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Pathogenic bacteria & virulence factors
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What is a pathogen? pathogenesis:
interpreted relative to outcome to host microbe host damage (disease) pathogenesis: Goal - not a comprehensive microbial pathogenesis course - use model bacterial systems to explore mechanisms of microbial pathogenesis
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Types of microbes causing infectious disease
Type Branch Cellular? Genome Nuclear Example (Kingdom) membrane? Metazoan Eucarya yes DNA yes Ascaris parasites (Animalia) lumbricoides Protozoan Eucarya yes DNA yes Plasmodium parasites (Protista) falciparum Fungi / Eucarya yes DNA yes Candida yeasts (Fungi) albicans Bacteria Eubacteria yes DNA no Streptococcus (not Archaea) pyogenes Viruses no DNA/RNA no Herpes simplex Prions no no genes no BSE (Mad Cow Disease)
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How do you identify a pathogen?
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Confirming Germ theory of disease
Robert A. Koch Koch’s Postulates Confirming Germ theory of disease Bacteria must be associated with the lesion Bacteria must be isolated in pure culture Isolated bacterium must produce disease when inoculated into human or animal Bacteria must be re-isolated from intentionally infected animal or human not all bacteria can be cultivated on artificial medium Caveats 2. Cultivation difficulties 3. Potential problem in developing appropriate animal model system no animal models for some diseases
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Molecular Koch’s Postulates
Nucleic acid sequence of pathogen should be found in association with disease or diseased organ Nucleic acid sequence should be absent from healthy individual Resolution of disease should result in decrease in pathogen associated nucleic acid sequences Presence of pathogenic nucleic acid in a healthy individual should predict development of disease Nature of the microorganism inferred from nucleotide sequence should be consistent with biological characteristics of organism Sequence based findings should be reproducible
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How to distinguish infection from colonization ~
colonization disease = infection vs. colonization by normal flora disease ≠ infection Diagnosticallysometimes difficult to distinguish between normal flora and pathogen colonization of an infectious agent no disease = asymptomatic carrier
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Asymptomatic colonization by pathogenic bacteria
Group B streptococci .… >24% of females - vaginal (neonatal septicemia / pneumonia / meningitis) Streptococcus pyogenes … % - nasopharynx (strep throat / rheumatic fever / “flesh-eating disease”/ scarlet fever) Streptococcus pneumoniae % - nasopharynx (pneumonia / septicemia / meningitis / ear infections) Staphylococcus aureus …. >40% - anterior nares (hospital infections, septicemia, pneumonia)
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Disease function of susceptibility of host relates to mechanism of
bacterial pathogenesis immune competent/compromised immunizations age trauma genetics antimicrobial therapy I. secretion of factors (toxins) II. direct host cell manipulation
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Host bacterial defenses
Natural barriers normal flora - affected by diet / antibiotics (competitive exclusion) pH - acidic / alkaline (inhibits growth) mucin - viscous glycoproteins (barrier / bacterial trapping) defensins - antibacterial peptides (damage bacterial membranes) collectins - lectins (bacterial aggregation) (PRR) epithelial shedding - (removes attached bacteria) Innate immune response PRR - (pattern recognition receptor) macrophages / PMNs / dendritic cells / NK cells / mast cells / basophils / eosinophils Acquired immune response B-cells / antibody production - extracellular bacteria T- cells / cytotoxity response - intracellular bacteria
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Emergence of infectious disease ~
Boundary Barrier habitat / niche (reservoir) homeostasis emerging infectious disease re-establish balance time habitat change adapt by regulation mutation gene transfer most successful bacteria achieve balance with environment (host)
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Two basic types of pathogens
overt (exogenous) pathogen - aggressive pathogen, requires acquired immunity for host defense opportunistic (endogenous) pathogen - becomes a pathogen when host is compromised damage to epithelium introduction of bacteria to sites where they are not normal flora - linked to presence of foreign body, catheters, prosthesis, biofilms disruption of normal flora by antibiotics suppression of immune system by drugs impairment of host defenses due to infection
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Types of diseases caused by bacteria
Localized infection: e.g. Clostridium tetani - spores enter / germinate in deep wound - toxin produced - toxin disseminates Disseminated infection: e.g. Staphylococcus aureus - wound infection / abcess - organism invades bloodstream - organism invades heart, kidney, lungs, brain bones Intoxication: e.g. Clostridium botulinum - spores in contaminated food germinate, multiply, produce toxin - toxin ingested - botulism
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What is the difference between virulence and pathogenicity?
virulence = pathogenicity (ability to cause disease)
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Measurement of virulence
(Salyers and Whitt, 2002) higher virulence lower virulence LD50 vs. ID50 LD50 - number of bacteria needed to kill 50% of animals ID50 - number of bacteria necessary to infect 50% of the animals exposed to the bacterium
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What is a virulence factor?
