Lecture 13

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University of Otago
Medical Laboratory Science
Jenny Rhodes

MELS223 Lecture 13 21/08/13 Intracellular survival Phagocytes have potent anti-microbial activites How do microbial pathogens survive (and sometimes replicate) in phagocytes and other types of human cells? Antimicrobial properties of phagocytes 1. Low phagosomal pH (V-ATPase) 2. Production of reactive oxygen species (ROS) 3. Cationic antimicrobial peptides (CAMPS) 4. Acquisition of proteases (e.g. cathepsins) Phagosome maturation (role of V-ATPase) Reactive Oxygen Species (ROS)  Generated from ground state (triplet) O2  Examples are superoxide anion and hydroxyl radical  Have an unpaired electron, making them highly reactive  Damage macromolecules (DNA, protein, lipids) by oxidation Killing of bacteria by cationic antimicrobial peptides (CAMPS) - Outer membrane and/or inner membrane of bacterium.- binds and destroys membrane Intracellular survival of microbial pathogens 1. Survival in an acidic compartment (Salmonella) 2. Avoidance of fusion with lysosome (Legionella, Mycobacterium) 3. Escape from vacuole (Listeria, Shigella) Survival of Salmonella in an acidic compartment  Salmonella resides in a ‘remodeled’ lysosomal compartment (pH is acidic, but not as acidic as a normal lysosome)  Intracellular survival requires two type III secretion systems (TTSS1 and TTSS2)  Other virulence factors needed for intracellular survival are: o Superoxide dismutase (SOD) o PhoP/PhoQ and PmrA/PmrB two component regulatory systems Superoxide dismutase and catalase protect Salmonella from ROS The Salmonella two-component regulatory systems PhoP/PhoQ and PmrA/PmrB protect against killing by CAMPs by covalently modifying LPS CAMPs bind to lipopolysaccharide (LPS) which is negatively charged in membrane. PhoP/PhoQ and PmrA/PmrB stimulate expression of bacterial genes that covalently modify LPS such that it no longer binds CAMPs Avoidance of fusion with the lysosome: Leginella pneumophila  Gram-negative, rod shaped  Cause of Legionnaires’ disease: Bacterial pneumonia  Infects both protists (amoebas) and humans  Facultative intracellular pathogen. Legionella replicates inside amoeba or human cells by interfering with host trafficking pathways that would otherwise kill bacteria Intracellular life cycle of Legionella  How is this bacterium able to grow in eukaryotic cells (amoeba and macrophages) that kill most other microbes?  Alters host intracellular trafficking! Features of Legionella-containing vacuoles (LCVs)  Allow efficient growth of bacteria  Lack anti-microbial characteristics (e.g acidification, presence of proteases, lysosomes, or ROS)  Contain membrane derived from the Endoplasmic Reticulum (ER) o Inhibition of export from the ER by using drugs or genetic approaches alters the structure of LCVs and inhibits growth of Legionella  By forming LCVs, Legionella protects itself from phagocytic killing and also creates a niche productive for replication Virulence factors of Legionella  Dot/Icm type IV secretion system
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