Combined Use of Serum and Urinary Antibody for Diagnosis of Tuberculosis

Singh, Krishna K.; Dong, Yuxin; Hinds, Laura R.; Keen, Marc A.; Belisle, John T.; Zolla‐Pazner, Susan; Achkar, Jacqueline M.; Nádas, Arthur; Arora, Vijay K.; Laal, Suman

doi:10.1086/376532

Cited by 30 publications

(29 citation statements)

References 29 publications

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“…Malate synthase (81 kDa), present in M. tuberculosis culture filtrates, the cell wall, and cytoplasmic subcellular fractions, is an enzyme of the glyoxylate pathway used by M. tuberculosis during intracellular replication in macrophages (90) and has adapted to function as an adhesin that enhances bacterial adherence to host cells (46). In sputum smear-positive patients, malate synthase achieved a sensitivity of 73% (95% CI, 58 to 85) and a specificity of 98% (95% CI, 95 to 100) (35,37,85,86,108). The likelihood ratio positive (40.78) was considerably higher for malate synthase than for other antigens.…”

Section: Resultsmentioning

confidence: 99%

Performance of Purified Antigens for Serodiagnosis of Pulmonary Tuberculosis: a Meta-Analysis

Steingart

Dendukuri

Henry

et al. 2009

Clin Vaccine Immunol

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170

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The failure to diagnose tuberculosis (TB) accurately and rapidly is a key challenge in curbing the epidemic (45,88,116). Sputum microscopy, currently the sole diagnostic test in most areas where TB is endemic, has several limitations; in particular, the sensitivity compared with that of culture is variable (80,97,104,116), multiple patient visits are required (56,93,114), considerable technical training is necessary, and the procedure is labor-intensive (45, 65). Antibody detection tests (serological tests) are used for the diagnosis of many infectious diseases and could potentially improve the means of diagnosis of TB. These tests measure the presence of specific antibodies (most often immunoglobulin G [IgG]) directed against immunodominant antigens of the pathogen in question. Compared with microscopy, antibody detection methods may enable the rapid diagnosis of TB, as these tests have the advantages of speed (results can be available within hours), technological simplicity, and minimal training requirements. In addition, these tests can be adapted to point-of-care formats that can be implemented at lower levels of health services in low-and middle-income countries (21,22,57,65).Efforts to develop antibody detection tests for the diagnosis of TB have been under way for decades, and the performance of these tests has been well described (13,17,22,32,40,47,48,52,60,64,100,107). Several systematic reviews of these tests have been published (discussed below) (28,94,95).First-generation antibody detection tests were based on crude mixtures of constituents and products of Mycobacterium tuberculosis, for example, culture filtrate proteins and purified protein derivative, the preparation used in the tuberculin skin test. Several of these early tests had low specificities, as the tests contained antigens shared among different bacterial species (1,22,48,57). During the past two decades, an increased understanding of humoral immune responses to M. tuberculosis and the new tools of

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Section: Resultsmentioning

confidence: 99%

Performance of Purified Antigens for Serodiagnosis of Pulmonary Tuberculosis: a Meta-Analysis

Steingart

Dendukuri

Henry

et al. 2009

Clin Vaccine Immunol

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170

137

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“…Our systematic studies of humoral responses in TB patients have identified a panel of potential candidates for devising a rapid POC test for TB, and immunodominant epitopes of some of these highly immunogenic M. tuberculosis antigens have been delineated (11,34,36,39,43,44). Since combinations of multiple antigens provide an increased sensitivity of antibody detection (11,15,17,42,53), it is likely that combinations of immunodominant epitopes from multiple highly immunogenic proteins of M. tuberculosis will enable the development of a peptide-based rapid test for TB. One or more of the six epitopes of LipC defined in these studies could make significant contributions to such a diagnostic test.…”

Section: Discussionmentioning

confidence: 99%

LipC (Rv0220) Is an Immunogenic Cell Surface Esterase of Mycobacterium tuberculosis

