Novel T-Cell Assays for the Discrimination of Active and Latent Tuberculosis Infection: The Diagnostic Value of PPE Family

Pourakbari, Babak; Mamishi, Setareh; Marjani, Majid; Rasulinejad, Mehrnaz; Mariotti, Sabrina; Mahmoudi, Shima

doi:10.1007/s40291-015-0157-0

Cited by 19 publications

(6 citation statements)

References 34 publications

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“…PPE68, EccD1, EspJ and PE35 were less frequently recognized in this study compared to previous reports213039, suggesting that our selected regions did not contain the immunogenic epitopes and warrants further exploration.…”

Section: Discussioncontrasting

confidence: 60%

“…One of these Ags, ESX-1 substrate protein C, (EspC, Rv3615c), has previously been identified as a highly recognized and Mtb specific antigen1319202122. Other potential candidates include the ESX-1 associated EspJ (Rv3878)2324, EspF (Rv3865)2526272829, the RD1 encoded PPE68 (Rv3873)23, PE35 (Rv3872)30, EccD1 (Rv3877)31 and the RD7 encoded Rv234832 (Table 1). By screening fragments in pools of three to seven peptides, we aimed to cover several antigens in the cocktail while retaining a low total number of peptides.…”

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confidence: 99%

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Introducing the ESAT-6 free IGRA, a companion diagnostic for TB vaccines based on ESAT-6

Rühwald

Thurah

Kuchaka

et al. 2017

Sci Rep

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There is a need for an improved vaccine for tuberculosis. ESAT-6 is a cardinal vaccine antigen with unique properties and is included in several vaccine candidates in development. ESAT-6 is also the core antigen in the IFN-γ release assays (IGRA) used to diagnose latent infection, rendering IGRA tests unspecific after vaccination. This challenge has prompted the development of a companion diagnostic for ESAT-6 based vaccines, an ESAT-6 free IGRA. We screened a panel of seven potential new diagnostic antigens not recognized in BCG vaccinated individuals. Three highly recognized antigens EspC, EspF and Rv2348c were identified and combined with CFP10 in an ESAT-6 free antigen cocktail. The cocktail was prepared in a field-friendly format, lyophilized with heparin in ready-to-use vacutainer tubes. The diagnostic performance of the ESAT-6 free IGRA was determined in a cross-validation study. Compared IGRA, the ESAT-6 free IGRA induced a comparable magnitude of IFN-γ release, and the diagnostic performance was on par with Quantiferon (sensitivity 84% vs 79%; specificity 99% vs 97%). The comparable performance of the ESAT-6 free IGRA to IGRA suggests potential as companion diagnostic for ESAT-6 containing vaccines and as adjunct test for latent infection.

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Section: Discussioncontrasting

confidence: 60%

mentioning

confidence: 99%

Introducing the ESAT-6 free IGRA, a companion diagnostic for TB vaccines based on ESAT-6

Rühwald

Thurah

Kuchaka

et al. 2017

Sci Rep

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“…The identification of valuable M. tuberculosis antigens is vital to the improvement of serodiagnostic methods of TB. In recent years, comparative genomic studies have identified some promising recombinant proteins for TB serodiagnosis such as ESAT‐6, CFP‐10, Hsp60 (Shekhawat et al ., ), PE35 (Baumann et al ., ), PPE57 (Chen et al ., ), PPE68 (Pourakbari et al ., ), Rv1168c, Rv1985c and Rv3878 (Dosanjh et al ., ). The combination of antigens ESAT‐6 and CFP‐10 has been used to identify individuals with active TB in commercial tests.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Rv0220, Rv2958c, Rv2994 and Rv3347c of Mycobacterium tuberculosis for serodiagnosis of tuberculosis

