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. 2018 Nov 26;13(11):e0207787.
doi: 10.1371/journal.pone.0207787. eCollection 2018.

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

Philip Raj Abraham  1 , Kamakshi Prudhula Devalraju  2 , Vishwanath Jha  1   3 , Vijaya Lakshmi Valluri  2 , Sangita Mukhopadhyay  1
Affiliations

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

Philip Raj Abraham et al. PLoS One. .

Abstract

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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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. PPE17 (Rv1168c) displays higher antibody responses in individuals with active TB and latent TB.
(A). Mean absorbance values (indicated by horizontal line) of PPE17 for active TB and LTBI individuals as well as QFT-negative subjects were compared following ELISA. (B). Data shown for individual samples in Fig 1A were re-plotted to show the mean ± SEM values. The mean ± SEM values for active TB, LTBI and QFT-negative subjects were 0.646 ± 0.035, 0.648 ± 0.041 and 0.113 ± 0.008 respectively.
Fig 2
Fig 2. PPE17 is more sensitive to detect active TB and LTBI individuals.
The percentages of high-level responders (samples showing antibody levels greater than or equal to the cut off values) shown in Fig 1A were calculated using a standard cut off value (mean OD492 of the QFT-negative sera plus 3 SD or 5 SD) for active TB and LTBI individuals.
Fig 3
Fig 3. PPE17 elicits stronger antibody responses in active TB and LTBI compared to ESAT-6: CFP-10 and PPD.
(A). Antibody responses to M. tuberculosis antigens PPE17, ESAT6:CFP10 and PPD were compared for LTBI individuals and active TB patients following ELISA. Results shown are in mean ± SEM.
Fig 4
Fig 4. Both full-length PPE17 (F-PPE17) and N-terminal domain of PPE17 (N-PPE17) proteins display higher antibody titers in LTBI individuals.
The mean absorbance values (OD492) of LTBI individuals were compared for F-PPE17 and N-PPE17 proteins following ELISA.
Fig 5
Fig 5. The N-terminal fragment of PPE17 (N-PPE17) predominantly recognize LTBI individuals.
(A). The sera of LTBI individuals pre-incubated with 500 nM of N-PPE17 protein were added to ELISA plates coated with 500 nM of F-PPE17 protein. After washing, the plates were incubated with anti-human IgG-HRP. Antibody response was measured as a function of absorbance read at 492 nm (OD492) using chromogenic substrate OPD and H2O2 as substrate.
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References

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