● Salmonella ○ Transmission ■ Primarily enters through Fecal oral routes (contaminated food and water) ■ M cells in intestinal epithelium ● Peyer’s patches ■ Type 3 secretion system (T3SS-1) encoded in Salmonella ■ Injects effector proteins = induce actin cytoskeletal rearrangements ● Membrane ruffles ● Bacterial uptake through macropinocytosis ○ Macrophage mediated Dissemination ■ Phagocytosis ● Translocation across intestinal barriers ● Phagocytosed by macrophage ■ Intracellular survival mechanisms ● Survive and replicate inside the modified phagosomal compartment (SCV) ○ Inhibition of phagosome lysosome fusion ○ modifies d SCV membrane ■ Through T3SS-2 Effector Protein Function SifA Maintains SCV membrane integrity SseJ Modifies host membrane lipids PipB2 Recruits kinesin for SCV positioning SpiC Inhibits vesicle trafficking to prevent phagolysosomal fusion ● Systematic Dissemination ○ Macrophage as trojan horse - destroy pathogens ■ But also used as salmonella vehicles for immune evasion ○ Salmonella infected macrophage => lymphatic system ■ Mesenteric lymph nodes ■ Spleen ■ Liver ■ Bone marrow ● Could lead to bacteremia ● Host immune response ○ Pattern Recognition REceptors ■ TLR4 and NOD receptor detects salmonella ■ Inflammasome activation ● Caspase-1 activation ● Secretion of IL-1B and IL-18 ● Pyroptosis infected macrophage ■ Th1-type CD4 t cells are critical ● Secretion of IFN-y ○ Activates macrophage = bactericidal ○ Production of ROS and NO ● B cell generates antibodies that targets LPS = outer membrane proteins ○ Evasion of immune response ■ Resistant to ROS and RNS internally of SCV ■ Downregulation of Flagellin ● Avoidance of TLR5 detection ■ Modulation of antigens presentation ● Could be done with MHC 2 expression on host ■ Persistent infection réservoirs ○ Clinical implications ■ Nontyphoidal salmonella (NTS) ● Self limiting gastroenteritis ● Can become invasive for infants + elder individuals ● Could be fatal to immunocompromised individuals ■ Typhoidal Salmonella ● Systematic typhoid fever ● Prompt antibiotic treatment is required ○ Fluoroquinolone azithromycin