A Phosphatidylinositol 3-Kinase Effector Alters Phagosomal Maturation to Promote Intracellular Growth of Francisella.
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.
['Ledvina|Hannah E|HE|', 'Kelly|Katherine A|KA|', 'Eshraghi|Aria|A|', 'Plemel|Rachael L|RL|', 'Peterson|S Brook|SB|', 'Lee|Brian|B|', 'Steele|Shaun|S|', 'Adler|Marlen|M|', 'Kawula|Thomas H|TH|', 'Merz|Alexey J|AJ|', 'Skerrett|Shawn J|SJ|', 'Celli|Jean|J|', 'Mougous|Joseph D|JD|']
D000818:Animals D001426:Bacterial Proteins D003593:Cytoplasm D004261:DNA Replication D004195:Disease Models, Animal D011992:Endosomes D005260:Female D005603:Francisella D005798:Genes, Bacterial D044404:Genomic Islands D057809:HEK293 Cells D006367:HeLa Cells D054884:Host-Pathogen Interactions D006801:Humans D050356:Lipid Metabolism D008264:Macrophages D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D010588:Phagosomes D058539:Phosphatidylinositol 3-Kinase D010716:Phosphatidylinositols D000067996:RAW 264.7 Cells D000069376:Type VI Secretion Systems D037521:Virulence Factors
effector Francisella pathogen phosphoinositide type VI secretion