Exploratory transcriptomic analysis of sex- and ethnicity-associated patterns in human macrophage responses to mycobacterial infection.

Authors

Francis Adu-Amankwaah, Ottovon Bismark Dakurah, Kayla Bubb, Bienyameen Baker

Published in

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. Pages 106013. Aug 23, 2026. Epub Aug 23, 2026.

Abstract

Host transcriptional responses are central to intracellular mycobacterial control, but the extent to which these responses vary by sex and self-reported ethnicity are not well defined. We previously showed that macrophages infected with mycobacterial species of differing pathogenicity display distinct immune signatures. Here, we performed an exploratory re-analysis of that dataset to assess sex- and ethnicity-associated patterns in infection-induced gene expression and to distinguish shared from subgroup-restricted DEG patterns.
A secondary transcriptomic analysis of human monocyte-derived macrophages from 12 donors with balanced representation by sex and ethnicity was performed. Macrophages were infected with Mycobacterium smegmatis (Msmeg), Mycobacterium bovis BCG (BCG), or Mycobacterium tuberculosis R179 (R179), with donor-matched uninfected macrophages as controls. Gene-level counts were analysed using a donor-aware edgeR-limma/voom pipeline. Differentially expressed genes (DEGs) were identified in overall, sex-stratified, and ethnicity-stratified comparisons. Shared and subgroup-specific DEGs were then defined within each infection condition. Formal infection × sex and infection × ethnicity interaction models were fitted for each mycobacterial condition, and functional enrichment analysis was performed on ranked shared-gene sets.
Overall, Msmeg induced the largest transcriptional response (1127 DEGs), followed by BCG (651) and R179 (436), with upregulated genes predominating in all comparisons. Ethnicity-stratified analysis showed a higher DEG burden in the blacks group (black group refers to black South African population, herein referred to people of colour (POC)) than in the White group (white group refers to white South African population, herein referred to White) across Msmeg (1151 vs 558), BCG (806 vs 77), and R179 (509 vs 24). Sex-stratified analysis showed more DEGs in males than females across Msmeg (803 vs 769), BCG (349 vs 192), and R179 (181 vs 43). The largest shared DEG sets were observed in Msmeg. Formal interaction models identified nominal subgroup-dependent infection-response signals, but no genes passed FDR correction in any infection × sex or infection × ethnicity model.
This exploratory secondary analysis suggests that human macrophage transcriptomic responses to mycobacterial infection vary by pathogen identity and show descriptive differences across sex and self-reported ethnicity strata. Because no genes passed FDR correction in the formal interaction models, these subgroup patterns should be interpreted as hypothesis-generating rather than definitive evidence of sex- or ethnicity-specific transcriptional regulation. Larger, ancestry-informed and covariate-rich cohorts are required to validate these findings.

PMID:
42633832
Bibliographic data and abstract were imported from PubMed on 24 Aug 2026.

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