Conserved neutrophil degranulation transcripts in HIV-TB coinfected children across East and Southern Africa.

BACKGROUND: HIV-tuberculosis (HIV-TB) coinfection poses a significant public health challenge among children in high-burden African regions. Most previous transcriptomic studies have concentrated on adults and non-African populations, primarily analyzing gene-level differential expression. This approach overlooks multi-isoform complexity and may obscure both inherent and pathogen-induced intragenic heterogeneity. This multi-center case-control study aimed to identify and characterize the transcript-level landscape of HIV-TB coinfection in children from different African regions.

METHODS: We analyzed whole-blood RNA sequencing data from 97 children with and without tuberculosis from Uganda (East Africa) and from Botswana and Eswatini (Southern Africa). Reads were quality-controlled, and low-abundance transcripts filtered out. Differential transcript expression was estimated using models that adjusted for batch, age, and sex, with multiple testing controlled by the Benjamini-Hochberg procedure. Pathway enrichment was performed on the set of differentially expressed transcripts.

RESULTS: Our analyses show geographic heterogeneity in immune responses; however, the top three gene pathways - immune system, innate immune system, and neutrophil degranulation are consistently conserved across regions. Although there is limited overlap among upregulated transcripts, four of the six shared differentially expressed transcripts (DETs) are enriched in neutrophil degranulation pathways, indicating a conserved transcriptional signature of HIV-TB coinfection. Additionally, we identify five genes with region-specific, non-overlapping isoforms, a distinction not detectable through gene-level analysis.

CONCLUSIONS: These findings demonstrate a conserved whole-blood transcriptomic signature in pediatric HIV-TB coinfection, while also highlighting regional variation at the isoform level. This supports the use of transcript-level analyses to identify biomarkers and enhance understanding of host responses in diverse African settings.