Gene expression responses to anti-tuberculous drugs in a whole blood model

Abstract

Background: There is a need for better tools to evaluate new or repurposed TB drugs. The whole blood bactericidal activity (WBA) assay has been advocated for this purpose. We investigated whether transcriptional responses in the WBA assay resemble TB responses in vivo, and whether the approach might additionally reveal mechanisms of action. Results: 1422 of 1798 (79%) of differentially expressed genes in WBA incubated with the standard combination of rifampicin, isoniazid, pyrazinamide and ethambutol were also expressed in sputum (P < 0.0001) obtained from patients taking the same combination of drugs; these comprised well-established treatment-response genes. Gene expression profiles in WBA incubated with the standard drugs individually, or with moxifloxacin or faropenem (with amoxicillin and clavulanic acid) clustered by individual drug exposure. Distinct pathways were detected for individual drugs, although only with isoniazid did these relate to known mechanisms of drug action. Conclusions: Substantial agreement between whole blood cultures and sputum and the ability to differentiate individual drugs suggest that transcriptomics may add value to the whole blood assay for evaluating new TB drugs.