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Modulation of mycobacterial-specific Th1 and Th17 cells in latent tuberculosis by coincident hookworm infection.

ABSTRACT: Hookworm infections and tuberculosis (TB) are coendemic in many parts of the world. It has been suggested that infection with helminth parasites could suppress the predominant Th1 (IFN-?-mediated) response needed to control Mycobacterium tuberculosis infection and enhance susceptibility to infection and/or disease. To determine the role of coincident hookworm infection on responses at steady-state and on M. tuberculosis-specific immune responses in latent TB (LTB), we examined the cellular responses in individuals with LTB with or without concomitant hookworm infection. By analyzing the expression of Th1, Th2, and Th17 subsets of CD4(+) T cells, we were able to demonstrate that the presence of coincident hookworm infection significantly diminished both spontaneously expressed and M. tuberculosis-specific mono- and dual-functional Th1 and Th17 cells. Hookworm infection, in contrast, was associated with expanded frequencies of mono- and dual-functional Th2 cells at both steady-state and upon Ag stimulation. This differential induction of CD4(+) T cell subsets was abrogated upon mitogen stimulation. Additionally, coincident hookworm infection was associated with increased adaptive T regulatory cells but not natural regulatory T cells in LTB. Finally, the CD4(+) T cell cytokine expression pattern was also associated with alterations in the systemic levels of Th1 and Th2 cytokines. Thus, coincident hookworm infection exerts a profound inhibitory effect on protective Th1 and Th17 responses in LTB and may predispose toward the development of active tuberculosis in humans.

SUBMITTER: George PJ

PROVIDER: S-EPMC3646958 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Modulation of mycobacterial-specific Th1 and Th17 cells in latent tuberculosis by coincident hookworm infection.

George Parakkal Jovvian PJ Anuradha Rajamanickam R Kumaran Paramasivam Paul PP Chandrasekaran Vedachalam V Nutman Thomas B TB Babu Subash S

Journal of immunology (Baltimore, Md. : 1950) 20130410 10

Hookworm infections and tuberculosis (TB) are coendemic in many parts of the world. It has been suggested that infection with helminth parasites could suppress the predominant Th1 (IFN-γ-mediated) response needed to control Mycobacterium tuberculosis infection and enhance susceptibility to infection and/or disease. To determine the role of coincident hookworm infection on responses at steady-state and on M. tuberculosis-specific immune responses in latent TB (LTB), we examined the cellular respo ...[more]

PMID: 23576678

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Project description:Mucosal-associated invariant T (MAIT) cells are innate like, and play a major role in restricting disease caused by Mycobacterium tuberculosis (Mtb) disease before the activation of antigen-specific T cells. Additionally, the potential link and synergistic function between diabetes mellitus (DM) and tuberculosis (TB) has been recognized for a long time. However, the role of MAIT cells in latent TB (LTB) DM or pre-DM (PDM) and non-DM (NDM) comorbidities is not known. Hence, we examined the frequencies (represented as geometric means, GM) of unstimulated (UNS), mycobacterial (purified protein derivative (PPD) and whole-cell lysate (WCL)), and positive control (phorbol myristate acetate (P)/ionomycin (I)) antigen stimulated MAIT cells expressing Th1 (IFNγ, TNFα, and IL-2), Th17 (IL-17A, IL-17F, and IL-22), and cytotoxic (perforin (PFN), granzyme (GZE B), and granulysin (GNLSN)) markers in LTB comorbidities by uniform manifold approximation (UMAP) and flow cytometry. We also performed a correlation analysis of Th1/Th17 cytokines and cytotoxic markers with HbA1c, TST, and BMI, and diverse hematological and biochemical parameters. The UMAP analysis demonstrated that the percentage of MAIT cells was higher; T helper (Th)1 cytokine and cytotoxic (PFN) markers expressions were different in LTB-DM and PDM individuals in comparison to the LTB-NDM group on UMAP. Similarly, no significant difference was observed in the geometric means (GM) of MAIT cells expressing Th1, Th17, and cytotoxic markers between the study population under UNS conditions. In mycobacterial antigen stimulation, the GM of Th1 (IFNγ (PPD and WCL), TNFα (PPD and WCL), and IL-2 (PPD)), and Th17 (IL-17A, IL-17F, and IL-22 (PPD and/or WCL)) cytokines were significantly elevated and cytotoxic markers (PFN, GZE B, and GNLSN (PPD and WCL)) were significantly reduced in the LTB-DM and/or PDM group compared to the LTB-NDM group. Some of the Th1/Th17 cytokines and cytotoxic markers were significantly correlated with the parameters analyzed. Overall, we found that different Th1 cytokines and cytotoxic marker population clusters and increased Th1 and Th17 (IL-17A, IL-22) cytokines and diminished cytotoxic markers expressing MAIT cells are associated with LTB-PDM and DM comorbidities.

Project description:Tuberculosis (TB) remains one of the most severe infectious diseases. It is still of paramount importance to establish more accurate, rapid, and efficient diagnostic methods. Since infection with Mycobacterium tuberculosis (M. tb) is largely mediated through the respiratory tract, IgA responses against mycobacterial proteins are worthy of investigation for their potential clinical utility. In this study, the IgA response targeting lipoprotein Z (LppZ) was determined by using a homemade ELISA with plasma of TB patients (N = 125), LTBI individuals (N = 92), healthy controls (HCs) (N = 165), as well as TB patients undergoing anti-TB treatment (N = 9). In parallel the antigen-specific IFN-? release from PBMCs triggered by LppZ and M. tb-specific ESAT-6 or CFP-10 was detected by using an ELISPOT assay. It was found that the LppZ-specific IgA level was dramatically higher in TB patients than in HCs (p < 0.0001). Compared to that before anti-TB treatment, the LppZ-specific IgA level decreased substantially after 2 months of anti-TB treatment (p = 0.0297) and remained at low levels until the end of the treatment. What is more, pulmonary TB patients exhibited significantly higher LppZ-specific IgA-values than extra-pulmonary TB patients (p = 0.0296). Interestingly, the LppZ-specific IgA-values were negatively correlated to the amounts of IFN-? released in response to LppZ with statistical significance (r = -0.5806, p = 0.0002). LppZ-specific IgA level was also higher in LTBI individuals than in HCs (p < 0.0001). Additionally there were some PPD+ HC individuals with high LppZ-specific IgA levels but the potential of this assay for identifying leaky LTBI in PPD+ HCs needs to be further investigated through follow-up studies. The sensitivity of detecting TB solely with ESAT-6 or CFP-10-specific IFN-? release was increased by including the LppZ-specific IgA results, respectively, from 86.11 to 100% and 88.89 to 100%; the sensitivity of screening for LTBI was increased from 80.36 to 83.93% and 57.14 to 69.64%, respectively. The higher LppZ-specific IgA responses in TB and LTBI populations than in controls indicated high immunoreactivity to LppZ upon M. tb infection. Although the assay was not efficient enough for independent application in sero-diagnosis, LppZ-specific IgA might become a complementary biomarker for the improvement of TB and LTBI screening.

Dataset Information

Modulation of mycobacterial-specific Th1 and Th17 cells in latent tuberculosis by coincident hookworm infection.

Publications

Modulation of mycobacterial-specific Th1 and Th17 cells in latent tuberculosis by coincident hookworm infection.

Similar Datasets

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