et al. 2012

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We have reported previously the identification of novel proteins of Mycobacterium tuberculosis by the immunoscreening of an expression library of M. tuberculosis genomic DNA with sera obtained from M. tuberculosis-infected rabbits at 5 weeks postinfection. In this study, we report the further characterization of one of these antigens, LipC (Rv0220). LipC is annotated as a member of the Lip family based on the presence of the consensus motif "GXSXG" characteristic of esterases. Although predicted to be a cytoplasmic enzyme, we provide evidence that LipC is a cell surface protein that is present in both the cell wall and the capsule of M. tuberculosis. Consistent with this localization, LipC elicits strong humoral immune responses in both HIV-negative (HIV ؊ ) and HIV-positive (HIV ؉ ) tuberculosis (TB) patients. The absence of anti-LipC antibodies in sera from purified protein derivative-positive (PPD ؉ ) healthy subjects confirms its expression only during active M. tuberculosis infection. Epitope mapping of LipC identified 6 immunodominant epitopes, 5 of which map to the exposed surface of the modeled LipC protein. The recombinant LipC (rLipC) protein also elicits proinflammatory cytokine and chemokine responses from macrophages and pulmonary epithelial cells. rLipC can hydrolyze short-chain esters with the carbon chain containing 2 to 10 carbon atoms. Together, these studies demonstrate that LipC is a novel cell surface-associated esterase of M. tuberculosis that is highly immunogenic and elicits both antibodies and cytokines/chemokines. There are an estimated 9 ϫ 10 6 new cases of tuberculosis (TB) and 2 ϫ10 6 TB-related deaths every year (55). Infection with Mycobacterium tuberculosis is initiated with the inhalation of a droplet bearing bacteria, and it takes months or years to progress to clinical TB. During this progression from initial infection to clinical disease, the in vivo bacteria adapt to continuously changing environments by altering their gene expressions (31,34,48,50). Previous studies to delineate culture filtrate (CF) proteins of M. tuberculosis that are recognized by antibodies during the natural course of disease progression demonstrated that the repertoire of antigens enlarges with the progression of infection (34)(35)(36)41). Interestingly, several of the M. tuberculosis antigens (malate synthase, MPT51, and ESAT6, for example) that elicit immune responses during the early stages of active infection have also been demonstrated to play important roles in the host-pathogen interaction (19-21, 57).To identify additional antigenic proteins of M. tuberculosis that are expressed during the early stages of active infection, we used sera obtained from M. tuberculosis aerosol-infected rabbits that were bled at 4 to 5 weeks postinfection to screen an expression library of M. tuberculosis genomic DNA (44). Antibodies in these sera identified several proteins known to contribute to the infection and survival of M. tuberculosis (exported repetitive protein [ERP], KatG, and MtrA) as well as novel prote...

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“…Reactivity of guinea pig or human sera with LFCFP or lysates of E. coli expressing His-tagged PPE-C protein or purified His-PPE-C protein was tested by Western blotting as described previously (44). Briefly, LFCFP, lysates of E. coli expressing the PPE-C protein, appropriate control lysates, or purified PPE-C protein was fractionated on 10% SDS-polyacrylamide gels under reducing conditions, and the Western blots were probed with anti-His monoclonal antibody (MAb) or E. coli lysate-absorbed sera from guinea pigs or humans (1:100) (23).…”

Section: Methodsmentioning

confidence: 99%

Immunogenicity of the Mycobacterium tuberculosis PPE55 (Rv3347c) Protein during Incipient and Clinical Tuberculosis

et al. 2005

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Approximately 5 to 10% of individuals who get infected with Mycobacterium tuberculosis progress to clinical tuberculosis (TB), whereas the remaining individuals develop a latent infection with the organism. Another 5 to 10% of these latently infected individuals reactivate their infection and progress to clinical TB during subsequent years/decades. In either case, active infection with M. tuberculosis is identified only when progression to bacteriologically detectable disease occurs. Thus, clinical TB, whether noncavitary paucibacillary or cavitary multibacillary disease, represents the late stages of a chronic disease process.Our studies of humoral immune responses elicited by M. tuberculosis at different stages of infection and disease progression have shown that the profile of antigenic proteins expressed by the in vivo bacteria that elicit antibodies correlates with the stage of the infection (21-23, 35-37, 45). Thus, purified-protein derivative-positive (PPD ϩ ) healthy individuals have antibodies to only a small subset (4-6) of the Ͼ100 culture filtrate proteins (CFP) of M. tuberculosis. In contrast, patients with noncavitary paucibacillary TB have antibodies directed against ϳ10 to 12 additional CFP antigens (35). As the disease progresses to the development of cavitary lesions, besides the presence of antibodies to the above-mentioned antigens, antibodies to an additional ϳ10 to 12 antigens appear. These results provide evidence that as M. tuberculosis adapts to different in vivo environments, the profile of antigenic proteins that are expressed changes. Evidence for adaptation by M. tuberculosis to different environmental conditions by altering gene/protein expression has also come from several other labs (3,11,12,29,32,41,42,47,49).M. tuberculosis is a slowly growing organism, and it takes weeks to months for the infection to progress to primary clinical TB. The time that elapses between the initiation of reactivation of latent infection and the manifestation of clinical TB is not known. The goal of the current studies was to identify antigenic proteins that are expressed during the asymptomatic, subclinical stages of infection when the in vivo M. tuberculosis bacilli replicate actively but the infection has not progressed to clinically identifiable disease (incipient, subclinical TB). Insight into these antigenic proteins will aid understanding of the host-pathogen interactions that lead to the progression of infection to clinical disease, and modulation of these host-pathogen interactions could potentially alter the outcome of infection. Moreover, antigenic proteins expressed during subclinical stages of active infection would also be useful for devising diagnostic markers that can differentiate between truly latent TB that is unlikely to progress to clinical disease and incipient, subclinical TB.

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Combined Use of Serum and Urinary Antibody for Diagnosis of Tuberculosis

Cited by 30 publications

References 29 publications

Performance of Purified Antigens for Serodiagnosis of Pulmonary Tuberculosis: a Meta-Analysis

Performance of Purified Antigens for Serodiagnosis of Pulmonary Tuberculosis: a Meta-Analysis

LipC (Rv0220) Is an Immunogenic Cell Surface Esterase of Mycobacterium tuberculosis

Immunogenicity of the Mycobacterium tuberculosis PPE55 (Rv3347c) Protein during Incipient and Clinical Tuberculosis

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