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Decreased phosphorylation of STAT-1, STAT-4 and cytokine release in MDR-TB patients with primary resistance

H J Kim1, D H Chung, M J Kim

  • 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union Against Tuberculosis and Lung Disease
|August 21, 2008
PubMed
Abstract

Insights

Multidrug-resistant tuberculosis (MDR-TB) patients with primary resistance show decreased STAT-1 and STAT-4 phosphorylation and reduced cytokine release, potentially explaining their poor prognosis. This impacts understanding of MDR-TB treatment outcomes.

Area of Science:

  • Immunology
  • Infectious Diseases
  • Molecular Biology

Background:

  • Multidrug-resistant tuberculosis (MDR-TB) treatment failure is higher in patients with primary resistance (no prior TB treatment).
  • Signal transducer and activator of transcription (STAT) pathways and cytokine release are crucial in immune responses to tuberculosis.

Purpose of the Study:

  • To investigate STAT-1 and STAT-4 phosphorylation and subsequent cytokine release in MDR-TB patients with primary resistance.
  • To determine if these molecular changes contribute to the poor prognosis observed in this patient group.

Main Methods:

  • Enrolled 32 patients: 10 treated TB, 12 MDR-TB with acquired resistance, 10 MDR-TB with primary resistance.
  • Stimulated peripheral blood mononuclear cells (PBMCs) with various antigens and cytokines (IFN-gamma, IL-12, PPD, M. tuberculosis lysate).
  • Analyzed intracellular pSTAT-1 and pSTAT-4 via flow cytometry and measured cytokine secretion (IFN-gamma, IL-12p40, TNF-alpha).

Main Results:

  • MDR-TB patients with primary resistance exhibited decreased pSTAT-1 and pSTAT-4 levels upon stimulation compared to those with acquired resistance.
  • Reduced secretion of IFN-gamma, IL-12p40, and TNF-alpha was observed in MDR-TB patients with primary resistance across various stimuli.
  • These molecular deficits were linked to the specific stimuli used in the study.

Conclusions:

  • Decreased STAT-1 and STAT-4 phosphorylation in PBMCs may be associated with impaired immune responses in MDR-TB patients with primary resistance.
  • Reduced cytokine release following stimulation suggests a compromised cellular immunity contributing to poor prognosis.
  • These findings highlight potential molecular mechanisms underlying treatment failure in primary resistant MDR-TB.

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