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46 Cards in this Set
- Front
- Back
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The Normal Microbiota
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In healthy humans:
•Internal tissues are normally devoid of microorganisms •eg. blood, lymph, CSF and muscles •Microorganisms are found in these tissues during disease Normal Microbiota: •Abundant on skin and the mucous membranes of the respiratory and gastrointestinal (GI) tracts •Contribute to development of GI tract and mucosal physiology •Protect against infection from other microorganisms by competition |
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Differences Between Pathogens & Normal Microbiota - Why do we need to know about normal microbiota?
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•Insight into:
•Possible infections if certain body sites are injured •Normal microbiota are potential pathogens if provided an opportunity to colonize / cause disease •Causes and consequences of colonization / growth of non-normal microbiota at certain body sites •The role of normal microbiota stimulating the host immune response |
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Why do pathogens cause disease?
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•Express virulence factors
–Not expressed by normal microbiota –Mediate: •adhesion (ligands for cells) •anti-phagocytic (capsule) •damage (toxin) •How do we know an organism can cause disease? |
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To cause disease, pathogens must:
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1. Enter the body
2. Colonise the host 3. Evade host defences 4. Multiply and disseminate 5. Cause damage to host |
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Barriers to Entry - Physical barriers
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•High salt, fatty acids (skin)
•Acid (stomach) •Mucous and cilia (LRT) •Peristalsis (GI tract) •Soluble mediators •eg. Lysozyme |
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Barriers to Entry - Innate immune responses:
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•complement
•phagocytosis •Toll-like receptors |
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Barriers to Entry - Adaptive immune responses:
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•antibodies
•cytotoxic T-cells |
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Colonisation of the host
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• Process whereby pathogens establish themselves within the host
• Must overcome physical barriers and innate immune response • Must out compete normal microbiota • Normally requires adherence of the bacteria to a mucosal surface • Normally host / tissue specific |
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Colonisation involves adherence to host cells
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(a) Introduction of bacteria into the mucosal environment (b) Adhesion of bacteria to epithelial cells (c) Invasion of epithelial cells
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Adherence to host cells
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•Mediated by external structures on the surface of bacteria called adhesins
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Adherence to host cells –pili (fimbriae)
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–Establish ‘loose’ or non-intimate adhesion
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Adherence to host cells –afimbrial adhesins
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–Establish ‘close’ or intimate adhesion
** •One type of pathogen may produce multiple adhesins |
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Pili / Fimbriae
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•Structurally similar to flagella but NOT involved in motility
•Fimbriae are generally shorter than pili • Facilitate adherence to the host cell • rod shaped, hollow cylinder structures • ordered helical array of protein subunits • subunit called pilin • Tip of pilus mediates adhesion • tip may be pilin or other proteins • tip confers host cell / tissue specificity • May be all over cell (peritrichous) or polar |
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What is Helicobacter pylori?
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•Gram negative microaerophilic curved rod
•Lives in the stomach •associated with gastritis, ulcers and gastric cancers and gastric lymphomas •~ 50% of world’s population infected •Most likely transmitted from person to person •food and water transmission? •Recognised by WHO – Class 1 carcinogen |
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•H. pylori causes:
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–most cases of chronic gastritis
–leading factor in pathogenesis of peptic ulcers |
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What does Helicobacter pylori do?
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Colonizes gastric mucus-secreting cells
•Fimbriae contribute to adhesion –adhere to host glycoprotein receptors on surface of gastric epithelial cells •Moves through the mucus layer –attaches to mucus-secreting cells •Produces UREASE –high urea concentration in stomach lining –urease cleaves urea to NH3 •alkaline microenvironment –resistance to stomach acid while bacterium is moving through the mucus layer |
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Pathogenic E. coli
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•Escherichia coli is a normal flora of the human digestive system
–Some E. coli strains are non-pathogenic •Some E. coli stains have acquired virulence factors –Mild to severe disease in humans and animals –Digestive and urinary tract infections, septicaemia, meningitis •Six categories of pathogenic E. coli –Enterotoxigenic (ETEC) –Enteropathogenic (EPEC) –Enterohaemorrhagic (EHEC) –Enteroinvasive (EIEC) –Enteroaggregative (EAggEC) –Diffusely adhering E. coli (DAEC) |
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Enterotoxigenic E. coli (ETEC)
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•Causes
–Diarrhoeal disease in humans and animals •Distribution –Worldwide but predominantly in the developing world •Endemic areas experience higher rates of transmission in warmer, wetter months •~80,000 cases / year in USA (CDC website) –Infants and young children → Infant diarrhoea –Travellers → Traveller’s diarrhoea •Transmission –Most commonly by contaminated food and water •Faecal contamination |
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ETEC - Pili
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• Produced by all ETEC strains
• Several types of pili have been characterised • Allow bacteria to attach to the host cell • ETEC do not invade the epithelial cells • Visualised by negative staining / electron microscopy |
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ETEC - Toxins
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Pathogenesis:
•Toxin production (Enterotoxins) •act on epithelial cells of the small intestine •Heat-labile toxin (LT) •Heat-stable toxin (ST) •Both toxins stimulate secretion of electrolytes and H2O into the intestinal lumen → diarrhoea –ETEC may produce either LT, or ST, or both toxins –Toxins are plasmid-encoded |
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Afimbrial Adhesins
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•Establish close or intimate associations with the host cell
•Usually outer membrane proteins (Gram negative) •Pathogens may possess > 1 afimbrial adhesin |
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Adherence: Capsules
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• Extracellular material
• made of polysaccharide (or protein) • well organised, difficult to wash off the cell • Can help prevent • dessication • immune evasion (avoid phagocytosis) • Sticky • aid adherence to surfaces, tissues, and to other bacterial cells • eg. Teeth |
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Colonisation involves adherence to host cells
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(a) Introduction of bacteria into the mucosal environment (b) Adhesion of bacteria to epithelial cells (c) Invasion of epithelial cells
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Invasion of the Host Cell - Why invade the host cell?
