bacterial pathogenesis Flashcards
definition of virulence factor
a component or trait of a pathogen that allows it to cause disease in a susceptible host
limitations of koch’s postulates
1) sometimes the organism is long gone by the time disease symptoms appear
2) many organisms are not cultivable
3) the disease may be specific to humans
T3S
“injectisome” functions as a hypodermic syringe; translocated effector proteins target various components and organelles of the host cell, corrupting their normal function for the benefit of the pathogen.
benefits of secreted virulence factors
- subverting host cell pathways to permit growth of intracellular pathogens
- preparing for the next round of infection: adhesins/invasins may be “premade” to be used later at a different site or in a different host
- preventing cell death
- remodeling the cell cytoskeleton so that the pathogen can attach better or move around the cell better
- getting around host defenses
pathogenicity is
acquired in quantum leaps rather than through gradual evolution
example of virulence plasmid
Shigella
example of phage
Cholera toxin
example of pathogenicity island
LEE: encodes T3S system and intimin; intimin does not have a receptor, so LEE brought one along
Stanley Falkow
1988 - molecular koch’s postulate
Falkow’s postulates
the gene(s) encoding the phenotype should be associated with pathogenic strains
inactivation of the gene(s) results in a reduction in virulence
restoration of the gene(s) into the avirulent mutant reestablishes virulence
virulence factors-1
colonization factors
adherence factors
invasion factors
virulence factors-2
toxins
immune evasion factors
other virulence factors (3 kinds)
motility
iron acquisiton
biofilms
adherence factors
the successful pathogen must compete with normal flora, overcome electrostatic repulsion.
initial host-pathogen interaction requires the functions of a bacterial adherence factor of a host receptor
bacterial adherence is often mediated by adhesins
invasion factors
distinguish between cell and tissue invasion
cell invasins promote internalization of pathogen into a cell
some do both
internalin
listeria invasion and cell-to-cell spread is mediated by protein named internalin
perio pathogen p. gingivalis has internalin homolog
membrane ruffling
salmonella uses T3S to secrete effectors that induce membrane ruffling
bacterial toxins (two types)
1) lipopolysaccharides associated with the cell wall of gram-negative bacteria; the LPS component of the gram negative outer membrane is also named endotoxin because of its association with the cell wall
2) proteins released into the extracellular environment (most of the protein toxins are exotoxins since they are released from the bacteria that act on host cells at a distance
endotoxin
LPS is composed of lipid A and core polysaccharide and O antigen and is released upon lysis of the bacterium during infection
lipid A
carries the endotoxin activity
O side chain
antigenic portion of LPS
endotoxemia
endotoxin in the blood
circulatory system effects of endotoxin
leukopenia followed by leukocytosis
other effects of endotoxin
effects on on metabolic and liver functions
decreased iron availability
hypoglycemia: abnormally low glucose levels
cellular death
organ necrosis
shock
death
2 broad classes of exotoxins
cellular targets
intracellular targets
cytolytic exotoxins
usually degradative enzymes or cytolysis - hemolysis, tissue necrosis, may be lethal when administered intravenously
intracellular targets
A-B dimeric exotoxins (B, binding; A, active)
B associated with absorption to cell surface and transfer of A across membrane. Once internalized, A enzymatically disrupts cell function.
receptor-mediated endocytosis (exotoxin internalization)
ADP-ribosylation of intracellular target host molecule
3 major types of bacterial cytolysis based on mechanisms of action
hydrolyze membrane phospholipids (phospholipases)
thiol(-SH)-activated cytolysins alter membrane permeability by binding to cholesterol
detergent-like activity on cell membranes; rapid rate of lysis
how do AB toxins work?
- bacterium produces and releases exotoxin
- b (binding) component of exotoxin attaches to host cell receptor.
- A-B exotoxin enters host cell by endocytosis.
- A-B exotoxin enclosed in pinched-off portion of plasma membrane during pinocytosis.
- A-B components of exotoxin separate. The A component alters cell function by inhibiting protein synthesis. The B component is released from the host cell.
examples of A-B exotoxins
anthrax toxin
shig toxin
cholera toxin
tetanus toxin
anthrax toxin
three separate proteins - protective antigen (PA); edema factor (EF); lethal factor (LF)
shiga toxin
chrom.-encoded - among most potent of all biologic toxins; inhibition of protein synthesis
cholera toxin
results in hypovolemic shock and death if no fluid/electrolyte replacement therapy
tetanus toxin
among most potent of all toxins, released upon lysis; spastic paralysis with trismus and spasms
botulinum toxins
among the most potent of biological toxins; flaccid paralysis and death
2 types of host defenses
non-specific
immune-mediated
strategies to avoid phagocytosis
- hide inside cells
- turn on flagellar motors
- provoke minimal inflammatory response
- secrete something to inhibit phagocyte chemotaxis or phagocyte uptake
- coat bacteria surface with host component to be recognized as self
- inhibit phagocytosis
examples of antiphagocytic substances
capsule k antigen m protein/fimbriae protein A slime layer o antigen
intracellular pathogens may also avoid phagocytic killing by
inhibitng phagolysosome fusion
surviving inside the phagolysosome
escaping from the phagosome
secreting aggressins
agressins
streptolysin O leukocidin exotoxin A adenylate A adenylate cyclase anthrax toxin EF
2 major mechanisms by which pathogens escape the humoral response
antigen mimicry
antigenic variation
antigen mimicry
the pathogen is naturally coated with antigens closely related to host constituents or borrows host constituents to coat itself with such that the immune system cannot distinguish between self and the pathogen
antigenic variation
the pathogen changes its antigen coat periodically to evade the ongoing immune response
3 criteria define phase variation
any need a bacterium may have to respond to rapidly changing environment
occurs by high frequency reversible genetic mechanism
no relationship between the varying trait and the underlying mechanism
3 criteria for antigenic variation
immune evasion, avoidance of immune selection
occurs by spontaneous mutation (antigenic drift)
occurs by a phase variation mechanism (when high frequency is needed)
what does most phase variation phenomena involve?
surface structures
exception: phase variation of DNA modificaiton
how was phase variation recognized historically?
by variation of colony morphology (e.g. opacity) or of easily measurable phenotypes (e.g. motility)
capsule
all-or-none on/off variation in some Gm+ and Gm-
pili (fimbriae)
phase variation mostly affects transcription at major promoter
flagella
phase variation may affect different components of the flagellum
surface proteins
Gm+ well wall or GM- OM proteins such as transporters, receptors, virulence factors or enzymes may phase vary
LPS and LOS
enzymes that modify side groups of O-antigen may phase vary
regulatory proteins
global or specific regulators
advantage of regulatory proteins
advantage is that only one gene needs to phase vary to affect the expression of many genes
genetic basis of phase variation
short sequence repeats and slipped-strand misrepairing
homologous recombination
site-specific recombination (inversion of a DNA element; insertion and excision of DNA elements)
homologous recombination
expressed allele and silent repertoire
frequency is higher than most other RecA-dependent HR events
Less homology required than in standard Rec-A dependent HR
additional cis-element required
site-specific recombination
conservative site-specific recombination can be lead to inversion, insertion or excision of DNA segment
