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33 Cards in this Set
- Front
- Back
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Pathogen related determinants |
- Virulence - Stability in environment - Route of entry - Infective dose - Tissue tropism - Susceptibility to host defence |
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Host related determinants |
- Species - Breed - Age - Sex - Genetic factors - Physiological factors - Immune competence |
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Modifying factors |
- Stress environment - Poor nutrition - Tissue damage - Immunosuppression - Metabolic dysfunction - Concurrent disease |
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What is a pathogen? |
A microorganism that is able to produce disease |
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What is pathogenicity? |
The ability of a microorganism to cause disease in another organism, namely the host
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What is virulence? |
The degree of pathogenicity |
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What is an opportunistic pathogen? |
Bacteria that do not need to cause disease to facilitate their own transmission - can cause disease in an immunocompromised host - may be able to survive in environment |
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What is an obligate pathogen?
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Requires a host for survival and transmission - infection with these organisms usually results in disease Example: brucella, leptospira, TB |
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Host mucosal defenses |
Mucous: - lysozyme - antibodies - peptides - complement factors - clearance by peristalsis or ciliary movement in airways - commensal flora - glycoproteins - tight junctions |
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What are virulence factors? |
Mechanisms to circumvent host defenses and multiply: 1. Establish infection (colonization) 2. Evade host defenses |
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Sites of entry |
Urogenital tract Digestive tract Respiratory tract Conjunctiva |
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Adherence of bacteria to cell and tissue surfaces |
Adherence to eukaryotic cell or tissue surface requires a receptor and a ligand receptor: specific carbohydrate or peptide residues on eukaryotic cell surface bacterial ligand: called an adhesin - typically a macromolecular component of bacterial cell surface 1. Tissue tropism: particular bacteria are known to have apparent preference for certain tissues over others - e.g. E. coli 0157 for digestive tract 2. Species specificity: infect only certain species of animals 3. Age specificity |
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Examples of adhesins: |
Fimbriae - sometimes called pili - virulence factor of Enterotoxigenic E. coli (ETEC) - most common cause of E. coli diarrhea in farm animals The fimbriae determine which species they bind to - some fimbria like pigs better, some ruminants ex: F4 Fimbriae (K88) - species specific, mostly pigs (all ages) - mediates binding to epithelium through small intestine - up to 50% of pigs lack the receptor for the F4 adhesin (so can't get sick with this) |
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How can we use virulence mechanisms of bacteria to prevent disease? |
Find a way to block ligand of bacteria ex: oral vaccination - generate antibodies to block where contact between ligand and receptor are made |
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What are invasins? |
Virulence factors that enable internalization of bacteria Type III secretion systems - machinery possessed by many gram- bacteria to deliver effector proteins - results in hijacking host cell-signaling secretion: into extracellular environment translocation: directly into host cell |
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Examples of Type III secretion system pathogenicity |
"Stick" - Enteropathogenic E. coli (EPEC) delivers receptor for one of its own adhesins into host cell membrane - basically injects its own receptor into cell, exposed on cell surface, so E. coli can sit on the surface of the cell "Enter" - Salmonella Typhimurium: - delivers effectors (invasins) that manipulate the host's actin cytoskeleton -> uptake of bacteria in membrane vacuoles A different salmonella can inject effector protein SpB, to induce enterocytes to transform into M cells - promote host colonization and invasion because M cells will take up the E. coli, expose them to macrophages and salmonella can survive in macrophages |
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What are spreading factors? |
Bacterial enzymes that affect the physical properties of tissue matrices and intercellular spaces, thereby promoting entry/spread of pathogen Hyaluronidase - streptococci, staphylococci, clostridia - attacks intracellular matrix of connective tissue by depolymerizing hyaluronic acid - bacteria moves more freely between cells Collagenase - Clostridium histolyticum, Clostridium perfringens - breaks down collagen, framework of muscles to facilitate gas gangrene Neuraminidase - intestinal pathogens such as Vibrio cholerae and Shigella dysenteriae - degrades neuraminic acid (sialic acid), residue in mucin in intestinal tract Streptokinase/Staphylokinase - streptococci and staphylococci - pathogens produce coagulase, to hide in blood clots - kinase enzymes convert inactive plasminogen to plasmin, which digests fibrin and prevents clotting of blood - bacteria can then be freed from blood clots and spread infection |
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Avoiding host defenses: |
Kill Hide Manipulate Resist |
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What areas of innate immune system can bacteria avoid? |
Complement Antimicrobial peptides Phagocytic defenses |
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How do bacteria evade the complement system (innate immunity)? |
Roles of complement: - tag microbes for destruction by phagocytic cells - microbial lysis (MAC) - generate pro-inflammatory response Capsules: - polysaccharide capsules can hide bacterial components - some bacterial capsules are able to inhibit formation of complement Lipopolysaccharides (LPS): principle targets of complement on gram-negative bacteria - LPS modification by attachment of sialic acid residues to the LPS O antigen - prevents effective MAC killing Destruction of complement component - Pseudomonas aeruginosa produces an extracellular elastase enzyme |
