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

Authors
  • Esmail, Hanif1, 2, 3, 4
  • Lai, Rachel P5
  • Lesosky, Maia2, 3, 6
  • Wilkinson, Katalin A2, 3, 5
  • Graham, Christine M7
  • Horswell, Stuart5
  • Coussens, Anna K2, 3, 8
  • Barry, Clifton E 3rd2, 3, 9, 10, 11
  • O'Garra, Anne7, 12
  • Wilkinson, Robert J1, 2, 3, 5
  • 1 Department of Medicine, Imperial College London, London W2 1PG, United Kingdom; [email protected] [email protected] , (United Kingdom)
  • 2 Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, Republic of South Africa. , (South Africa)
  • 3 Department of Medicine, University of Cape Town, Cape Town 7925, Republic of South Africa. , (South Africa)
  • 4 Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom. , (United Kingdom)
  • 5 The Francis Crick Institute, London NW1 2AT, United Kingdom. , (United Kingdom)
  • 6 Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town 7925, Republic of South Africa. , (South Africa)
  • 7 The Francis Crick Institute, Laboratory of Immunoregulation and Infection, London NW1 2AT, United Kingdom. , (United Kingdom)
  • 8 Division of Medical Microbiology, Department of Pathology, University of Cape Town, Cape Town 7925, Republic of South Africa. , (South Africa)
  • 9 Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, Republic of South Africa. , (South Africa)
  • 10 Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
  • 11 Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town 7925, Republic of South Africa. , (South Africa)
  • 12 National Heart and Lung Institute, Imperial College London, London W2 1PJ, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Jan 30, 2018
Volume
115
Issue
5
Identifiers
DOI: 10.1073/pnas.1711853115
PMID: 29339504
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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 [18F]-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 Fcγ 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 Fcγ 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 Fcγ 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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