Toxoplasma gondii macrophage migration inhibitory factor shows anti- Mycobacterium tuberculosis potential via AZIN1/STAT1 interaction

Sci Adv. 2024 Oct 25;10(43):eadq0101. doi: 10.1126/sciadv.adq0101. Epub 2024 Oct 25.

Abstract

Mycobacterium tuberculosis (MTB) is a pathogenic bacterium, belonging to the family Mycobacteriaceae, that causes tuberculosis (TB). Toxoplasma gondii macrophage migration inhibitory factor (TgMIF), a protein homolog of macrophage migration inhibitory factor, has been explored for its potential to modulate immune responses during MTB infections. We observed that TgMIF that interacts with CD74, antizyme inhibitor 1 (AZIN1), and signal transducer and activator of transcription 1 (STAT1) modulates endocytosis, restoration of mitochondrial function, and macrophage polarization, respectively. These interactions promote therapeutic efficacy in mice infected with MTB, thereby presenting a potential route to host-directed therapy development. Furthermore, TgMIF, in combination with first-line TB drugs, significantly inhibited drug-resistant MTB strains, including multidrug-resistant TB. These results demonstrate that TgMIF is potentially a multifaceted therapeutic agent against TB, acting through immune modulation, enhancement of mitochondrial function, and dependent on STAT1 and AZIN1 pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / metabolism
  • Anti-Bacterial Agents* / pharmacology
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Binding Sites
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Chemotactic Factors* / genetics
  • Chemotactic Factors* / metabolism
  • Chemotactic Factors* / pharmacology
  • Drug Resistance, Bacterial
  • Endocytosis / drug effects
  • Female
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Lung Injury / etiology
  • Lung Injury / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mycobacterium tuberculosis* / drug effects
  • Mycobacterium tuberculosis* / metabolism
  • Protein Binding
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction* / drug effects
  • Toxoplasma* / genetics
  • Toxoplasma* / metabolism
  • Tuberculosis* / drug therapy
  • Tuberculosis* / genetics
  • Tuberculosis* / metabolism
  • Tuberculosis* / pathology

Substances

  • macrophage migration enhancement factor
  • Chemotactic Factors
  • Anti-Bacterial Agents
  • STAT1 Transcription Factor
  • ornithine decarboxylase antizyme inhibitor
  • Carrier Proteins
  • invariant chain
  • Histocompatibility Antigens Class II
  • Antigens, Differentiation, B-Lymphocyte