Expression of TNF-alpha-dependent apoptosis-related genes in the peripheral blood of Malagasy subjects with tuberculosis

PLoS One. 2013 Apr 12;8(4):e61154. doi: 10.1371/journal.pone.0061154. Print 2013.

Abstract

The majority of Mycobacterium tuberculosis (Mtb) infections remain asymptomatic with only up to 10% progressing to clinical tuberculosis. However, the constituents of the effective "protective immunity" against tuberculosis responsible for containing most infections remain unknown. Evaluating gene transcriptional profiles in tuberculosis clinical cohorts is one approach to understanding the spectrum of tuberculosis progression. It is clear that apoptosis plays a role in the control of tuberculosis but the utility of apoptosis-related genes as surrogate markers of protection against tuberculosis has not been well investigated. To characterize potential surrogate markers that could discriminate different phases of the clinical tuberculosis spectrum, we investigated gene expression of several TNF-alpha dependent apoptotic genes (TNFR1, TNFR2, FLICE, FLIPs) by real-time RT-PCR of peripheral blood cells from cohorts of individuals with active tuberculosis or potential exposure to tuberculosis. Newly diagnosed tuberculosis patients (n = 23), their close household contacts (n = 80), and community controls (n = 46) were tested at intervals over a period of up to two years. Latent infection or previous Mtb contact was assessed by ELISPOT and TST and complete blood counts were performed during the follow up. Results showed significant upregulation of FLIPs expression by infected individuals regardless of clinical status at entry to the study. A higher percentage of lymphocytes was found in the infected household contacts that remained healthy. In contrast, in individuals with active TB, a significant upregulation of TNFR2 expression, a significantly higher percentage of monocytes and a significantly decreased lymphocyte count were seen, compared to subjects that remained healthy. Moreover, the household contacts who subsequently developed signs of TB also had a significantly high number of monocytes. These data suggest tuberculosis may be associated with decreased T-cell survival (perhaps due to apoptosis) while inhibition of apoptosis in monocytes could lead to a relative increase in these cells: a situation predicted to favour Mtb.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antigens, Bacterial / metabolism
  • Apoptosis / genetics*
  • Bacterial Proteins / metabolism
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Endemic Diseases
  • Enzyme-Linked Immunospot Assay
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation*
  • Humans
  • Interferon-gamma / metabolism
  • Leukocyte Count
  • Madagascar / epidemiology
  • Male
  • Middle Aged
  • Mycobacterium tuberculosis
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Tuberculin Test
  • Tuberculosis / blood*
  • Tuberculosis / epidemiology
  • Tuberculosis / genetics*
  • Tuberculosis / microbiology
  • Tumor Necrosis Factor-alpha / blood*
  • Young Adult

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma

Grant support

This work was funded by the Institut Pasteur de Madagascar core budget and was part of the VACSIS project, which was funded by the European Commission through the EU INCO contract ICA4-CT-2002-10052. The funders had no role in study design, data collection and analysis, decision to publish,or preparation of the manuscript.