4.8 Article

Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1711853115

Keywords

tuberculosis; HIV; complement; immune complex; incipient disease

Funding

  1. Wellcome Trust [090170, 203135, 104803, FC00110218]
  2. Bill and Melinda Gates Foundation/Wellcome Trust Grand Challenges in Global Health [37822]
  3. NIH/National Institute of Allergy and Infectious Diseases
  4. NIH [R01 HL106804]
  5. Francis Crick Institute - Cancer Research UK [FC00110218]
  6. UK Medical Research Council [FC00110218]
  7. European Union [HEALTH F3-2012-305578]
  8. National Research Foundation of South Africa [96841]
  9. Medical Research Council of South Africa [SHIP-02-2013]
  10. Francis Crick Institute
  11. NIH TB Research Unit [1U19AI111276]
  12. MRC [MC_U117565642, MC_U117588499] Funding Source: UKRI
  13. Cancer Research UK
  14. The Francis Crick Institute [10126] Funding Source: researchfish
  15. Medical Research Council [MC_U117565642, MC_U117588499, 1365570, 1105853] Funding Source: researchfish
  16. The Francis Crick Institute [10218, 10002] Funding Source: researchfish
  17. Wellcome Trust [104803/Z/14/Z] Funding Source: researchfish

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The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better understanding of the early events in subclinical disease will facilitate the development of diagnostics and interventions that improve TB control. This is particularly relevant in the context of HIV-1 coinfection where progression of TB is more likely. In a recent study using [F-18]-fluoro-2-deoxy-D-glucose positron emission/computed tomography (FDG-PET/CT) on 35 asymptomatic, HIV-1-infected adults, we identified 10 participants with radiographic evidence of subclinical disease, significantly more likely to progress than the 25 participants without. To gain insight into the biological events in early disease, we performed blood-based whole genome transcriptomic analysis on these participants and 15 active patients with TB. We found transcripts representing the classical complement pathway and Fc gamma receptor 1 overabundant from subclinical stages of disease. Levels of circulating immune (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript abundance. To validate our findings, we analyzed transcriptomic data from a publicly available dataset where samples were available in the 2 y before TB disease presentation. Transcripts representing the classical complement pathway and Fc gamma receptor 1 were also differentially expressed in the 12 mo before disease presentation. Our results indicate that levels of antibody/antigen complexes increase early in disease, associated with increased gene expression of C1q and Fc gamma receptors that bind them. Understanding the role this plays in disease progression may facilitate development of interventions that prevent this, leading to a more favorable outcome and may also be important to diagnostic development.

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