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Bacterial evasion of host-derived antimicrobial peptides on mucosal surfaces |
CAMPs (cationic antimicrobial peptides) HDPs (host defense peptides) Mechanisms of evasion: - alter techoic acids or LPS - charge modification of outer surface - Enzymatic degradation (e.g. proteases) - expulsion from cell (transporters) |
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Overcoming host phagocytic defenses |
1. Avoid contact with phagocytes 2. Inhibit phagocytic engulfment 3. survive inside phagocyte 4. kill or damage phagocyte |
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Avoiding contact with phagocytes |
1. remain confined in regions inaccessible to phagocytes - luminal surfaces of GI tract, oral cavity, urinary tract, mammary gland, kidney tubule 2. hide the antigenic surface of bacterial cell - staphylococcus aureus: cell-bound coagulase which clots fibrin on bacterial surface - group A streptococci: hyaluronic capsule 3. Inhibit phagocyte chemotaxis - fractions of Mycobacterium tuberculosis are known to inhibit leukocyte migration |
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Inhibition of phagocytic engulfment |
Antiphagocytic substances on bacterial surface: - polysaccharide capsules of S. penumoniae and Kelbsiella penumoniae - M protein and fimbriae of group A streptococci - Sufrace slime (polysaccharide) produced by psuedomonas aeruginosa - O antigen associated with LPS of E. coli - cell bound or soluble protein A produced by staphylococcus aureus |
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Survival inside of phagocytes |
Why? - Intracellular environment guards the bacteia against activities of extracellular bactericides, antibodies, drugs etc 1. Inhibition of phagosome-lysosome fusion - Salmonella, Legionella, Chlamydia, Mycobacterium avium 2. resistant to inhibition and killing by lysosomal constituents - bacillus anthracis, staphylococcus aureus, Xociella burnetii 3. escape from phagosome - Rickettsias produce phospholipase enzyme that lyses the phagosome membrane within thirty seconds of ingestion |
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Kill or damage phagocytes |
Killing of phagocytes before ingestion: 1. Hemolysins: extracellular enzymes secreted by many gram-positive pathogens - pyogenic cocci (S. pyogenes, S aureus) 2. Streptolysin: secreted by pathogenic streptococci - Streptolysin O binds to cholesterol in membranes -> lysosomal granules in neutrophils explode, release contents into cell cytoplasm Killing phagocytes after ingestion - Many intracellular pathogens (Mycobacterium, Brucella, Listeria) eventually destroy macrophages, but mechanisms not understood) |
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Resistance to antibody-dependent defenses |
Aggressive/acute infection or production of toxins - not time for adaptive immune response to respond Proteinases Cell wall protection: peptidoglycan, LPS, capsule - prevent antibodies from binding Hide intracellularly Antigenic mimicry (Campy LPS and strep M protein) Binding of host proteins Superantigens: divert productive immune response (Strep and Staph non-specifically stimulate T or B cells) |
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What is antigenic variation? |
Changing antigens between serotypes >2500 serotypes of Salmonella enterica based on differences in cell wall (O) antigens or flagellar (H) antigens 80 different antigenic types of Streptococcus pyogenes based on M-proteins on cell surface >100 strains of Streptococcus pneumoniae depending on their capsular polysaccharide antigens |
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2 Broad qualities of pathogenic bacteria by which they cause disease: |
1. invasiveness: ability to inviade tissues - Mechanisms for colonization: adhesins, invasins - ability to overcome host defense mechanisms 2. Toxigenesis: ability to produce toxins Exotoxins - produced inside mostly gram-positive bacteria as part of their growth and metabolism. Then secreted or released following lysis into surrounding medium Endotoxins - part of the outer portion of the cell wall (LPS etc) of gram-negative bacteria. Liberated when bacteria die and cell wall breaks apart - cause cytotoxic effects at tissue sites REMOTE from original point of invasion or growth |
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Bacterial Protein Toxins |
Exotoxins - differentiate virulent strains from non-virulent strains Many protein toxins are basically enzymes: - denatured by heat, acid, proteolytic enzymes - have high biological activity (act catalytically) - exhibit specificity of action; highly specific (receptor on target cell) |
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Attachment and entry of A-B protein toxins |
Many protein toxins (especially those that at intracellularly) consist of 2 components 1. subunit A is responsible for enzymatic activity of toxin 2. subunit B mediates binding to hose cell membrane (specific receptor) and internalization by endocytosis Example: Shiga Toxin (stx)-producing E. coli (STEC) - Following retrograde transfer through golgi apparatus, toxin becomes associated with rough endoplasmic reticulum, from which it is released in cytosol. Subunit A is cleaved and interacts with 28S rRNA of 60S ribosomes leading to inhibition of protein synthesis --> cell death |
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Endotoxins: LPS and virulence of Gram-negative bacteria |
toxicity associated with lipid component (lipid A) LPS remains associated with cell wall until disintegration of bacteria (autolysis, external lysis, phagocytic digestion) Results in wide spectrum of nonspecific pathophysiological reactions related to inflammation: - fever - changes in white blood cell counts - disseminated intravascular coagulation - hypotension - shock - death |
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Bacterial damage to host
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1. Direct bacterial actions (virulence factors): proteases, hemolysins, toxins Toxin induced damage can include: - cardiovascular disturbance - destruction of blood cells - diarrhea (disruption in tight junctions) - disruption of nervous sytem - plasma membrane disruption - inhibition of protein synthesis - shock 2. Inducing host immune responses - reactive oxygen and nitrogen species - inflammation - septic shock |
