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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

Differentially abundant transcripts associated with progression to TB-IRIS were identified early before onset of clinical symptoms.(a) Whole-blood samples were collected longitudinally and the median onset of TB-IRIS was 13 days. (b) Microarray was performed with 22 whole-blood samples (13 TB-IRIS and 9 non-IRIS). Twenty-two transcripts (20 genes) were differentially abundant at week 0.5 (days 2–5 post ART) in those patients who eventually developed TB-IRIS, compared with non-IRIS. Transcript intensity values were normalized to the median of all samples. Transcripts are clustered vertically where green represents decreased abundance and red represents increased abundance. Patient arms are clustered horizontally where blue represents non-IRIS and orange represent TB-IRIS. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for Benjamini–Hochberg false discovery rate (BH-FDR) (P=0.05). (c) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 55 transcripts (50 genes) were found to be differentially abundant in TB-IRIS patients, compared with non-IRIS controls. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for BH-FDR (P=0.05). One sample was excluded from the analysis, owing to the lack of corresponding baseline.
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f1: Differentially abundant transcripts associated with progression to TB-IRIS were identified early before onset of clinical symptoms.(a) Whole-blood samples were collected longitudinally and the median onset of TB-IRIS was 13 days. (b) Microarray was performed with 22 whole-blood samples (13 TB-IRIS and 9 non-IRIS). Twenty-two transcripts (20 genes) were differentially abundant at week 0.5 (days 2–5 post ART) in those patients who eventually developed TB-IRIS, compared with non-IRIS. Transcript intensity values were normalized to the median of all samples. Transcripts are clustered vertically where green represents decreased abundance and red represents increased abundance. Patient arms are clustered horizontally where blue represents non-IRIS and orange represent TB-IRIS. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for Benjamini–Hochberg false discovery rate (BH-FDR) (P=0.05). (c) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 55 transcripts (50 genes) were found to be differentially abundant in TB-IRIS patients, compared with non-IRIS controls. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for BH-FDR (P=0.05). One sample was excluded from the analysis, owing to the lack of corresponding baseline.

Mentions: Longitudinal whole-blood samples were collected from patients with HIV-associated TB commencing ART (Fig. 1a). We investigated the molecular path of immune dysregulation leading to TB-IRIS by inspecting transcriptomic changes in TB-IRIS and non-IRIS patients by using two different normalization approaches. First was a modified method from one previously described2526, in which signal intensities were normalized to the median of all samples. The second approach normalized each sample to its corresponding baseline (week 0). Differentially expressed genes identified by both approaches are listed in Supplementary Table 2.


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)

Differentially abundant transcripts associated with progression to TB-IRIS were identified early before onset of clinical symptoms.(a) Whole-blood samples were collected longitudinally and the median onset of TB-IRIS was 13 days. (b) Microarray was performed with 22 whole-blood samples (13 TB-IRIS and 9 non-IRIS). Twenty-two transcripts (20 genes) were differentially abundant at week 0.5 (days 2–5 post ART) in those patients who eventually developed TB-IRIS, compared with non-IRIS. Transcript intensity values were normalized to the median of all samples. Transcripts are clustered vertically where green represents decreased abundance and red represents increased abundance. Patient arms are clustered horizontally where blue represents non-IRIS and orange represent TB-IRIS. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for Benjamini–Hochberg false discovery rate (BH-FDR) (P=0.05). (c) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 55 transcripts (50 genes) were found to be differentially abundant in TB-IRIS patients, compared with non-IRIS controls. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for BH-FDR (P=0.05). One sample was excluded from the analysis, owing to the lack of corresponding baseline.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Differentially abundant transcripts associated with progression to TB-IRIS were identified early before onset of clinical symptoms.(a) Whole-blood samples were collected longitudinally and the median onset of TB-IRIS was 13 days. (b) Microarray was performed with 22 whole-blood samples (13 TB-IRIS and 9 non-IRIS). Twenty-two transcripts (20 genes) were differentially abundant at week 0.5 (days 2–5 post ART) in those patients who eventually developed TB-IRIS, compared with non-IRIS. Transcript intensity values were normalized to the median of all samples. Transcripts are clustered vertically where green represents decreased abundance and red represents increased abundance. Patient arms are clustered horizontally where blue represents non-IRIS and orange represent TB-IRIS. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for Benjamini–Hochberg false discovery rate (BH-FDR) (P=0.05). (c) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 55 transcripts (50 genes) were found to be differentially abundant in TB-IRIS patients, compared with non-IRIS controls. Significance of pathways over-represented by differentially abundant genes was calculated by Fisher's exact test corrected for BH-FDR (P=0.05). One sample was excluded from the analysis, owing to the lack of corresponding baseline.
Mentions: Longitudinal whole-blood samples were collected from patients with HIV-associated TB commencing ART (Fig. 1a). We investigated the molecular path of immune dysregulation leading to TB-IRIS by inspecting transcriptomic changes in TB-IRIS and non-IRIS patients by using two different normalization approaches. First was a modified method from one previously described2526, in which signal intensities were normalized to the median of all samples. The second approach normalized each sample to its corresponding baseline (week 0). Differentially expressed genes identified by both approaches are listed in Supplementary Table 2.

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