Julian Rood; Week 5 MED1022; Microbiology
Bacteria invade host cells as they are either obligate intracellular parasites; to hide from immune response or disseminate to deeper tissues. Zipper mechanism involves tight envelopment of bacteria by mammalian cell membrane, involves high affinity binding between invasin and host molecule, exploits host pathways used for adhesion and receptor mediated endocytosis. Yersinia, Listeria monocytogenes (listeriosis) and Neisseria (meningococcus; meningitis). Internalisation requires and active actin cytoskeleton, may invade many cell types, entry is passive for the bacteria, InlA (internalin) coated beads can invade.
Trigger mechanis involves a type 3 secretion system. T3SS effector molecules trigger cell entry. They form a macropinocytic vacuole, brief contact involves large scale actin polymerisation and formation of ruffles on the host cell surface. Ruffles fold over bacteria and engulf them. Shigella and salmonella spp. use this system. It is a gram negative secretion system and has a distinctive needle shape which 'injects' effector molecules into host cells via attachment.
Evasion of host defences can be done to soluble factors (complement, antibodies) by avoiding complement fixation (serum resistance), destroying antibodies/avoiding detection by antibodies. They avoid phagocytosis by avoiding or killing the phagocyte. Phagocytosis can be facilitated by opsonisation. Killing follows phagolysosome fusion and activation of oxygen dependant and independant killing pathways. C3b on complement allows opsonisation. Oxygen dependent killing involves respiratory burst (NADPH oxidase), oxygen radicals (O2, H2O2, OCl). Oxygen independant are low pH, proteolytic enzymes, lysosymes, lactoferrin and membrane damaging proteins.
Bacteria can kill phagocytes by secreting a toxin (staph aureus- haemolysin, salmonella typhi induces apoptosis). They can prevent opsonisation by preventing complement activation, preventing antibody binding, coating with host proteins. They can have a capsule to prevent contact with phagocyte. They can survive in phagocytes by preventing lysosyme fusion (prevents maturation of phagolysosome, avoids exposure to toxic lysosomal components, phagosome can fail to acidify). They can escape from the lysosome into the cytoplasm (Shigella spp). They can survive in phagocytes by producing antioxidants or inhibiting the respiratory burst- pathogen may produce catalase, can prevent activation of resp burst.
Bacteria can have different niches- low pH (intralysosomal), neutral pH, cytosolic. Intralysosomal has access to nutrients but risks hydrolytic attack, compartment interacts with endosomal network of cell, antigen sampling is carried out by MHC of cell. Some cells that exist in this niche are coxiella burnetii (causative agent of Q fever). Intravacuolar niche is when pathogen blocks phagosome maturation allowing it to fail to fuse to lysosomes. Vacuole may exist outside normal membrane trafficking pathways. Cells with an intravacuolar niche include S typhimurium, salmonella containing vacuoles and they prevent phagolysosome fusion. The phagosome is devoid of cation-dependant-mannose-6-phosphate receptor and lysosomal enzymes.
Cytosolic niche is where the pathogen escapes to the cytoplasm to avoid the hostile environment, pathogen exhibits membrane disrupting activity (Shigella, Listeria), has maximal activity at low pH. They recruit host cytoskeletal proteins and induce actin polymerisation. They form an actin tail and propel bacteria to adjacent cells.
Listeria enters with InlA and InlB (internalin), has lysis of vacuole, cell to cell spread and lysis of the two membrane vacuole in the new cell.