Salmonella Modulates Vesicular Traffic by Altering Phosphoinositide Metabolism

Abstract

Salmonella enterica, the cause of food poisoning and typhoid fever, induces actin cytoskeleton rearrangements and membrane ruffling to gain access into nonphagocytic cells, where it can replicate and avoid innate immune defenses. Here, we found that SopB, a phosphoinositide phosphatase that is delivered into host cells by a type III secretion system, was essential for the establishment of Salmonella's intracellular replicative niche. SopB mediated the formation of spacious phagosomes following bacterial entry and was responsible for maintaining high levels of phosphatidylinositol-three-phosphate [PtdIns(3)P] in the membrane of the bacteria-containing vacuoles. Absence of SopB caused a significant defect in the maturation of the Salmonella-containing vacuole and impaired bacterial intracellular growth.

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

“…Similarly to Legionella effectors, CvpB uses PIs for membrane anchoring, apparently using a nonconventional lipid-binding domain as previously reported for the Legionella effectors SidC and SidM (42,43). Similarly to the Salmonella effector SopB, Coxiella CvpB triggers an increase in PI(3)P levels of infected cells to favor the biogenesis of a spacious replicative compartment (40). CvpB, however, does not possess PI3-kinase activity.…”

“…Mycobacterium tuberculosis (35,36) and Legionella pneumophila (37,38) use effectors to deplete PI(3)P at the surface of their vacuoles to block phagosomal maturation and avoid fusion with degradative compartments. On the contrary, Salmonella enterica serovar Typhimurium uses the SPI-1 substrate SopB to maintain elevated levels of PI(3)P at the surface of Salmonella-containing vacuoles, favoring their biogenesis (39)(40)(41). Based on previous reports, the main source of PI(3)P-positive membranes for CCVs are early endosomes and autophagosomes (4).…”

The Salmonella-containing vacuole—Moving with the times

“…SopB is a phosphoinositide (PI) phosphatase that contributes to efficient closing off of the phagocytic cup [28] by hydrolysis of PI(4,5)P 2 and has also been shown to be required for PI3P accumulation on the newly formed SCV [29]. The role of PI3P in SCV biogenesis remains unclear; it is required for EEA1, Vamp8 and Lamp1, but not rab5, recruitment [29][30][31][32][33]. It may well be critical for SCV biogenesis but this has not been conclusively demonstrated and furthermore the in vivo substrate, or substrates, of SopB phosphatase activity remain undefined.…”

Lipidomics of host–pathogen interactions

“…Lysobisphosphatidic acid and phosphoinositides regulate release of VSV nucleocapsid into cytoplasm [13] SigD/SopB is a type III bacterial derived phosphoinositide phosphatase [29,112] Molecular species of phosphatidylcholine and phosphatidylethanolamine are altered in host plasmamembrane after Plasmodium infection [116] GP Ethanolamine phospholipids required for Sindbis virus production [111] Intracellular mycobacteria release a heterogeneous mixture of lipids [27,113] Growth arrest of Plasmodium [117] and Toxoplasma [85] by disruption of phosphatidylcholine synthesis Semliki Forest virus mRNA capping enzyme requires association with anionic membrane phospholipids for activity [14] Phosphatidylinositol mannosides stimulate fusion of early endosomes with mycobacterial phagosomes [30] Glycosylated phosphatidylinositol causes phagosome maturation arrest [114] SapM, a mycobacterial derived phosphatase hydrolyses PI3P contributing to inhibition of phagolysosome maturation [115] Sphingosine 1-kinase is recruited to nascent phagosomes [118] Inhibition of sphingolipid biosynthesis in T. gondii blocks replication [119] SP Sphingomyelin metabolism important for P. falciparum development [120] Inhibition of cholesterol biosynthesis inhibits Hepatitis C virus RNA replication [15] Inhibition of cholesterol acquisition by the host lowers T. gondii replication [40] ST Cholesterol esterification essential for optimal T. gondii proliferation [121,122] Isopreonoid synthesis inhibitors with anti-malarial [123] and anti-T. gondii activity [124] PR Block of protein farnesylation as antiapicomplexan therapies [125] 5…”

“…Salmonella typhimurium uses its SigD/SopB phosphatase to interfere with phosphoinositide metabolism of the host. This leads to the generation of a spacious replicative vacuole and blocking of maturation into phagolysosomes [29]. Intracellular bacteria release chemically distinct mixtures of lipids which interfere with membrane trafficking.…”