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Methylated HBHA produced in M. smegmatis discriminates between active and non-active tuberculosis disease among RD1-responders

Delogu, Giovanni and Chiacchio, Teresa and Vanini, Valentina and Butera, Ornella and Cuzzi, Gilda and Bua, Alessandra and Molicotti, Paola and Zanetti, Stefania Anna Lucia and Lauria, Francesco Nicola and Grisetti, Susanna and Magnavita, Nicola and Fadda, Giovanni and Girardi, Enrico and Goletti, Delia (2011) Methylated HBHA produced in M. smegmatis discriminates between active and non-active tuberculosis disease among RD1-responders. PLoS One, Vol. 6 (3), e18315. ISSN 1932-6203. Article.

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DOI: 10.1371/journal.pone.0018315

Abstract

Background.
A challenge in tuberculosis (TB) research is to develop a new immunological test that can help distinguish, among subjects responsive to QuantiFERON TB Gold In tube (QFT-IT), those who are able to control Mtb replication (remote LTBI, recent infection and past TB) from those who cannot (active TB disease). IFN-γ; response to the Heparin-binding-hemagglutinin (HBHA) of Mtb has been associated with LTBI, but the cumbersome procedures of purifying the methylated and immunological active form of the protein from Mtb or M. bovis Bacillus Calmette et Guerin (BCG) have prevented its implementation in a diagnostic test. Therefore, the aim of the present study was to evaluate the IFN-γ response to methylated HBHA of Mtb produced in M. smegmatis (rHBHAms) in individuals at different stages of TB who scored positive to QFT-IT.

Methodology/Principal Findings.
87 individuals at different stages of TB who scored positive to QFT-IT were selected. IFN-γ response to in vitro whole blood stimulation with rHBHAms was evaluated by short-term and long-term tests and detected by ELISA or flow cytometry. We demonstrated that the IFN-γ response to rHBHAms is mediated by CD4+ T-cells with an effector-memory phenotype. This response, evaluated by short-term-tests, is significantly lower in active TB than in remote LTBI (p = 0.0010) and past TB (p = 0.0152). These results were confirmed by long-term tests. The qualitative data confirmed that IFN-γ responses higher than the cut-off point identified by ROC analysis are associated with the status of non-active disease.

Conclusions.
In this study we show that the T-cell response to a recombinant and methylated HBHA of Mtb produced in M. smegmatis is useful to discriminate between active and non-active TB disease among those responsive to QFT-IT in a whole blood system. Further studies are needed to improve the accuracy of the assay.

Item Type:Article
ID Code:5878
Status:Published
Refereed:Yes
Uncontrolled Keywords:Tuberculosis (TB) disease, M. smegmatis(rHBHAms), QuantiFERON TB Gold In tube (QFT-IT), M. bovis Bacillus Calmette et Guerin (BCG)
Subjects:Area 06 - Scienze mediche > MED/07 Microbiologia e microbiologia clinica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Public Library of Science
ISSN:1932-6203
Copyright Holders:© 2011 Delogu et al.
Deposited On:05 Apr 2011 08:34

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