Plas H, Deffur A, Schutz C, Bloom C, Munagala I, Anguiano E, Goliath R, Maartens G, Banchereau J, Chaussabel D, O'Garra A, Wilkinson RJ - Nat Commun (2015)

Bottom Line: Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB.Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients.These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

View Article: PubMed Central - PubMed

Affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.

ABSTRACT
Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

No MeSH data available.


Related in: MedlinePlus

Transcriptomic signature of TB-IRIS at week 2 predicts activation of innate signalling pathways and production of proinflammatory cytokines and chemokines.The TREM1, TLR and IL-1 signalling pathways are interconnected. Molecules in red were those found to be differentially abundant in the signatures of TB-IRIS patients at week 2 (normalization to median). Molecule activity prediction was performed using Ingenuity Pathway Analysis: molecules in orange were predicted to be upregulated and those in blue predicted to be downregulated.
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f3: Transcriptomic signature of TB-IRIS at week 2 predicts activation of innate signalling pathways and production of proinflammatory cytokines and chemokines.The TREM1, TLR and IL-1 signalling pathways are interconnected. Molecules in red were those found to be differentially abundant in the signatures of TB-IRIS patients at week 2 (normalization to median). Molecule activity prediction was performed using Ingenuity Pathway Analysis: molecules in orange were predicted to be upregulated and those in blue predicted to be downregulated.

Mentions: We next performed both regulator and molecule activity prediction27 of the week 2 signature by using the 125 genes identified by the normalization to median approach. Proinflammatory cytokines including oncostatin M, IFN-γ, tumour necrosis factor (TNF) and IL-1 were predicted to be the upstream regulators of the week 2 signature (Supplementary Table 5). In addition, CSF-3 (granulocyte colony-stimulating factor) and IL-5 were also predicted to be activated upstream at week 2, suggesting activation of adaptive immunity. An array of proinflammatory cytokines and chemokines were predicted to be activated at week 2, including TNF-α, IL-1β, IL-6, IL-8, IL-12, IL-18, granulocyte–macrophage colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 (Fig. 3). Signalling appeared to be mediated by TLR and IL-1/18 receptor via the MyD88 adaptor and TREM1-induced activation of inflammasomes and TLR, resulting in the activation of nuclear factor-κB and subsequent production of cytokines and chemokines (Fig. 3).


HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.

Lai RP, Meintjes G, Wilkinson KA, Graham CM, Marais S, Van der Plas H, Deffur A, Schutz C, Bloom C, Munagala I, Anguiano E, Goliath R, Maartens G, Banchereau J, Chaussabel D, O'Garra A, Wilkinson RJ - Nat Commun (2015)

Transcriptomic signature of TB-IRIS at week 2 predicts activation of innate signalling pathways and production of proinflammatory cytokines and chemokines.The TREM1, TLR and IL-1 signalling pathways are interconnected. Molecules in red were those found to be differentially abundant in the signatures of TB-IRIS patients at week 2 (normalization to median). Molecule activity prediction was performed using Ingenuity Pathway Analysis: molecules in orange were predicted to be upregulated and those in blue predicted to be downregulated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595995&req=5

f3: Transcriptomic signature of TB-IRIS at week 2 predicts activation of innate signalling pathways and production of proinflammatory cytokines and chemokines.The TREM1, TLR and IL-1 signalling pathways are interconnected. Molecules in red were those found to be differentially abundant in the signatures of TB-IRIS patients at week 2 (normalization to median). Molecule activity prediction was performed using Ingenuity Pathway Analysis: molecules in orange were predicted to be upregulated and those in blue predicted to be downregulated.
Mentions: We next performed both regulator and molecule activity prediction27 of the week 2 signature by using the 125 genes identified by the normalization to median approach. Proinflammatory cytokines including oncostatin M, IFN-γ, tumour necrosis factor (TNF) and IL-1 were predicted to be the upstream regulators of the week 2 signature (Supplementary Table 5). In addition, CSF-3 (granulocyte colony-stimulating factor) and IL-5 were also predicted to be activated upstream at week 2, suggesting activation of adaptive immunity. An array of proinflammatory cytokines and chemokines were predicted to be activated at week 2, including TNF-α, IL-1β, IL-6, IL-8, IL-12, IL-18, granulocyte–macrophage colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 (Fig. 3). Signalling appeared to be mediated by TLR and IL-1/18 receptor via the MyD88 adaptor and TREM1-induced activation of inflammasomes and TLR, resulting in the activation of nuclear factor-κB and subsequent production of cytokines and chemokines (Fig. 3).

Bottom Line: Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB.Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients.These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

View Article: PubMed Central - PubMed

Affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.

ABSTRACT
Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

No MeSH data available.


Related in: MedlinePlus