HIV-Tuberculosis-Associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling

Rachel P J Lai, Graeme Meintjes, Katalin A. Wilkinson, Christine M. Graham, Suzaan Marais, Helen Van Der Plas, Armin Deffur, Charlotte Schutz, Chloe Bloom, Indira Munagala, Esperanza Anguiano, Rene Goliath, Gary Maartens, Jacques Banchereau, Damien J. Chaussabel, Anne O'Garra, Robert J. Wilkinson

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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.

Original languageEnglish
Article number8451
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 24 Sep 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lai, R. P. J., Meintjes, G., Wilkinson, K. A., Graham, C. M., Marais, S., Van Der Plas, H., Deffur, A., Schutz, C., Bloom, C., Munagala, I., Anguiano, E., Goliath, R., Maartens, G., Banchereau, J., Chaussabel, D. J., O'Garra, A., & Wilkinson, R. J. (2015). HIV-Tuberculosis-Associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling. Nature Communications, 6, [8451]. https://doi.org/10.1038/ncomms9451