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Dynamic antibody responses to the Mycobacterium tuberculosis proteome.

ABSTRACT: Considerable effort has been directed toward controlling tuberculosis, which kills almost two million people yearly. High on the research agenda is the discovery of biomarkers of active tuberculosis (TB) for diagnosis and for monitoring treatment outcome. Rational biomarker discovery requires understanding host-pathogen interactions leading to biomarker expression. Here we report a systems immunology approach integrating clinical data and bacterial metabolic and regulatory information with high-throughput detection in human serum of antibodies to the entire Mycobacterium tuberculosis proteome. Sera from worldwide TB suspects recognized approximately 10% of the bacterial proteome. This result defines the M. tuberculosis immunoproteome, which is rich in membrane-associated and extracellular proteins. Additional analyses revealed that during active tuberculosis (i) antibody responses focused on an approximately 0.5% of the proteome enriched for extracellular proteins, (ii) relative target preference varied among patients, and (iii) responses correlated with bacillary burden. These results indicate that the B cell response tracks the evolution of infection and the pathogen burden and replicative state and suggest functions associated with B cell-rich foci seen in tuberculous lung granulomas. Our integrated proteome-scale approach is applicable to other chronic infections characterized by diverse antibody target recognition.

SUBMITTER: Kunnath-Velayudhan S

PROVIDER: S-EPMC2930474 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Dynamic antibody responses to the Mycobacterium tuberculosis proteome.

Kunnath-Velayudhan Shajo S Salamon Hugh H Wang Hui-Yun HY Davidow Amy L AL Molina Douglas M DM Huynh Vu T VT Cirillo Daniela M DM Michel Gerd G Talbot Elizabeth A EA Perkins Mark D MD Felgner Philip L PL Liang Xiaowu X Gennaro Maria L ML

Proceedings of the National Academy of Sciences of the United States of America 20100728 33

Considerable effort has been directed toward controlling tuberculosis, which kills almost two million people yearly. High on the research agenda is the discovery of biomarkers of active tuberculosis (TB) for diagnosis and for monitoring treatment outcome. Rational biomarker discovery requires understanding host-pathogen interactions leading to biomarker expression. Here we report a systems immunology approach integrating clinical data and bacterial metabolic and regulatory information with high- ...[more]

PMID: 20668240

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Project description:Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a global health burden. While M. tuberculosis is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that lead to differential disease across organs. Attention has focused on differences in T cell responses in the control of M. tuberculosis in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood-brain barrier, here we characterized the antibody profiles across the blood and brain compartments in TBM and determined whether M. tuberculosis-specific humoral immune responses differed between M. tuberculosis infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different M. tuberculosis antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n = 10) versus TBM (n = 60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4) and the capacity of M. tuberculosis-specific antibodies to bind to Fc receptors or C1q and to activate innate immune effector functions (complement and natural killer cell activation; monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against M. tuberculosis, characterized by an enrichment of M. tuberculosis-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited M. tuberculosis-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared with individuals with pulmonary TB, despite having lower IgG titres and Fcγ receptor-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs versus brain) and demonstrate a highly compartmentalized M. tuberculosis-specific antibody response within the CSF in TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease.

Project description:Human infection with Mycobacterium tuberculosis results in a continuum of ill-defined, clinical manifestations with stable latent M. tuberculosis infection (LTBI) and severe active disease at the ends. Identifying different states of infection is of importance to tuberculosis (TB) control since risk of developing active disease varies among different asymptomatic states while infectiousness varies among patients with different bacterial burden. We investigated changes in proteome-scale antibody responses during disease progression in a non-human primate model of tuberculosis. We probed M. tuberculosis proteome microarrays with serial sera collected from three infection-outcome groups (active, reactivation, and latent). We found that each infection outcome is associated with characteristic changes in the antibody levels and number of antigenic targets, which suggested an association between antibody responses and bacillary burden. Additional proteome-scale serological profiling of > 400 human TB suspects established that antibody responses are positively associated with bacterial load. Thus tuberculosis-specific antibody levels and number of antigenic targets increases with disease progression. Serum samples collected from adult patients with suspected tuberculosis during a multi-site study was used to probe whole proteome microarrays. Subject recruitment was conducted under uniform protocols approved by the institutional ethics committee at each site. Final diagnosis of active TB was based on positive M. tuberculosis culture results. The active TB patients were further subdivided into smear-positive and negative disease based on results of Ziehl-Neelsen staining of sputum smears for acid fast bacilli. Active TB was excluded as a diagnosis (Non-TB Disease [NTBD] patients) based on having negative M. tuberculosis culture and smear results and on having an alternate diagnosis. All subjects were presumably negative for HIV infection given the very low incidence of HIV infection in the study sites. Sera from 169 TB and 242 NTBD patients were selected for microarray probing. The control sera (n = 14) which was used to generate negative control distribution for each protein were negative to latent M. tuberculosis infection, as indicated by negative results to tuberculin skin test.

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Dynamic antibody responses to the Mycobacterium tuberculosis proteome.

Publications

Dynamic antibody responses to the Mycobacterium tuberculosis proteome.

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