Abstract
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.
Plain language summary
Tuberculosis (TB) is difficult to diagnose in children with HIV, yet they are at a high risk of contracting it. We analyzed gene expression in the blood of children living with HIV with and without TB in Uganda, Botswana, and Eswatini. We focused on transcripts with at least a fourfold increase in abundance in HIV-TB coinfection. While children from different regions had different gene expression, many were involved in similar cellular processes, such as certain parts of the innate immune system, with four of the six shared transcripts. Our findings highlight the conserved nature of the immune response and underscore the need for studies across different regions to better understand these infections in children.
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Data availability
All source data underlying the graphs and charts presented in the main text and Supplementary Information are available in Figshare under the title “CAfGEN RNA-seq count matrices and supporting processed data for ‘Conserved neutrophil degranulation transcripts in HIV-TB coinfected children across East and Southern Africa’” (https://doi.org/10.6084/m9.figshare.30551264). The RNA-seq datasets generated and analyzed during the current study are being deposited under the project name “CAfGEN RNA-seq Data” into the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/) in accordance with the H3Africa Consortium consensus agreement. Data deposition is being coordinated through H3ABioNet/AfriGen-D, the authorized H3Africa data submission center, in accordance with the NIH H3Africa Data Access and Release Policy. The datasets will become publicly discoverable on the EGA once accession identifiers are issued. Access will be controlled and granted only to bona fide researchers whose proposed use aligns with the participants’ informed consent, subject to approval by the H3Africa Data and Biospecimen Access Committee (DBAC). Requests for access should be submitted via the H3Africa data portal (https://www.h3abionet.org/resources/h3africa-archive). Until the accession number is available, qualified researchers may contact the corresponding author for information on the submission status or to initiate the access request process.
Code availability
Scripts used for data analysis are available at https://github.com/katagirya53.
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Acknowledgements
We would like to acknowledge Nasinghe Emmanuel, Gaseene Sebetso, Thembela Mavuso, Bheki Ntshangase, Buhle Dlamini, Abhilash Sathyamoorthi, Bathusi Mathuba, Yves Mafulu, Gerald Mboowa, Harriet Nakayiza, Edgar Kigozi, Fred Katabazi, Keboletse Mokete, Lesego Ketumile, Kennedy Sichone, Keofentse Mathuba, LeToya Balebetse, Muambi Muyaya, Nancy Zwane, Nicholas Muriithi, Sibongile Mumanga, Thabo Diphoko, Thobile Jele, and Thato Regonamanye. Finally, we acknowledge the families and children who participated in the study. The project described was supported by Award Number U54AI110398, administered by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), and the National Human Genome Research Institute (NHGRI), as part of the NIH Common Fund H3Africa Initiative. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number U01HD114479. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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E.K., B.M., S.K., M.W., G.M., A.K., B.N., M.M., G.A., I.K., S.W.M., M.L.J., C.B., G.M.#, and N.H.: conceptualization, writing–review and editing, funding acquisition, investigation, and project administration. E.K., S.K., S.M., M.W., M.A., J.M., A.M., B.N., G.R., B.M., L.W., and K.M.: data curation. E.K., S.K., S.M., and N.H.: formal analysis. G.M., N.H., S.K., M.L.J., D.P.K., C.B., D.K., G.A.: funding acquisition. E.K., S.K., G.K., G.R., B.N., M.M., C.B., G.M., and N.H.: methodology. SK, GK, MD: project administration. G.M., N.H., M.L.J., and E.M.W.: supervision. E.K., S.K., S.M., G.M., M.A., F.A.R., D.K., and N.H.: validation and writing–original draft. The CAfGEN Consortium coordinated participant recruitment, sample processing, and sequencing, and contributed to data curation and quality control. All authors contributed to the article and approved the submitted version. GM = Graeme Mardon and GM# = Gerald Mboowa
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Gerald Mboowa is an Editorial Board Member for Communications Medicine but was not involved in the editorial review or peer review, nor in the decision to publish this article.
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Katagirya, E., Mlotshwa, B., Kyobe, S. et al. Conserved neutrophil degranulation transcripts in HIV-TB coinfected children across East and Southern Africa. Commun Med (2026). https://doi.org/10.1038/s43856-025-01284-w
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DOI: https://doi.org/10.1038/s43856-025-01284-w
