Limits...
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 in TB-IRIS onset are associated with innate signalling pathways.(a) Microarray was performed with 26 whole-blood samples (13 TB-IRIS and 13 non-IRIS). One hundred and thirty-eight transcripts (125 genes) were differentially abundant in the whole blood of the TB-IRIS patients at week 2. 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). (b) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 319 transcripts (281 genes) were found to be differentially abundant in TB-IRIS patients. 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
getmorefigures.php?uid=PMC4595995&req=5

f2: Differentially abundant transcripts in TB-IRIS onset are associated with innate signalling pathways.(a) Microarray was performed with 26 whole-blood samples (13 TB-IRIS and 13 non-IRIS). One hundred and thirty-eight transcripts (125 genes) were differentially abundant in the whole blood of the TB-IRIS patients at week 2. 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). (b) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 319 transcripts (281 genes) were found to be differentially abundant in TB-IRIS patients. 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: Applying the same analytical approaches described above, we identified a 138-transcript (125 gene) signature associated with TB-IRIS at week 2 by normalizing to the median (Fig. 2a and Supplementary Table 3). Functional analysis of these 125 differentially abundant transcripts indicated upregulation of several innate response pathways, with TLR and TREM1-induced inflammasome signalling being most over-represented (Fig. 2a), again suggesting an important role of innate antigen recognition and cytokine signalling in the inflammatory response in TB-IRIS. When the transcriptional data were normalized to their corresponding baseline values, we identified 319 transcripts (281 genes) differentially abundant in TB-IRIS patients at week 2 (Fig. 2b and Supplementary Table 4). Functional pathway analysis again indicated innate immune signalling pathways including TLR, IFN and IL-1 signalling to be over-represented in TB-IRIS (Fig. 2b). Of the 281 genes identified, 70 overlapped with the 125 genes identified by normalization to the median. The large number of overlapping genes indicates they are conserved in TB-IRIS regardless of analytical method. Functional analysis of the overlapping transcripts again indicated the innate immune components, with TLR, TREM-1 and IL-1 being the most enriched biological processes. Corticosteroid therapy was prescribed in ten of the patients (four of whom had microarray performed) at the time of ART commencement but it was not a confounding factor in the transcriptomic analysis.


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 in TB-IRIS onset are associated with innate signalling pathways.(a) Microarray was performed with 26 whole-blood samples (13 TB-IRIS and 13 non-IRIS). One hundred and thirty-eight transcripts (125 genes) were differentially abundant in the whole blood of the TB-IRIS patients at week 2. 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). (b) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 319 transcripts (281 genes) were found to be differentially abundant in TB-IRIS patients. 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

f2: Differentially abundant transcripts in TB-IRIS onset are associated with innate signalling pathways.(a) Microarray was performed with 26 whole-blood samples (13 TB-IRIS and 13 non-IRIS). One hundred and thirty-eight transcripts (125 genes) were differentially abundant in the whole blood of the TB-IRIS patients at week 2. 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). (b) Using an alternative analytical approach by normalizing transcript intensity to its corresponding baseline (week 0) value, 319 transcripts (281 genes) were found to be differentially abundant in TB-IRIS patients. 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: Applying the same analytical approaches described above, we identified a 138-transcript (125 gene) signature associated with TB-IRIS at week 2 by normalizing to the median (Fig. 2a and Supplementary Table 3). Functional analysis of these 125 differentially abundant transcripts indicated upregulation of several innate response pathways, with TLR and TREM1-induced inflammasome signalling being most over-represented (Fig. 2a), again suggesting an important role of innate antigen recognition and cytokine signalling in the inflammatory response in TB-IRIS. When the transcriptional data were normalized to their corresponding baseline values, we identified 319 transcripts (281 genes) differentially abundant in TB-IRIS patients at week 2 (Fig. 2b and Supplementary Table 4). Functional pathway analysis again indicated innate immune signalling pathways including TLR, IFN and IL-1 signalling to be over-represented in TB-IRIS (Fig. 2b). Of the 281 genes identified, 70 overlapped with the 125 genes identified by normalization to the median. The large number of overlapping genes indicates they are conserved in TB-IRIS regardless of analytical method. Functional analysis of the overlapping transcripts again indicated the innate immune components, with TLR, TREM-1 and IL-1 being the most enriched biological processes. Corticosteroid therapy was prescribed in ten of the patients (four of whom had microarray performed) at the time of ART commencement but it was not a confounding factor in the transcriptomic analysis.

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