Detection of Active Tuberculosis Infection by T Cell Responses to Early‐Secreted Antigenic Target 6‐kDa Protein and Culture Filtrate Protein 10

Arend, Sandra M.; Andersen, Peter; Meijgaarden, Krista E. van; Skjøt, Rikke Louise Vinther; Subronto, Yanri Wijayanti; Dissel, Jaap T. van; Ottenhoff, Tom H. M.

doi:10.1086/315448

Cited by 186 publications

(139 citation statements)

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“…The very high specificity of the Rv3879c peptides and the non-cross-reactive sequences of Rv3873, together with their sensitivity of around 50% in culture-confirmed TB patients, identify these peptides as candidates for inclusion in a cocktail of peptides for a T-cell-based diagnostic test. T-cell responses to peptides spanning the lengths of ESAT-6 and CFP10 have been detected in 70 to 80% of TB patients by IFN-␥ ELISA and in around 90% of TB patients by IFN-␥ ELISPOT assay (3,4,6,26,28). We have identified peptides that may further enhance the sensitivity of T-cell-based assays with ESAT-6 and CFP10 without compromising specificity.…”

Section: Vol 72 2004 T-cell Responses To Novel M Tuberculosis Genementioning

confidence: 95%

“…Two of the low-molecular-mass potent T-cell antigens identified by Andersen and colleagues, early secretory antigen target 6 (ESAT-6) and culture filtrate protein 10 (CFP10), are encoded in RD1 (2, 10) and have been intensively investigated in animal models and humans over the last few years (4,7,15,16,26,30,32,33,36,40). Studies using several different assays, including lymphoproliferation, gamma interferon (IFN-␥) enzyme-linked immunosorbent assay (ELISA), and IFN-␥ enzyme-linked immunospot (ELISPOT) assay, have shown that they are strong targets of the cellular immune response in animal models, TB patients, and contacts (4,11,24,28,30,35,(37)(38)(39).…”

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confidence: 99%

“…Studies using several different assays, including lymphoproliferation, gamma interferon (IFN-␥) enzyme-linked immunosorbent assay (ELISA), and IFN-␥ enzyme-linked immunospot (ELISPOT) assay, have shown that they are strong targets of the cellular immune response in animal models, TB patients, and contacts (4,11,24,28,30,35,(37)(38)(39). However, we know very little about the remaining seven RD1 gene products.…”

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confidence: 99%

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Evaluation of T-Cell Responses to Novel RD1- and RD2-EncodedMycobacterium tuberculosisGene Products for Specific Detection of Human Tuberculosis Infection

