Detection of urine lipoarabinomannan is associated with proinflammatory innate immune activation, impaired host defense, and organ dysfunction in adults with severe HIV-associated tuberculosis in Uganda

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dc.contributor.authorMatthew, J. Cummings
dc.contributor.authorBakamutumaho, Barnabas
dc.contributor.authorKomal, Jain
dc.contributor.authorAdam Price
dc.contributor.authorOwor, Nicholas
dc.contributor.authorKayiwa, John
dc.contributor.authorNamulondo, Joyce
dc.contributor.authorByaruhanga, Timothy
dc.contributor.authorMuwanga, Moses
dc.contributor.authorNsereko, Christopher
dc.contributor.authorNayiga, Irene
dc.contributor.authorKyebambe, Stephen
dc.contributor.authorXiaoyu, Che
dc.contributor.authorStephen, Sameroff
dc.contributor.authorRafal, Tokarz
dc.contributor.authorWai, Wong
dc.contributor.authorThomas, S. Postler
dc.contributor.authorMichelle, H. Larsen
dc.contributor.authorW. Ian, Lipkin
dc.contributor.authorLutwama, Julius J.
dc.contributor.authorMax, R. O’Donnell
dc.date.accessioned2025-03-03T17:07:18Z
dc.date.available2025-03-03T17:07:18Z
dc.date.issued2023
dc.description.abstractBackground: The immunopathology of disseminated HIV-associated tuberculosis (HIV/TB), a leading cause of critical illness and death among persons living with HIV in sub-Saharan Africa, is incompletely understood. Reflective of hematogenously disseminated TB, detection of lipoarabinomannan (LAM) in urine is associated with greater bacillary burden and poor outcomes in adults with HIV/TB. Methods: We determined the relationship between detection of urine TB-LAM, organ dysfunction, and host immune responses in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. Generalized additive models were used to analyze the association between urine TB-LAM grade and concentrations of 14 soluble immune mediators. Whole-blood RNA-sequencing data were used to compare transcriptional profiles between patients with high- vs. low-grade TB-LAM results. Results: Among 157 hospitalized persons living with HIV, 40 (25.5%) had positive urine TB-LAM testing. Higher TB-LAM grade was associated with more severe physiologic derangement, organ dysfunction, and shock. Adjusted generalized additive models showed that higher TB-LAM grade was significantly associated with higher concentrations of mediators reflecting proinflammatory innate and T-cell activation and chemotaxis (IL-8, MIF, MIP-1β/CCL4, and sIL-2Ra/sCD25). Transcriptionally, patients with higher TB-LAM grades demonstrated multifaceted impairment of antibacterial defense including reduced expression of genes encoding cytotoxic and autophagy-related proteins and impaired cross-talk between innate and cell-mediated immune effectors. Conclusions: Our findings add to emerging data suggesting pathobiological relationships between LAM, TB dissemination, innate cell activation, and evasion of host immunity in severe HIV/TB. Further translational studies are needed to elucidate the role for immunomodulatory therapies, in addition to optimized anti-TB treatment, in this often critically ill population.
dc.identifier.citationCummings, M. J., Bakamutumaho, B., Jain, K., Price, A., Owor, N., Kayiwa, J., ... & O'Donnell, M. R. (2023). Brief Report: Detection of Urine Lipoarabinomannan Is Associated With Proinflammatory Innate Immune Activation, Impaired Host Defense, and Organ Dysfunction in Adults With Severe HIV-Associated Tuberculosis in Uganda. JAIDS Journal of Acquired Immune Deficiency Syndromes, 93(1), 79-85. doi:10.1097/QAI.0000000000003159.
dc.identifier.other10.1097/QAI.0000000000003159.
dc.identifier.urihttps://nru.uncst.go.ug/handle/123456789/10032
dc.language.isoen
dc.publisherJAIDS Journal of Acquired Immune Deficiency Syndromes
dc.titleDetection of urine lipoarabinomannan is associated with proinflammatory innate immune activation, impaired host defense, and organ dysfunction in adults with severe HIV-associated tuberculosis in Uganda
dc.typeArticle
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