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. 2018 Jan 8;18(1):26.
doi: 10.1186/s12879-017-2929-0.

Potential of DosR and Rpf antigens from Mycobacterium tuberculosis to discriminate between latent and active tuberculosis in a tuberculosis endemic population of Medellin Colombia

Leonar Arroyo  1 , Diana Marín  2 , Kees L M C Franken  3 , Tom H M Ottenhoff  3 , Luis F Barrera  4   5
Affiliations

Potential of DosR and Rpf antigens from Mycobacterium tuberculosis to discriminate between latent and active tuberculosis in a tuberculosis endemic population of Medellin Colombia

Leonar Arroyo et al. BMC Infect Dis. .

Abstract

Background: Tuberculosis (TB) remains one of the most deadly infectious diseases. One-third to one-fourth of the human population is estimated to be infected with Mycobacterium tuberculosis (Mtb) without showing clinical symptoms, a condition called latent TB infection (LTBI). Diagnosis of Mtb infection is based on the immune response to a mixture of mycobacterial antigens (PPD) or to Mtb specific ESAT-6/CFP10 antigens (IGRA), highly expressed during the initial phase of infection. However, the immune response to PPD and IGRA antigens has a low power to discriminate between LTBI and PTB. The T-cell response to a group of so-called latency (DosR-regulon-encoded) and Resuscitation Promoting (Rpf) antigens of Mtb has been proved to be significantly higher in LTBI compared to active TB across many populations, suggesting their potential use as biomarkers to differentiate latent from active TB.

Methods: PBMCs from a group LTBI (n = 20) and pulmonary TB patients (PTB, n = 21) from an endemic community for TB of the city of Medellín, Colombia, were in vitro stimulated for 7 days with DosR- (Rv1737c, Rv2029c, and Rv2628), Rpf- (Rv0867c and Rv2389c), the recombinant fusion protein ESAT-6-CFP10 (E6-C10)-, or PPD-antigen. The induced IFNγ levels detectable in the supernatants of the antigen-stimulated cells were then used to calculate specificity and sensitivity in discriminating LTBI from PTB, using different statistical approaches.

Results: IFNγ production in response to DosR and Rpf antigens was significantly higher in LTBI compared to PTB. ROC curve analyses of IFNγ production allowed differentiation of LTBI from PTB with areas under the curve higher than 0.70. Furthermore, Multiple Correspondence Analysis (MCA) revealed that LTBI is associated with higher levels of IFNγ in response to the different antigens compared to PTB. Analysis based on decision trees showed that the IFNγ levels produced in response to Rv2029c was the leading variable that best-classified disease status. Finally, logistic regression analysis predicted that IFNγ produced by PBMCs in response to E6-C10, Rv2029c, Rv0867c (RpfA) and Rv2389c (RpfA) antigens correlates best with the probability of being latently infected.

Conclusions: The Mtb antigens E6-C10, Rv2029c (PfkB), Rv0867c (RpfA) and Rv2389c (RpfA), may be potential candidates to discriminate LTBI from PTB.

Keywords: DosR; IFNγ biomarkers; Latency; Rpf; Tuberculosis.

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Conflict of interest statement

Ethics approval and consent to participate

TB patients and LTBI individuals signed an informed consent previously approved by the Ethics Committee of the Instituto de Investigaciones Médicas of the Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Comparison of the IFNγ levels in LTBI and PTB in response to RD-1 Esat6-Cfp10 (E6-C10), DosR and Rpf antigens. PBMCs (1 × 105) were cultured for 7 days, in the presence or absence of PPD, E6-C10 and the DosR and Rpf antigens. IFNγ levels in LTBI (orange circles) and PTB (blue circles) were determined by Luminex. Mann-Whitney U-test was used to calculate statistical differences between groups and p-values are shown in the graphs (*, p < 0.05; **, p < 0.01; ***, p < 0.001)
Fig. 2
Fig. 2
Multiple correspondence analysis for the IFNγ levels in response to RD-1 Esat6-Cfp10 (E6-C10), DosR and Rpf antigens in LTBI and PTB
Fig. 3
Fig. 3
Decision-tree diagram based on CHAID analysis, showing the antigens that better influence the prediction of being LTBI or PTB
See this image and copyright information in PMC

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