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• Obligate intracellular parasites
• Hide from immune response • Escape normal microbiota • Disseminate to deeper tissues |
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Invasion:
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•Mediated by bacterial invasins
–Single protein or complexes of proteins –Binding of the invasin to host cell ligands alters cell cytoskeleton –Cytoskeleton alteration facilitates invasion •Passive or active uptake by host cells •Passive invasion → active entry (by pathogen) without triggering host cell contractile event •May be into cells (invasion) •May be through cells (transcytosis) •Usually mediated by host cell in response to a bacterial trigger |
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Mechanisms of Invasion
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Three basic mechanisms
-Phagocytosis -Receptor-mediated endocytosis |
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Mechanisms of Invasion - Phagocytosis
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entry into specific immune cells likes macrophages, monocytes & neutrophils, dependent on host cell contractile system
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Mechanisms of Invasion - Receptor-mediated endocytosis
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entry into non-professional phagocytic cells by active host cell internalization
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Mechanisms of Invasion - Pinocytosis
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membrane ruffles trap large membrane-bound pockets of extracellular medium, requires no energy from pathogen (passive)
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Invasion of the Host Cell
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•Between cells
–Via gap junctions •Intercellular channels (1.5 - 2nm diameter) that permit passage of ions and small molecules –And / or polymorphonucleocytes •Through cells –Transcytosis → vesicle mediated trafficking of macromolecules across membranes by endocytosis |
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Shigella flexneri
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•Gram negative bacillus, non-motile
• Faecal-oral transmission • Bacillary dysentery (bloody diarrhoea) or Shigellosis • Invasive pathogen –Intestinal epithelial cells –Intestinal macrophages |
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Invasion by Shigella flexneri
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-membrane ruffle
-Shigella bacterium -cell surface |
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Invasion by Shigella spp.
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• Bacteria are phagocytosed by intestinal macrophages (Peyer’s patch cells)
• inducing ruffling and macropinocytosis • Lysis of the phagolysosome • Bacterial proliferation • Move through host cell cytoplasm using the host cytoskeleton (actin) • Invade adjacent epithelial cells |
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Summary
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1. A pathogen must colonise its host to establish an infection
2. Colonisation occurs after the host’s natural barriers are breached 3. Colonisation usually requires adhesion, if only transiently 4. Adhesion may be loose or close / intimate 5. Adhesion is mediated by organised protein polymers (pili / fimbriae) or membrane-bound proteins (afimbrial adhesins) 6. Targets (receptors) for bacterial adhesins are often carbohydrates 7. Bacteria may invade host cells |
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Evasion of host defences
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-Soluble factors
-Professional phagocytes |
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Evasion of host defences - Soluble factors
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• complement
• antibodies • Avoid complement fixation • Destroy antibodies, avoid detection by antibodies |
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Evasion of host defences - Professional phagocytes
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• macrophages
• neutrophils / PMNs • Avoid phagocytosis and / or kill phagocyte |
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Soluble factors - Complement
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• Heat-labile proteins found in human blood plasma
• Over 30 proteins • Complement System • Functions to: • Defend against bacteria by facilitating and enhancing phagocytosis • Bridging the innate and adaptive immune response • Dispose of waste (immune complexes, dead host cells, etc.) |
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Soluble factors - Avoid complement fixation - Use a capsule to prevent activation of complement
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–eg. Streptococcus pneumoniae
–eg. Neisseria meningitidis - No activation --> Pathogen - Non-pathogen--> Activation |
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Soluble factors - Avoid complement fixation - Avoid complement fixation
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• Bind antibody by its Fc end
• eg. Staphylococcal protein A • eg. Streptococcus pyogenes protein G - Complement can’t bind to Fc end of antibody → no activation = pathogen - Complement normally fixed by Fc end of IgG or IgM → activation = non pathogen |
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Soluble factors - Destroy antibodies
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•Specific proteases which cleave IgA
•IgA functions as a dimer •IgA protease cleaves at the hinge •eg. Neisseria gonorrhoeae |
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Soluble factors - Avoid detection by antibodies - Remain inside host cells:
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• strategy used by many viruses and some bacteria
• key is NOT to display antigens on cell surface • microbe must be able to survive in harsh intracellular environment |
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Soluble factors - Avoid detection by antibodies - Host mimicry:
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• eg. N. meningitidis
• causes meningitis (headache, rash, rapid death) • capsule of N. meningitidis type B is made up of sialic acid • sialic acid is a common component of human cell surface sugars (gangliosides) • people produce an extremely poor immune response to capsule B (even if vaccinated) |
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Soluble factors - Avoid detection by antibodies - Coat with host proteins:
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• coat with immunoglobulin (Ig)
• bind Fc end of antibody using an Fc receptor Complement and phagocytes can’t bind to Fc end of antibody (Fc unavailable because its bound to the bacterial cell) |
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Soluble factors - Avoid detection by antibodies - Colonise a privileged site (that has poor access for antibodies)
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• (inside cells)
• skin • central nervous system • gall bladder • cyst (parasites) **Concealment of antigens |
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Soluble factors - Avoid detection by antibodies - Antigenic or phase variation
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• Mutation
• Recombination • Gene switching |
