TY - JOUR
T1 - Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes
AU - DZIF-TB cohort study group
AU - DiNardo, Andrew R.
AU - Gandhi, Tanmay
AU - Heyckendorf, Jan
AU - Grimm, Sandra L.
AU - Rajapakshe, Kimal
AU - Nishiguchi, Tomoki
AU - Reimann, Maja
AU - Kirchner, H. Lester
AU - Kahari, Jaqueline
AU - Dlamini, Qiniso
AU - Lange, Christoph
AU - Goldmann, Torsten
AU - Marwitz, Sebastian
AU - Abhimanyu,
AU - Cirillo, Jeffrey D.
AU - Kaufmann, Stefan H.E.
AU - Netea, Mihai G.
AU - van Crevel, Reinout
AU - Mandalakas, Anna M.
AU - Coarfa, Cristian
AU - Avsar, Korkut
AU - Günther, Gunar
AU - Bern, Inselspital
AU - Hoelscher, Michael
AU - Ibraim, Elmira
AU - Kalsdorf, Barbara
AU - Kontsevaya, Irina
AU - van Leth, Frank
AU - Maurer, Florian P.
AU - Müller, Marius
AU - Nitschkowski, Dörte
AU - Olaru, Ioana D.
AU - Popa, Cristina
AU - Rachow, Andrea
AU - Rolling, Thierry
AU - Rybniker, Jan
AU - Salzer, Helmut J.F.
AU - Sanchez-Carballo, Patricia
AU - Schuhmann, Maren
AU - Schaub, Dagmar
AU - Spinu, Victor
AU - Suárez, Isabelle
AU - Terhalle, Elena
AU - Unnewehr, Markus
AU - Weiner, January
N1 - Publisher Copyright:
© 2022 European Respiratory Society. All rights reserved.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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.
AB - 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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U2 - 10.1183/13993003.02263-2021
DO - 10.1183/13993003.02263-2021
M3 - Article
C2 - 35169026
AN - SCOPUS:85127319829
SN - 0903-1936
VL - 60
JO - The European respiratory journal
JF - The European respiratory journal
IS - 3
M1 - 2102263
ER -