A Rab20-Dependent Membrane Trafficking Pathway Controls M. Tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity

Cell Host Microbe. 2017 May 10;21(5):619-628.e5. doi: 10.1016/j.chom.2017.04.004.

Abstract

The intracellular pathogen Mycobacterium tuberculosis (Mtb) lives within phagosomes and also disrupts these organelles to access the cytosol. The host pathways and mechanisms that contribute to maintaining Mtb phagosome integrity have not been investigated. Here, we examined the spatiotemporal dynamics of Mtb-containing phagosomes and identified an interferon-gamma-stimulated and Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes. This pathway functions to promote endosomal membrane influx in infected macrophages, and is required to preserve Mtb phagosome integrity and control Mtb replication. Rab20 is specifically and significantly upregulated in the sputum of human patients with active tuberculosis. Altogether, we uncover an immune-regulated cellular pathway of defense that promotes maintenance of Mtb within intact membrane-bound compartments for efficient elimination.

Keywords: Rab GTPases; Rab20; macrophage; mycobacterium; phagosome; tuberculosis.

MeSH terms

  • Animals
  • Antigens, Bacterial / metabolism
  • Bacterial Proteins / metabolism
  • Cell Culture Techniques
  • Disease Models, Animal
  • Endosomes / metabolism
  • Female
  • Host-Pathogen Interactions / physiology*
  • Humans
  • Interferon-gamma / metabolism
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / microbiology
  • Membranes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / growth & development*
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / metabolism*
  • Mycobacterium tuberculosis / pathogenicity
  • Phagosomes / enzymology
  • Phagosomes / immunology
  • Phagosomes / metabolism*
  • Phagosomes / microbiology*
  • Protein Transport / physiology*
  • RAW 264.7 Cells
  • Sequence Analysis, RNA
  • Spatio-Temporal Analysis
  • Sputum
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Interferon-gamma
  • Rab20 protein, human
  • rab GTP-Binding Proteins