medRxiv : the preprint server for health sciences · 2026
Proteomic Immune Signatures of Severe HIV-Associated Tuberculosis in Sub-Saharan Africa: A Prospective, Multicenter Analysis from Uganda.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Ross Jesse E, Tomoiaga Alin S, Owor Nicholas, Lu Xuan, Shinyale Joseph, Kiyingi Tonny, Asasira Ignatius, Eliku Peter James, Nsubuga John Bosco, Nsereko Christopher, Nayiga Irene, Kyebambe Stephen, Ochar Thomas, Kiwubeyi Moses, Nankwanga Rittah, Nie Kai, Xie Hui, Miake-Lye Sam, Villagomez Bryan, Qi Jingjing, Reynolds Steven J, Nakibuuka Martina Cathy, Kayiwa John, Haumba Mercy, Nakaseegu Joweria, Che Xiaoyu, Hoffman Risa, Belperio John A, Lutwama Julius J, Kim-Schulze Seunghee, O'Donnell Max R, Bakamutumaho Barnabas, Cummings Matthew J
Аннотация
OBJECTIVE: Severe tuberculosis (TB) is a major cause of critical illness and death in people living with HIV (PLWH) worldwide. Despite this, the immunopathology of severe HIV-associated TB (HIV/TB) is poorly understood. We aimed to identify an immunopathologic signature of severe HIV/TB in sub-Saharan Africa.
DESIGN AND SETTING: We analyzed proteomic data from two prospective observational cohorts of adults hospitalized with severe undifferentiated infection in Uganda: an urban discovery cohort (Entebbe, N=241) and a rural validation cohort (Tororo, N=253).
PATIENTS: Adults (age ≥18 years) hospitalized with severe febrile illness.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Across both cohorts, severe HIV-associated TB was common, affecting 18% of participants in the discovery cohort and 21% in the validation cohort. Overall mortality was significant (30-day mortality of 22% in the discovery cohort & 60-day mortality of 26% in the validation cohort). Participants were stratified into three HIV/TB phenotypes: HIV-negative without TB, PLWH without TB, and PLWH with microbiologically diagnosed TB. We applied ordinal random forest models in the discovery cohort to identify proteins strongly predictive of progressive HIV/TB phenotype. In both cohorts, PLWH with microbiologically diagnosed TB were at highest risk of critical illness and death (30-day mortality of 42% in the discovery cohort & 60-day mortality of 52% in the validation cohort). An eight-protein signature reliably distinguished this phenotype, reflecting mediators of macrophage/dendritic cell activation (LAMP3), NK- and T-cell stimulation and cytotoxicity (CD70, CRTAM), B-cell activation (IGLC2), protease-mediated tissue injury (PRSS2), dysregulated coagulation (SERPINA5), extracellular matrix remodeling (EFEMP1), and GH/IGF axis dysregulation (IGFBP3).
CONCLUSIONS: We identified an immunologic signature of severe HIV-associated TB defined by mediators of macrophage/dendritic cell and cytotoxic lymphocyte activation, extracellular matrix remodeling, and dysregulated coagulation. These findings offer new insight into HIV/TB pathobiology and highlight potential targets for host-directed therapies in this high-risk population.
KEY POINTS: Question: What host-response patterns characterize severe HIV-associated tuberculosis among adults hospitalized with severe febrile illness in sub-Saharan Africa?Findings: In two prospective cohorts of adults hospitalized with severe febrile illness in Uganda, severe HIV-associated tuberculosis accounted for 18-21% of cases and was associated with higher rates of physiological instability and mortality. An eight-protein host-response signature reproducibly distinguished this high-risk phenotype, reflecting immune activation, tissue injury, extracellular matrix remodeling, and dysregulated coagulation.Meaning: Severe HIV-associated tuberculosis is associated with a distinct, high-risk clinical phenotype characterized by reproducible host-response patterns that may inform risk stratification and host-directed therapeutic strategies.
DESIGN AND SETTING: We analyzed proteomic data from two prospective observational cohorts of adults hospitalized with severe undifferentiated infection in Uganda: an urban discovery cohort (Entebbe, N=241) and a rural validation cohort (Tororo, N=253).
PATIENTS: Adults (age ≥18 years) hospitalized with severe febrile illness.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Across both cohorts, severe HIV-associated TB was common, affecting 18% of participants in the discovery cohort and 21% in the validation cohort. Overall mortality was significant (30-day mortality of 22% in the discovery cohort & 60-day mortality of 26% in the validation cohort). Participants were stratified into three HIV/TB phenotypes: HIV-negative without TB, PLWH without TB, and PLWH with microbiologically diagnosed TB. We applied ordinal random forest models in the discovery cohort to identify proteins strongly predictive of progressive HIV/TB phenotype. In both cohorts, PLWH with microbiologically diagnosed TB were at highest risk of critical illness and death (30-day mortality of 42% in the discovery cohort & 60-day mortality of 52% in the validation cohort). An eight-protein signature reliably distinguished this phenotype, reflecting mediators of macrophage/dendritic cell activation (LAMP3), NK- and T-cell stimulation and cytotoxicity (CD70, CRTAM), B-cell activation (IGLC2), protease-mediated tissue injury (PRSS2), dysregulated coagulation (SERPINA5), extracellular matrix remodeling (EFEMP1), and GH/IGF axis dysregulation (IGFBP3).
CONCLUSIONS: We identified an immunologic signature of severe HIV-associated TB defined by mediators of macrophage/dendritic cell and cytotoxic lymphocyte activation, extracellular matrix remodeling, and dysregulated coagulation. These findings offer new insight into HIV/TB pathobiology and highlight potential targets for host-directed therapies in this high-risk population.
KEY POINTS: Question: What host-response patterns characterize severe HIV-associated tuberculosis among adults hospitalized with severe febrile illness in sub-Saharan Africa?Findings: In two prospective cohorts of adults hospitalized with severe febrile illness in Uganda, severe HIV-associated tuberculosis accounted for 18-21% of cases and was associated with higher rates of physiological instability and mortality. An eight-protein host-response signature reproducibly distinguished this high-risk phenotype, reflecting immune activation, tissue injury, extracellular matrix remodeling, and dysregulated coagulation.Meaning: Severe HIV-associated tuberculosis is associated with a distinct, high-risk clinical phenotype characterized by reproducible host-response patterns that may inform risk stratification and host-directed therapeutic strategies.