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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Eric Katagirya,
  • Busisiwe Mlotshwa,
  • Samuel Kyobe,
  • Savannah Mwesigwa,
  • Gaone Retshabile,
  • Lesedi Williams,
  • Marion Amujal,
  • John Mukisa,
  • Gerald Mboowa,
  • David P. Kateete,
  • Misaki Wayengera,
  • Sununguko Wata Mpoloka,
  • Angella N. Mirembe,
  • Ishmael Kasvosve,
  • Koketso Morapedi,
  • Makhosazana Dlamini,
  • Betty Nsangi,
  • Grace P. Kisitu,
  • Adeodata R. Kekitiinwa,
  • Gabriel Anabwani,
  • Moses L. Joloba,
  • Eddie Mujjwiga Wampande,
  • Dithan Kiragga,
  • Florence Anabwani-Richter,
  • Chester W. Brown,
  • Graeme Mardon,
  • Neil A. Hanchard,
  • Mogomotsi Matshaba,
  • Masego Tsimako- Johnstone,
  • Keofentse Mathuba

摘要

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.