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

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Title: Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis
Authors: Esmail, H
Lai, R
Lesosky, M
Wilkinson, K
Graham, C
Horswell, S
Coussens, A
Barry III, CE
O'Garra, A
Wilkinson, RJ
Item Type: Journal Article
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.
Issue Date: 30-Jan-2018
Date of Acceptance: 12-Dec-2017
URI: http://hdl.handle.net/10044/1/56430
DOI: 10.1073/pnas.1711853115
ISSN: 0027-8424
Publisher: National Academy of Sciences
Start Page: E964
End Page: E973
Journal / Book Title: Proceedings of the National Academy of Sciences
Volume: 115
Issue: 5
Copyright Statement: Published under the PNAS license.
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Funder's Grant Number: 090170/Z/09/Z
104803/Z/14/Z
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
tuberculosis
HIV
complement
immune complex
incipient disease
POST PRIMARY TUBERCULOSIS
MYCOBACTERIAL ANTIGENS
ANTIBODIES
PATHOGENESIS
SIGNATURE
CELLS
HIV
complement
immune complex
incipient disease
tuberculosis
Antibodies
Antigen-Antibody Complex
Cluster Analysis
Coinfection
Comorbidity
Complement System Proteins
Disease Progression
Fluorodeoxyglucose F18
HIV Infections
Humans
Interferons
Oligonucleotide Array Sequence Analysis
Positron Emission Tomography Computed Tomography
Signal Transduction
Transcription, Genetic
Transcriptional Activation
Transcriptome
Tuberculosis
Humans
Tuberculosis
HIV Infections
Disease Progression
Fluorodeoxyglucose F18
Interferons
Antibodies
Antigen-Antibody Complex
Oligonucleotide Array Sequence Analysis
Cluster Analysis
Comorbidity
Signal Transduction
Transcription, Genetic
Complement System Proteins
Transcriptional Activation
Transcriptome
Coinfection
Positron Emission Tomography Computed Tomography
Publication Status: Published
Online Publication Date: 2018-01-16
Appears in Collections:Department of Infectious Diseases
National Heart and Lung Institute
Faculty of Medicine