Any microbial product or strategy that contributes to disease ~ Infectious process ~ colonization growth establish disease
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Virulence factors of bacteria
I. adherence / colonization: pili motility / chemotaxis (flagella) outer membrane proteins II. infectious process: exotoxins / endotoxins type III / type IV secretion processes intracellular growth (invasion) III. protection against host defense: capsule / cell wall / outer membrane antigenic variation biofilm formation
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I. Adherence / colonization:
pili motility / chemotaxis (flagella) outer membrane proteins
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pilus-pili-fimbraie Function: - in attachment
Scanning electron micrograph showing microcolonies of EPEC displaying the characteristic localized adherence pattern of adherence to HEp-2 cells. Function: - in attachment - movement on host cell surface - immunodominant protein neutralized by host antibodies vaccine candidate
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flagellum / flagella Function: helical filament rotates - used for
- swimming - chemotaxis - filaments rotate together either clockwise or counterclockwise ccw rotation = smooth swimming cw rotation = a “tumble” - flagellin - PAMP
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flagella movement: Smooth swimming Tumble
Macnab, Ornston, 1977 Kahn 1978) Smooth swimming Tumble (Copyright: ASM Hoch and Silhavy p. 91,) counter-clockwise rotation clockwise rotation
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chemotaxis: (movement in response to an environmental stimuli)
no attractant attractant - bacteria move by a biased random walk
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outer membrane proteins
(Prasadarao et al, Infect. Immun. 1999) E. coli invasion E. coli - OmpA facilitated binding / invasion Antibody - against OmpA blocks invasion outer membrane proteins (OMPs) Function: - adhesin - invasion
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II. Infectious process exotoxins / endotoxins
type III / type IV secretion system intracellular growth Model infectious agents will be used to examine mechanisms of bacterial pathogenesis
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Bacterial model systems ~
Bacterial toxins: diphtheria toxin - cholera toxin Clostridium neurotoxins S S A-subunit B-subunit L enzyme activity / receptor binding / internalization intracellular trafficking mechanism of toxicity protein design (structure vs. function) vaccine production tool to manipulate host cell function toxin re-design for therapeutics biological warfare
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Bacterial model systems ~
Intracellular survival (invasion): Shigella flexneri Listeria moncytogenes Legionella pneumophilia macropinocytosis/memb ruffling zipper-type coiling phagocytosis (from P. Cossart, Cellular Microbiology, 2000) Mycobacterium tuberculosis Yersinia spp. Listeria monocytogenes
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Bacterial model systems ~
Bacterial secretion: (Kubori, 1998, Blocker, 2001, Plano, 2001) type III secretory process direct manipulation of host cell signaling proteins Pseudomonas aeruginosa Salmonella spp.
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Bacterial model systems ~
Emerging diseases: Escherichia coli Comparison of pathogens EPEC ETEC EAggEC EHEC - (OH157:H7) EIEC Salmonella Shigella DAEC - diffusely adhering E. coli
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III. Bacterial protection against host defense
antigenic variation capsule / cell wall / outer membrane biofilm formation
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Neisseria gonorrhoeae adaptation - antigenic variation of pili
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capsule /cell wall /outer membrane
The surface of Bacillus anthracis. The bacterial membrane is evident as the innermost layer surrounding the cytoplasm. P denotes the peptidoglycan cell wall. S refers to the S-layer which consists of two proteins including the major antigen. C denotes the poly-D-glutamic acid capsule that is exterior to and completely covers the S-layer proteins. (From Mesnage, et al. Journal of Bacteriology, 180:52-58, 1998)
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capsule (highly hydrated gelatinous matrix - composed of carbohydrates and proteins) Function: - resistance to phagocytosis, desiccation, antibiotics, detergents - highly antigenic (K antigen of bacteria) used in vaccines - attachment / sequestration of nutrients - loss of capsule can result in loss of virulence Streptococcus pneumoniae - Capsule is composed of polysaccharide. It is the most important determinant of virulence ~ allows the bacteria to escape phagocytes in the lung. India ink stain. (K. Todar) Bacillus anthracis - Capsule is composed of poly-D-glutamic acid. It is anti-phagocytic and protects the bacteria from complement- mediated lysis in serum or blood. Fluorescent- tagged antibody. (CDC) Streptococcus pyogenes - Capsule is composed of hyaluronic acid, the same polymer found in human connective tissue. This is an antigenic disguise that prevents bacterial recognition by the immune system. Transmission electron micrograph. (M. Fazio, V. Fischetti, Rockefeller University)
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(living capsule - 3D-bacterial community growing on a surface)
biofilm (living capsule - 3D-bacterial community growing on a surface) Function: - resistance to antibodies, phagocytosis, desiccation,antibiotics, detergents - attachment / sequestration of nutrients - formation of inter-dependent microbial communities ( quorum_talk.html) Bacterial biofilm - magnified 7,000x Examples of biofilms: dental plaque growth on catheters growth in heart tissue chronic cystic fibrosis lung infection natural biofilm - slimy (green) mass attached to rocks in mountain streams
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Concepts terms ~ pathogenesis /virulence, colonization, infection, disease understanding of a pathogen ~ origin of emerging infectious disease types of diseases caused by bacteria definition of virulence factor ~ types of virulence factors those that affect: I. adherence / colonization II. infectious process III. protection against host defense
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