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Mycobacterium tuberculosis-Induced Bronchoalveolar Lavage Gene Expression Signature in Latent Tuberculosis Infection Is Dominated by Pleiotropic Effects of CD4+ T Cell-Dependent IFN-? Production despite the Presence of Polyfunctional T Cells within the Airways.

ABSTRACT: Tuberculosis (TB) remains a worldwide public health threat. Development of a more effective vaccination strategy to prevent pulmonary TB, the most common and contagious form of the disease, is a research priority for international TB control. A key to reaching this goal is improved understanding of the mechanisms of local immunity to Mycobacterium tuberculosis, the causative organism of TB. In this study, we evaluated global M. tuberculosis-induced gene expression in airway immune cells obtained by bronchoalveolar lavage (BAL) of individuals with latent TB infection (LTBI) and M. tuberculosis-naive controls. In prior studies, we demonstrated that BAL cells from LTBI individuals display substantial enrichment for M. tuberculosis-responsive CD4+ T cells compared with matched peripheral blood samples. We therefore specifically assessed the impact of the depletion of CD4+ and CD8+ T cells on M. tuberculosis-induced BAL cell gene expression in LTBI. Our studies identified 12 canonical pathways and a 47-gene signature that was both sensitive and specific for the contribution of CD4+ T cells to local recall responses to M. tuberculosis In contrast, depletion of CD8+ cells did not identify any genes that fit our strict criteria for inclusion in this signature. Although BAL CD4+ T cells in LTBI displayed polyfunctionality, the observed gene signature predominantly reflected the impact of IFN-? production on a wide range of host immune responses. These findings provide a standard for comparison of the efficacy of standard bacillus Calmette-Guérin vaccination as well as novel TB vaccines now in development at impacting the initial response to re-exposure to M. tuberculosis in the human lung.

SUBMITTER: Jarvela J

PROVIDER: S-EPMC6783366 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Mycobacterium tuberculosis-Induced Bronchoalveolar Lavage Gene Expression Signature in Latent Tuberculosis Infection Is Dominated by Pleiotropic Effects of CD4+ T Cell-Dependent IFN-γ Production despite the Presence of Polyfunctional T Cells within the Airways.

Jarvela Jessica J Moyer Michelle M Leahy Patrick P Bonfield Tracey T Fletcher David D Mkono Wambura N WN Aung Htin H Canaday David H DH Dazard Jean-Eudes JE Silver Richard F RF

Journal of immunology (Baltimore, Md. : 1950) 20190920 8

Tuberculosis (TB) remains a worldwide public health threat. Development of a more effective vaccination strategy to prevent pulmonary TB, the most common and contagious form of the disease, is a research priority for international TB control. A key to reaching this goal is improved understanding of the mechanisms of local immunity to Mycobacterium tuberculosis, the causative organism of TB. In this study, we evaluated global M. tuberculosis-induced gene expression in airway immune ...[more]

PMID: 31541022

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Project description:BackgroundThe diagnosis of active pulmonary tuberculosis (TB) remains a challenge in clinic, especially for sputum negative pulmonary TB. Bronchoalveolar lavage fluid (BALF) has higher sensitivity than sputum for detection of Mycobacterium tuberculosis (Mtb). However, bronchoscopy is invasive and costly, and not suitable for all patients. In order to make TB patients get more benefit from BALF for diagnosis, we explore which indicator might be used to optimize the choice of bronchoscopy.MethodsA total of 1539 sputum-smear-negative pulmonary TB suspects who underwent bronchoscopy were recruited for evaluation. The sensitivity, specificity and accuracy of Mtb detection in sputum and BALF were compared. Odds ratios and 95% confidence intervals were used to assess variables that associated with positive acid-fast bacilli (AFB) smear, Mtb culture and nucleic acid amplification test (NAAT) of BALF in sputum-negative and non-sputum-producing pulmonary TB suspects.ResultsBALF has significantly higher sensitivity (63.4%) than sputum (43.5%) for Mtb detection by culture and NAAT. 19.7% (122/620) sputum-negative and 40.0% (163/408) non-sputum-producing suspects had positive bacteriological results in BALF. Among sputum-negative and non-sputum-producing pulmonary TB suspects, the positivity of Mtb detection in BALF is associated with a younger age, the presence of pulmonary cavities and a positive result of interferon-gamma release assay (IGRA). Sputum-negative patients under 35 years old with positive IGRA and pulmonary cavity had 84.8% positivity of Mtb in BALF.ConclusionsOur study indicated that combination of age, the presence of pulmonary cavity, and the result of IGRA is useful to predict the positivity of Mtb detection in BALF among sputum-negative and non-sputum producing pulmonary TB suspects. Those who are under 35 years old, positive for the presence of pulmonary cavity and IGRA, should undergo bronchoscopy to collect BAFL for Mtb tests, as they have the highest possibility to get bacteriologically confirmation of TB.

Project description:Background: The Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) assay has shown good diagnostic efficacy in brushing and biopsy tissue samples from patients with tracheobronchial tuberculosis (TBTB). However, its diagnostic value in bronchoalveolar lavage fluid (BALF) is still unclear. Therefore, the present retrospective study aimed to evaluate the diagnostic value of the Xpert MTB/RIF assay in BALF. Methods: The clinical data of 266 patients with suspected TBTB from January 2018 to October 2020 were pooled with complete details of bronchial brush and bronchoalveolar lavage samples. Smears of the bronchial brushings were stained with Auramine O stain to detect acid-fast bacilli (AFB), and BALF samples were used for culturing MTB with the BACTEC MGIT 960 system and the Xpert MTB/RIF assay. The diagnostic performance of these methods was assessed and compared. Results: A total of 266 patients suspected to have TBTB were enrolled in the final analysis. Of these patients, 179 patients were confirmed to have TBTB and 87 patients were non-TBTB. The sensitivity of the Xpert MTB/RIF assay in BALF (87.2%) was significantly higher than that of the brush smear for AFB (35.2%, p < 0.001). No significant difference was observed between the sensitivities of the Xpert MTB/RIF assay in BALF and MTB culture in BALF (87.2 vs. 84.9%, p = 0.542). The specificities of the Xpert MTB/RIF assay in BALF, MTB culture in BALF, and the bronchial brush smear were 97.7, 97.7, and 98.9%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of the Xpert MTB/RIF assay in BALF, MTB culture in BALF, and the bronchial brush smear were 98.7 and 78.7%, 98.7 and 75.9%, and 98.4 and 42.6%, respectively. Among the MTB culture-positive patients with TBTB detected by the Xpert assay, 27.0% (20/74) were identified to be resistant to RIF. Conclusions: The Xpert MTB/RIF assay in BALF enables a rapid and accurate diagnosis of TBTB and identification of RIF resistance, which is crucial for timely and proper treatment. Moreover, in patients with TBTB, BALF could be used as an alternative to bronchial brushing and biopsy tissues for the Xpert MTB/RIF assay.

Dataset Information

Mycobacterium tuberculosis-Induced Bronchoalveolar Lavage Gene Expression Signature in Latent Tuberculosis Infection Is Dominated by Pleiotropic Effects of CD4+ T Cell-Dependent IFN-? Production despite the Presence of Polyfunctional T Cells within the Airways.

Publications

<i>Mycobacterium tuberculosis</i>-Induced Bronchoalveolar Lavage Gene Expression Signature in Latent Tuberculosis Infection Is Dominated by Pleiotropic Effects of CD4<sup>+</sup> T Cell-Dependent IFN-γ Production despite the Presence of Polyfunctional T Cells within the Airways.

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