et al. 2004

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The tuberculin skin test for diagnosing Mycobacterium tuberculosis infection suffers from antigenic crossreactivity of purified protein derivative with BCG, resulting in poor specificity in BCG-vaccinated populations. Comparative genomics has identified several genetic regions in M. tuberculosis and M. bovis that are deleted in M. bovis BCG. Proteins encoded in these regions will form the basis of new specific T-cell-based blood tests that do not cross-react with BCG, but only two, early secretory antigen target 6 and culture filtrate protein 10, have been studied in detail in humans. We investigated four novel gene products, encoded by RD2 (Rv1989c) and RD1 (Rv3873, Rv3878, and Rv3879c), that are absent from most or all of the vaccine strains of BCG, respectively. Sixty-seven overlapping peptides were tested in ex vivo gamma interferon enzyme-linked immunospot assays in 49 patients with culture-confirmed tuberculosis and 38 healthy BCG-vaccinated donors. Forty-five percent (95% confidence interval [CI], 31 to 57%) and 53% (95% CI, 39 to 67%) of the tuberculosis patients responded to Rv3879c and Rv3873, respectively, identifying these proteins as major M. tuberculosis T-cell antigens in humans, while 35 and 25% of the patients responded to Rv3878 and Rv1989c, respectively. Of the 38 BCG-vaccinated donors, 1 (2.6%) responded to peptides from Rv3878 and Rv3879c, 3 (7.9%) responded to Rv3873, and none responded to Rv1989c. Exclusion of cross-reactive peptides encoded in conserved motifs of Rv3873, a PPE family member, increased its specificity to 97.4%. The high specificity of Rv3879c peptides and nonconserved Rv3873 sequences, together with their moderate sensitivity in tuberculosis patients, identifies these peptides as candidates for inclusion in new T-cell-based tests for M. tuberculosis infection.Accurate diagnosis of tuberculosis (TB) infection is essential for the treatment, prevention, and control of this resurgent disease (1). Since Mycobacterium tuberculosis is often difficult to culture from patients with active TB, and impossible to culture from healthy latently infected people, an immunebased diagnostic test indicating the presence or absence of M. tuberculosis infection would be very useful for the diagnosis of active TB and screening for latent M. tuberculosis infection. The only widely used test is the century-old tuberculin skin test (TST), which has many drawbacks. Foremost among these is its poor specificity (21). This results from the broad antigenic cross-reactivity of purified protein derivative (PPD), a crude mixture of more than 200 M. tuberculosis proteins widely shared among M. tuberculosis, M. bovis Bacillus CalmetteGuérin (BCG), and most environmental mycobacteria (22). Hence, false-positive results are common in people with environmental mycobacterial exposure and previous BCG vaccination. Since most of the world's population is BCG vaccinated and since the confounding effect of BCG persists for up to 15 years after vaccination (41), this is a significant problem. Thus, there has been a...

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Section: Vol 72 2004 T-cell Responses To Novel M Tuberculosis Genementioning

confidence: 95%

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confidence: 99%

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confidence: 99%

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Evaluation of T-Cell Responses to Novel RD1- and RD2-EncodedMycobacterium tuberculosisGene Products for Specific Detection of Human Tuberculosis Infection

et al. 2004

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“…Both ESAT-6 and CFP-10 have shown great promise as immunodiagnostic reagents for TB in humans and cattle (2,5,39,44). It has been shown that combining M. tuberculosis ESAT-6 and CFP-10 in a diagnostic test for infection or exposure to TB could provide the level of specificity and sensitivity necessary to detect exposure to TB (2).…”

Section: Vol 72 2004 B-and T-cell Epitopes Of Cfp-10 3167mentioning

confidence: 99%

Comparative Analysis of B- and T-Cell Epitopes ofMycobacterium lepraeandMycobacterium tuberculosisCulture Filtrate Protein 10

et al. 2004

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Culture filtrate protein 10 (CFP-10) from Mycobacterium tuberculosis is a well-characterized immunodominant 10-kDa protein antigen known to elicit a very potent early gamma interferon response in T cells from M. tuberculosis-infected mice and humans. The sequence of the Mycobacterium leprae homologue of CFP-10 shows only 40% identity (60% homology) at the protein level with M. tuberculosis CFP-10 and thus has the potential for development as a T-or B-cell reactive antigen for specific diagnosis of leprosy. Antisera raised in mice or rabbits against recombinant M. leprae and M. tuberculosis CFP-10 proteins reacted only with homologous peptides from arrays of overlapping synthetic peptides, indicating that there was no detectable cross-reactivity at the antibody level. Sera from leprosy and tuberculosis patients were also specific for the homologous protein or peptides and showed distinct patterns of recognition for either M. leprae or M. tuberculosis CFP-10 peptides. At the cellular level, only 2 of 45 mouse T-cell hybridomas raised against either M. leprae or M. tuberculosis CFP-10 displayed a cross-reactive response against the N-terminal heterologous CFP-10 peptide, the region that exhibits the highest level of identity in the two proteins; however, the majority of peptide epitopes recognized by mouse T-cell hybridomas specific for each protein did not cross-react with heterologous peptides. Coupled with the human serology data, these results raise the possibility that peptides that could be used to differentiate infections caused by these two related microorganisms could be developed. Immunohistochemical staining of sections of M. leprae-infected nude mouse footpads resulted in strongly positive staining in macrophages and dendritic cells, as well as weaker staining in extracellular areas, suggesting that M. leprae CFP-10, like its homologue in M. tuberculosis, is a secreted protein.The number of cases of leprosy worldwide has been reduced dramatically through aggressive World Health Organizationsponsored multidrug therapy, from approximately 10 million cases in 1985 to a little fewer than 700,000 cases today (46-48). However, with the unabated emergence of more than 600,000 new cases per year, there is the possibility that the source of infection is not being addressed (16). The single greatest need in leprosy research is the development of definitive diagnostic tools that identify sources of leprosy and routes of transmission. The recent completion of the genome sequences of both Mycobacterium tuberculosis (8) and Mycobacterium leprae (9) provides an opportunity to identify leprosy-specific antigens that might serve this purpose. A similar comparative approach has allowed identification of genes in the RD1 region that are deleted from Mycobacterium bovis BCG but present in M. tuberculosis and can therefore distinguish between infection with M. tuberculosis and vaccination with BCG (22). Among the deleted antigens are two low-molecular-weight proteins, culture filtrate protein 10 (CFP-10) (Rv3874) and ESAT-6...