You

Wan

et al. 2017

Microbial Biotechnology

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SummaryTuberculosis (TB), the leading cause of death among infectious diseases worldwide, is caused by Mycobacterium tuberculosis (M. tuberculosis). Early accurate diagnosis means earlier prevention, treatment and control of TB. To confirm efficient diagnostic antigens for M. tuberculosis, the serodiagnosis value of four recombinant proteins including Rv0220, Rv2958c, Rv2994 and Rv3347c was evaluated in this study. The specificities and sensitivities of four recombinant proteins were determined based on enzyme‐linked immunosorbent assay (ELISA) by screening sera from smear‐positive pulmonary TB patients (n = 92), uninfected individuals (n = 60) and patients with Mycoplasma pneumoniae (n = 32) that potentially cross‐react with M. tuberculosis. The ELISAs showed that Rv0220, Rv2958c, Rv2994 and Rv3347c exhibited high specificities and sensitivities in detecting immunoglobulin G (IgG) antibody, with 98.3/91.3%, 91.7/85.9%, 93.3/89.1% and 93.3/80.4% respectively. According to the receiver‐operating characteristic (ROC) analysis, the area under the ROC of the target proteins was 0.988, 0.969, 0.929 and 0.945 respectively. Western blot was established to evaluate the immunoreactivities of target proteins to mice and human sera. Results demonstrated that Rv0220, Rv2958c, Rv2994 and Rv3347c could specifically recognize TB‐positive sera and the sera of mice immunized with the corresponding protein. Thus, Rv0220, Rv2958c, Rv2994 and Rv3347c were valuable potential diagnostic antigens for M. tuberculosis.

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“…One of the highly immunogenic PPE protein, PPE55 (Rv3347c) was reported to be expressed during incipient and clinical TB and suggested to be useful for differentiating between latent TB and incipient, subclinical TB [ 32 ]. Another group studied IL-2 response against PE35 and PPE68 between active TB patients and LTBI and concluded that PPE68 induced IL-2 could be used as a sensitive and specific biomarker for discriminating TB from LTBI [ 33 ]. All these studies made an effort to identify PE/PPE proteins to be used as diagnostic antigen for LTBI, however, major limitations of these studies was the use of low number of samples from the LTBI group.…”

Section: Discussionmentioning

confidence: 99%

PPE17 (Rv1168c) protein of Mycobacterium tuberculosis detects individuals with latent TB infection

et al. 2018

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Latent tuberculosis infection (LTBI) is a clinically distinct category of Mycobacterium tuberculosis (Mtb) infection that needs to be diagnosed at the initial stage. We have reported earlier that one of the Mtb proline-proline-glutamic acid (PPE) proteins, PPE17 (Rv1168c) is associated with stronger B-cell and T-cell responses and could be used to diagnose different clinical categories of active TB patients with higher specificity and sensitivity than PPD and ESAT-6. Based on these observations we further tested the potential of PPE17 for the diagnosis of LTBI. We tested 198 sera samples collected from LTBI individuals (n = 61), QFT-negative (n = 58) and active TB patients (n = 79). Individuals were defined as LTBI by QuantiFERON-TB Gold In-Tube test (QFT–GIT) positive results, while active TB patients were confirmed based on the guidelines of the Revised National TB Control Programme of India. The antibody responses against PPE17, ESAT-6:CFP-10 and PPD were compared in these subjects by enzyme-linked immunosorbent assay. We observed that LTBI individuals show a higher sero-reactivity to PPE17 as compared to currently used latent TB diagnostic antigens like ESAT-6, CFP-10 and PPD. The LTBI and active TB patients display almost similar sensitivity. Interestingly, PPE17 could discriminate LTBI positive subjects from the QFT-negative subjects (P < 0.001). Our study hints that PPE17 may be used as a novel serodiagnostic marker to screen the latently infected subjects and may also be used as a complimentary tool to the QFT–GIT.

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Novel T-Cell Assays for the Discrimination of Active and Latent Tuberculosis Infection: The Diagnostic Value of PPE Family

Abstract: This study confirms IL-2 induced by PE35 and PPE68 as a sensitive and specific biomarker and highlights IL-2 as new promising adjunct markers for discriminating of LTBI and active TB disease.

Cited by 19 publications

References 34 publications

Introducing the ESAT-6 free IGRA, a companion diagnostic for TB vaccines based on ESAT-6

Introducing the ESAT-6 free IGRA, a companion diagnostic for TB vaccines based on ESAT-6

Evaluation of Rv0220, Rv2958c, Rv2994 and Rv3347c of Mycobacterium tuberculosis for serodiagnosis of tuberculosis

PPE17 (Rv1168c) protein of Mycobacterium tuberculosis detects individuals with latent TB infection

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