Gene Expression Signatures Identify Biologically and Clinically Distinct Tuberculosis Endotypes

Authors

Andrew R DiNardo
Tanmay Gandhi
Jan Heyckendorf
Sandra L Grimm
Kimal Rajapakshe
Tomoki Nishiguchi
Maja Reimann
H Lester Kirchner
Jaqueline Kahari
Qiniso Dlamini
Christoph Lange
Torsten Goldmann
Sebastian Marwitz
DZIF-TB cohort study group
Abhimanyu
Jeffrey D Cirillo
Stefan H E Kaufmann
Mihai G Netea
Reinout van Crevel
Anna M Mandalakas
Cristian Coarfa

Publication Date

9-1-2022

Journal

European Respiratory Journal

DOI

10.1183/13993003.02263-2021

PMID

35169026

PMCID

PMC9474892

PubMedCentral® Posted Date

9-15-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Cytokines, Humans, Inflammation, RNA, Transcriptome, Tuberculosis

Abstract

BACKGROUND:In vitro, animal model and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.

METHODS: A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients was used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as were two RNA-sequencing (seq) cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated to clarify stimulated from unstimulated immune responses.

RESULTS: A discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Endotype A is characterised by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B has increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced cure rate. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.

CONCLUSION: These findings provide evidence that metabolic and immune profiling could inform optimisation of endotype-specific host-directed therapies for tuberculosis.

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