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“…In addition immunoreactive orthologs are not expressed in most NTM species (Sorensen et al, 1995;Harboe et al, 1996;Anderson et al, 2000). Several studies have reported that RD1-based (ESAT-6 and/or CFP-10) IFN-γ assays have higher specificity than TST, and are less influenced by previous BCG vaccination (Ravn et al, 1999;Arend et al, 2000;Brock et al, 2001;Mori et al, 2004;Pai et ai., 2004). Newer generation test kits using these two individual antigens have already been developed and reports of their utility are now beginning to emerge (Pai et ai., 2004;Ferrara et al, 2005;Kang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the diagnostic utility of a whole-blood interferon-γ assay for determining the risk of exposure to Mycobacterium tuberculosis in Bacille Calmette-Guerin (BCG)-vaccinated individuals

Eum

Lee

Kwak

et al. 2008

Diagnostic Microbiology and Infectious Disease

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We evaluated the utility of the "QuantiFERON®-TB Gold in tube" (QuantiFERON®) test that uses TB-specific antigens for the diagnosis of latent infection in such individuals. We also examined the correlation between the IFN-γ response to these antigens and the exposure risk to TB by evaluating antigen-specific IFN-γ release in comparison with IFN-γ release in response to PPD in three groups; medical students, nurses in a TB hospital, and TB patients. All nurses and TB patients responded to PPD whereas 79.2 % (p=0.04) and 52 % (p<0.0001) responded to QuantiFERON®, respectively. In the medical students, only 10.4 % responded to QuantiFERON® while 85.2 % were positive to PPD (p < 0.0001). There was also a significant correlation between the levels of IFN-γ production and the duration of employment in the group of nurses at the TB hospital suggesting on-going exposure in this high risk group. Thus these results demonstrate that Mycobacterium tuberculosis-specific IFN-γ release assay accurately discriminates low and high risk healthy subjects and might therefore be a useful diagnostic tool for the diagnosis of latent infection in BCG-vaccinated individuals.

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Detection of Active Tuberculosis Infection by T Cell Responses to Early‐Secreted Antigenic Target 6‐kDa Protein and Culture Filtrate Protein 10

Cited by 186 publications

References 18 publications

Evaluation of T-Cell Responses to Novel RD1- and RD2-EncodedMycobacterium tuberculosisGene Products for Specific Detection of Human Tuberculosis Infection

Evaluation of T-Cell Responses to Novel RD1- and RD2-EncodedMycobacterium tuberculosisGene Products for Specific Detection of Human Tuberculosis Infection

Comparative Analysis of B- and T-Cell Epitopes ofMycobacterium lepraeandMycobacterium tuberculosisCulture Filtrate Protein 10

Evaluation of the diagnostic utility of a whole-blood interferon-γ assay for determining the risk of exposure to Mycobacterium tuberculosis in Bacille Calmette-Guerin (BCG)-vaccinated individuals

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