Blood gene signatures reveal early immune shifts under linezolid tuberculosis therapy

The findings, published in BMC Pulmonary Medicine, show that swapping ethambutol for linezolid for either two or four weeks produces a distinct pattern of gene expression compared with the standard regimen, and that two candidate genes measured at baseline were independently associated with radiographic improvement at four weeks.

Paired blood samples, collected at baseline and at week four, were available from 48 participants: 12 receiving the standard regimen, 18 receiving the two-week linezolid substitution and 18 receiving the four-week substitution.

The transcriptomic analysis identified distinct sets of genes that were up-regulated or down-regulated early in treatment. Linezolid-containing regimens were associated with early transcriptional changes that differed from those seen under the standard regimen. Exploratory enrichment analyses pointed to involvement of antigen processing and presentation, T-cell activation and immune signaling pathways, suggesting that the composition of the drug regimen shapes which host immune programs are most active in the first weeks of therapy.

Notably, the differences between the two-week and four-week linezolid exposures were minimal, indicating that the duration of linezolid substitution within this range had little detectable effect on the early blood transcriptome. This observation suggests that the transcriptional signature associated with linezolid-containing therapy emerges quickly and is largely insensitive to whether the drug replaces ethambutol for two or four weeks.

In this validation step, higher baseline levels of FOXP3 and UBE2D4 were independently associated with radiographic improvement at four weeks. FOXP3 encodes a transcription factor central to regulatory T-cell function, while UBE2D4 participates in ubiquitin-conjugating activity, and both emerged as candidate markers linked to early clinical response.

However, no transcript examined in the study predicted the time to negative culture conversion, a key microbiological endpoint in tuberculosis treatment. The authors therefore position these gene expression measures as candidate biomarkers of early treatment effect rather than as predictors of the standard measure of treatment success based on culture status over time.

The work addresses a gap in knowledge about how linezolid-containing regimens affect host gene expression. Blood transcriptomic profiling can reflect host responses to tuberculosis treatment, but the transcriptional effects of linezolid-containing regimens in drug-susceptible pulmonary TB had remained poorly characterized.

The authors conclude that transcriptomic analysis demonstrated distinct early, regimen-specific gene expression differences in linezolid-containing regimens compared with the standard regimen, and that several candidate genes showed clinically relevant associations. These findings support the potential of such transcripts as biomarkers for predicting treatment outcomes in pulmonary tuberculosis, while the absence of an association with culture conversion time underscores the need for further evaluation before any clinical use.

Subject of Research: Early whole-blood gene expression responses to linezolid-containing versus standard anti-tuberculosis regimens in drug-susceptible pulmonary tuberculosis

Article Title: Transcriptome analysis for differential gene expression profiles of linezolid-containing anti-tuberculosis regimen in drug-susceptible pulmonary tuberculosis

Article References: Lee, J.-K., Park, K., Yim, J.-J., Won, S., & Kim, D. K. (2026). Transcriptome analysis for differential gene expression profiles of linezolid-containing anti-tuberculosis regimen in drug-susceptible pulmonary tuberculosis. BMC Pulmonary Medicine. https://doi.org/10.1186/s12890-026-04786-y

Image Credits: AI Generated

DOI: 10.1186/s12890-026-04786-y

Keywords: tuberculosis, linezolid, transcriptomics, gene expression, RNA sequencing, biomarkers, FOXP3, UBE2D4, drug-susceptible TB, radiographic improvement, qRT-PCR, immune signaling