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PreprintCC BYbioRxiv

Distinct transcriptional remodeling of immune and metabolic pathways in severe undernutrition during latent tuberculosis infection does not consistently predict tuberculosis progression across independent cohorts

  • Reuben S. Maghembe1,2,3
  • Vesla I. Kullaya4,5
  • Peter M. Mbelele2,6
  • Ritah Francis Mutagonda7
  • Samweli Bahati8
  • Kennedy M. Ngowi4
  • Lydia Nakiyingi9,10,11
  • Megan Null3
  • Jon M. Jacobs12
  • William Evan Johnson13
  • Pranay Sinha14
  • Scott K. Heysell3
2 more authors
  • Stellah George Mpagama2
  • Sana Syed15,16
16 affiliations
  1. 1Department of Microbiology and Parasitology, Faculty of Medicine, St. Francis University College of Health and Allied Sciences (SFUCHAS), Ifakara, Tanzania.
  2. 2Kibong'oto Infectious Diseases Hospital (KIDH), Kilimanjaro, Tanzania.
  3. 3Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  4. 4Kilimanjaro Clinical Research Institute (KCRI), Kilimanjaro Christian Medical Centre (KCMC), Moshi, Tanzania.
  5. 5Department of Medical Biochemistry and Molecular Biology, KCMC University, Moshi, Tanzania.
  6. 6Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
  7. 7Department of Clinical Pharmacy and Pharmacology, School of Pharmacy, Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam, Tanzania.
  8. 8Department of Omics and Computational Biology, AfroBiomics Co. Ltd., Bridge Street, Kivukoni, Dar es Salaam, Tanzania.
  9. 9Department of Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
  10. 10Makerere University Biomedical Research Centre, Makerere University College of Health Sciences, Kampala, Uganda.
  11. 11Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
  12. 12Environmental Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
  13. 13Section of Computational Biomedicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
  14. 14Section of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
  15. 15Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
  16. 16Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.
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Abstract

Background: Undernutrition increases tuberculosis (TB) risk, but whether severe undernutrition during latent TB infection (LTBI) produces blood transcriptional changes that resemble active disease or identify future TB remains unclear. Methods: We reanalyzed whole-blood RNA sequencing from adults with LTBI in GSE152218, comparing severe undernutrition (BMI <16 kg/m2; n=16) with adequate nutrition (BMI >=18.5 kg/m2; n=11). Genes and Reactome pathways were evaluated. A seven-module summary was compared with active TB among severely undernourished adults and tested prospectively in GSE79362 and GC6-74/GSE94438 after pathway-representation assessment. Results: No genes reached FDR <0.05 in the primary model; two did only in sensitivity analysis. In contrast, 241 Reactome pathways were significant and directionally concordant in both models (NES rho=0.954), including complement/Fc-receptor, B-cell, phospholipid/phagocytosis, neutrophil, vascular, autophagy, and cytokine-signaling pathways. Most changed opposite to the active-TB comparison (178/241; pathway rho=-0.390). The seven-module score was unrelated to baseline progression in GSE79362 (adjusted OR per SD=1.090; P=0.6922). In GC6, four modules met the prespecified representation criterion; their baseline score was inversely associated with progression (adjusted OR per SD=0.711; P=0.0218), but secondary and longitudinal analyses were non-confirmatory. Conclusions: Severe undernutrition during LTBI is associated with reproducible immune- and metabolism-related transcriptional remodeling that differs from active-TB biology and does not consistently identify future TB progression.

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Cite

BibTeXRIS
BibTeX
@misc{maghembe2026distinct,
  title = {{Distinct transcriptional remodeling of immune and metabolic pathways in severe undernutrition during latent tuberculosis infection does not consistently predict tuberculosis progression across independent cohorts}},
  author = {Reuben S. Maghembe and Vesla I. Kullaya and Peter M. Mbelele and Ritah Francis Mutagonda and Samweli Bahati and Kennedy M. Ngowi and Lydia Nakiyingi and Megan Null and Jon M. Jacobs and William Evan Johnson and Pranay Sinha and Scott K. Heysell and Stellah George Mpagama and Sana Syed},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.26.756475},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.26.756475v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Distinct transcriptional remodeling of immune and metabolic pathways in severe undernutrition during latent tuberculosis infection does not consistently predict tuberculosis progression across independent cohorts
AU  - Reuben S. Maghembe
AU  - Vesla I. Kullaya
AU  - Peter M. Mbelele
AU  - Ritah Francis Mutagonda
AU  - Samweli Bahati
AU  - Kennedy M. Ngowi
AU  - Lydia Nakiyingi
AU  - Megan Null
AU  - Jon M. Jacobs
AU  - William Evan Johnson
AU  - Pranay Sinha
AU  - Scott K. Heysell
AU  - Stellah George Mpagama
AU  - Sana Syed
PY  - 2026
DA  - 2026/10/26
PB  - bioRxiv
DO  - 10.64898/2026.10.26.756475
UR  - https://www.biorxiv.org/content/10.64898/2026.10.26.756475v1
AB  - Background: Undernutrition increases tuberculosis (TB) risk, but whether severe undernutrition during latent TB infection (LTBI) produces blood transcriptional changes that resemble active disease or identify future TB remains unclear. Methods: We reanalyzed whole-blood RNA sequencing from adults with LTBI in GSE152218, comparing severe undernutrition (BMI <16 kg/m2; n=16) with adequate nutrition (BMI >=18.5 kg/m2; n=11). Genes and Reactome pathways were evaluated. A seven-module summary was compared with active TB among severely undernourished adults and tested prospectively in GSE79362 and GC6-74/GSE94438 after pathway-representation assessment. Results: No genes reached FDR <0.05 in the primary model; two did only in sensitivity analysis. In contrast, 241 Reactome pathways were significant and directionally concordant in both models (NES rho=0.954), including complement/Fc-receptor, B-cell, phospholipid/phagocytosis, neutrophil, vascular, autophagy, and cytokine-signaling pathways. Most changed opposite to the active-TB comparison (178/241; pathway rho=-0.390). The seven-module score was unrelated to baseline progression in GSE79362 (adjusted OR per SD=1.090; P=0.6922). In GC6, four modules met the prespecified representation criterion; their baseline score was inversely associated with progression (adjusted OR per SD=0.711; P=0.0218), but secondary and longitudinal analyses were non-confirmatory. Conclusions: Severe undernutrition during LTBI is associated with reproducible immune- and metabolism-related transcriptional remodeling that differs from active-TB biology and does not consistently identify future TB progression.
SN  - 2692-8205
ER  -