Zipper Mechanism Ingestion occurs by sequential engagement of the phagocyte membrane with the particle surface. Pseudopod advance proceeds no further than the receptor-ligand interaction permits.

TRIGGER MECHANISM Particle binding initiates an ‘all or none’ phagocytic response.

Salmonellosis Factors for disease: Pathogen – Virulence? Host – Immune function? Environment – Dose? http://www.worldwidevaccines.com/typhoid/typhoid_4.jpg

Salmonella Virulence SPI-1: TTSS to deliver effector proteins to cytoplasm that induce cytoskeletal rearrangments to facilitate Salmonella uptake in SCV. SPI-2: TTSS to deliver effector proteins from SCV to cell cytoplasm that induce focal actin condensation around SCV. spv: prevents actin polymerization needed for F-actin filament formation.

SIGNALS FROM OUTSIDE How to invade non-phagocytic cells? SPI-1 TTSS: Activate regulators Cdc42 and Rac1 in host. Bacteria-host interaction to promote polymerization and bundling of actin filaments. Restore normal actin dynamics after invasion.

MEMBRANE RUFFLING Ruffles, Macropinocytosis, Engulfment: Sop B, E, E2 activate GTPases Cdc42, Rac1. Activate WASP, Scar/Wave, Arp2/3 to initiate actin polymerization. Translocate: SipC – Insert in target cell membrane, direct filament formation at sites adjacent to bacteria? SipA – ‘Molecular staple’ to stabilize actin filaments. SptP – Reverse cytoskeletal rearrangements.

SIGNALS FROM INSIDE How to proliferate within cells? SPI-2 TTSS: SpvB: Translocate effectors from SCV to cytoplasm: Form filamentous endosomes Decrease recruitment of NADPH oxidase Change SCV fusion pathway VAP formation of actin around SCV SpvB: Depolymerizes actin from F filaments to G monomers with ADP ribosylation.

TIMING IS EVERYTHING Events are carefully orchestrated: Focal actin polymerization for cell invasion. Caused by SPI-1 effectors Reversed by SptP Focal actin condensation for effects from SCV. Caused by SPI-2 effectors Reversed by SpvB Depolymerization leads to apoptosis and further Salmonella phagocytosis!

Does all this talk of phagocytosis make you hungry? The End http://www.sph.tulane.edu/%7Edmsander/WWW/Video/Macmov.html