A Phosphatidylinositol 3-Kinase Effector Alters Phagosomal Maturation to Promote Intracellular Growth of Francisella

Cell Host Microbe. 2018 Aug 8;24(2):285-295.e8. doi: 10.1016/j.chom.2018.07.003. Epub 2018 Jul 26.


Many pathogenic intracellular bacteria manipulate the host phago-endosomal system to establish and maintain a permissive niche. The fate and identity of these intracellular compartments is controlled by phosphoinositide lipids. By mechanisms that have remained undefined, a Francisella pathogenicity island-encoded secretion system allows phagosomal escape and replication of bacteria within host cell cytoplasm. Here we report the discovery that a substrate of this system, outside pathogenicity island A (OpiA), represents a family of wortmannin-resistant bacterial phosphatidylinositol (PI) 3-kinase enzymes with members found in a wide range of intracellular pathogens, including Rickettsia and Legionella spp. We show that OpiA acts on the Francisella-containing phagosome and promotes bacterial escape into the cytoplasm. Furthermore, we demonstrate that the phenotypic consequences of OpiA inactivation are mitigated by endosomal maturation arrest. Our findings suggest that Francisella, and likely other intracellular bacteria, override the finely tuned dynamics of phagosomal PI(3)P in order to promote intracellular survival and pathogenesis.

Keywords: Francisella; effector; pathogen; phosphoinositide; type VI secretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / metabolism
  • Cytoplasm / microbiology
  • DNA Replication
  • Disease Models, Animal
  • Endosomes / microbiology
  • Female
  • Francisella / genetics
  • Francisella / growth & development*
  • Francisella / pathogenicity*
  • Genes, Bacterial / genetics
  • Genomic Islands
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions / physiology*
  • Humans
  • Lipid Metabolism
  • Macrophages / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phagosomes / metabolism*
  • Phagosomes / microbiology*
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphatidylinositols / metabolism
  • RAW 264.7 Cells
  • Type VI Secretion Systems / metabolism
  • Virulence Factors / metabolism


  • Bacterial Proteins
  • PdpC protein, Francisella tularensis
  • Phosphatidylinositols
  • Type VI Secretion Systems
  • Virulence Factors
  • Phosphatidylinositol 3-Kinase