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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

Weighted temporal molecular distance to health of 43 consistently overabundant transcripts differentiate TB-IRIS patients from non-IRIS controls.Forty-three genes were consistently overabundant in TB-IRIS by different analytical and technical platforms. These genes are associated with innate signalling pathways, namely TREM1, TLR and IL-1 signalling (Fisher's exact test with Benjamini–Hochberg false discovery rate (BH-FDR), P=0.05). The weighted temporal molecular distance measured the total transcriptional perturbation of the 43 genes at each time point relative to its baseline (week 0) mean. The mean, s.e.m. and P-values are displayed (unpaired t-test with Welch's correction; *P≤0.05 and **P≤0.01).
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f5: Weighted temporal molecular distance to health of 43 consistently overabundant transcripts differentiate TB-IRIS patients from non-IRIS controls.Forty-three genes were consistently overabundant in TB-IRIS by different analytical and technical platforms. These genes are associated with innate signalling pathways, namely TREM1, TLR and IL-1 signalling (Fisher's exact test with Benjamini–Hochberg false discovery rate (BH-FDR), P=0.05). The weighted temporal molecular distance measured the total transcriptional perturbation of the 43 genes at each time point relative to its baseline (week 0) mean. The mean, s.e.m. and P-values are displayed (unpaired t-test with Welch's correction; *P≤0.05 and **P≤0.01).

Mentions: To determine a signature that consisted only of the most conserved genes differentially abundant across all technical or analytical approaches, we overlapped the genes identified at week 2 in all three approaches, resulting in a 43-transcript signature. Functional analysis indicated over-representation of several innate immune signalling pathways, including TREM-1 (P=0.0002), TLR (P=0.0002), IL-1 (P=0.0009) and type I IFN (P=0.0022) (Fig. 5). A ‘weighted temporal molecular distance' algorithm was further applied to quantify changes in abundance of these 43 transcripts over time (Fig. 5). The weighted temporal molecular distance algorithm measures the transcriptional perturbation of specified genes at a given time point relative to the mean at week 0. The non-IRIS patients had no significant changes in the level of the 43 genes at week 0, 0.5, 1 or 2. By contrast, there was significant transcriptional perturbation at week 2 in TB-IRIS patients compared with week 0 (P=0.0268). Furthermore, there was a significant difference in the transcript levels of these 43 transcripts between the TB-IRIS and the non-IRIS patients as early as 2–5 days post ART (week 0.5; P=0.008), before IRIS-associated clinical symptoms were apparent, suggesting that these genes are specifically associated with, and represent the earliest pathways involved in triggering clinical progression to, TB-IRIS.


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)

Weighted temporal molecular distance to health of 43 consistently overabundant transcripts differentiate TB-IRIS patients from non-IRIS controls.Forty-three genes were consistently overabundant in TB-IRIS by different analytical and technical platforms. These genes are associated with innate signalling pathways, namely TREM1, TLR and IL-1 signalling (Fisher's exact test with Benjamini–Hochberg false discovery rate (BH-FDR), P=0.05). The weighted temporal molecular distance measured the total transcriptional perturbation of the 43 genes at each time point relative to its baseline (week 0) mean. The mean, s.e.m. and P-values are displayed (unpaired t-test with Welch's correction; *P≤0.05 and **P≤0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Weighted temporal molecular distance to health of 43 consistently overabundant transcripts differentiate TB-IRIS patients from non-IRIS controls.Forty-three genes were consistently overabundant in TB-IRIS by different analytical and technical platforms. These genes are associated with innate signalling pathways, namely TREM1, TLR and IL-1 signalling (Fisher's exact test with Benjamini–Hochberg false discovery rate (BH-FDR), P=0.05). The weighted temporal molecular distance measured the total transcriptional perturbation of the 43 genes at each time point relative to its baseline (week 0) mean. The mean, s.e.m. and P-values are displayed (unpaired t-test with Welch's correction; *P≤0.05 and **P≤0.01).
Mentions: To determine a signature that consisted only of the most conserved genes differentially abundant across all technical or analytical approaches, we overlapped the genes identified at week 2 in all three approaches, resulting in a 43-transcript signature. Functional analysis indicated over-representation of several innate immune signalling pathways, including TREM-1 (P=0.0002), TLR (P=0.0002), IL-1 (P=0.0009) and type I IFN (P=0.0022) (Fig. 5). A ‘weighted temporal molecular distance' algorithm was further applied to quantify changes in abundance of these 43 transcripts over time (Fig. 5). The weighted temporal molecular distance algorithm measures the transcriptional perturbation of specified genes at a given time point relative to the mean at week 0. The non-IRIS patients had no significant changes in the level of the 43 genes at week 0, 0.5, 1 or 2. By contrast, there was significant transcriptional perturbation at week 2 in TB-IRIS patients compared with week 0 (P=0.0268). Furthermore, there was a significant difference in the transcript levels of these 43 transcripts between the TB-IRIS and the non-IRIS patients as early as 2–5 days post ART (week 0.5; P=0.008), before IRIS-associated clinical symptoms were apparent, suggesting that these genes are specifically associated with, and represent the earliest pathways involved in triggering clinical progression to, TB-IRIS.

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