Bacteriology - pathogenesis Flashcards
What is the name of bacterial that replicate in the host without causing disease?
Commensals
What are virulence factors?
Bacterial adaptations that contribute to pathogenesis
What features of bacteria aid colonization?
Pili, fimbriae and polysaccharide capsules
What do Koch’s postulates describe?
They are four criteria designed to establish a causative relationship between a microbe and a disease
What are Koch’s postulates?
1) The microorganisms must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms
2) The microorganism must be isolate from a diseased organism and grown in pure culture
3) The cultured microorganism should cause disease when introduced into a healthy organism
4) The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identified to the original specific causative agent
What is bacteraemia?
The presence of bacteria in the blood
What can bacteraemia lead to?
The immune response to the bacteria can cause sepsis and septic shock
Which severe infections can cause bacteraemia?
Pneumonia or meningitis
What is sepsis?
When the body’s response to infection causes injury to its tissues and organs
What is septic shock?
Condition that occurs when sepsis leads to life-threatening low blood pressure
Give basic examples of immune evasion
- Host mimicry
- Antigenic variation
- Recruitment of immune modulators
- Subversion of immune responses
How may gene transcription be regulated during bacterial growth?
- Nutrient sensing
- Two component signal transduction
- Quorum sensing
What is nutrient sensing?
Gene transcription regulated by detection of specific nutrients
What is two-component signal transduction?
Sensor detects an environmental factor and phosphorylates a regulator that activates gene transcription
What is quorum sensing?
Changes in cell-population density alter levels of diffusible autoinducers (that increase in concentration as a function of cell density) that bind to transcriptional activators inducing gene transcription - in effect, quorum sensing is a mechanism of communication between bacteria
Give an example of a bacterial cell component that mediates adhesion
Type 1 pili → mediate E.coli adhesion to human bladder epithelial cells → cystitis
Give examples of intracellular pathogens
Salmonella
Shigella
MTB
What is speticemia?
The poisoning of the blood by bacteria of their toxins
How may bacteria invade tissues?
- enzymes that degrade matrix (e.g. hyraluronidase, elastase)
- Some IC bacteria use ligand receptor interactions to gain access to a cell → example is TB → uptake is initiated by interaction between either the macrophage mannose receptor or the complement receptors, and bacterial surface proteins
What types of bacteria secrete exotoxins?
Both G+ and G-
What is the composition of exotoxins?
They are proteins
What are invasins?
Toxins that have a local activity in promoting bacterial invasion
What are exotoxins usually encoded on?
Plasmid or bacteriophage DNA, rather than on the bacterial chromosome
Do endo- or exotoxins have a higher toxicity?
Exotoxins
Do endo- or exotoxins have a higher specificity to bacterial strains?
Exotoxins
Give examples of some mechanisms of action of exotoxins?
ADP-ribosylation Protease activity Cleavage of other substances Superantigens Glucosyltransferases Pore-forming toxins
What are molecular Koch’s postulates?
A set of experimental criteria that must be satisfied to show that a gene found in a pathogenic microorganism encodes a product that contributes to the disease caused by the pathogen
What are genes that satisfy molecular Koch’s postulates known as?
Virulence factors
What are the molecular Koch’s postulates?
1 - the disease phenotype should be associated with the pathogenic members of a genus, or strains of a species - it should be absent from pathogenic ones
2 - Specific inactivation of virulence trait genes should lead to a loss in pathogenicity
3 - Reversion or replacement of the mutated gene leads to restoration of pathogenicity
Example of exotoxin acting via protease acitvity
Botulinum toxin released by Clostridium botulinum
What does botulinum toxin do?
It is a neurotoxin which functions by cleaving SNARE proteins involves in the release of ACh at the NMJ → inhibits ACh release at NMJ → muscle paralysis
Give an example of a toxin that cleaves something other than proteins
Alpha toxin secreted by Clostridium perfringens
What does alpha toxins from Clostridium perfringes do?
It is a phospholipase which cleaves cell membranes and kills the cell
How do superantigens function?
By binding non-specifically to MHCII of APCs which then activate Th cells, without any need to undergo intracellular processing → massive release of cytokines which causes symptoms of toxic shock such as hypotension and fever
Give example of toxin acting as glucosyltransferase
Toxins A and B released from Clostridium dificile
What do toxins A and B released from C.dificile do?
They glycosylate GTPase which usually maintain the actin cytoskeleton → leads to apoptosis → this leads to characteristic watery diarrhoea due to compromised intercellular junctions
Example of extracellular pathogen
Neiserria meningitidis
Where does endotoxin come from?
outer leaflet of the outer bacterial cell membrane in Gram negative bacteria
What does LPS consist of?
- Conserved lipid A which is the endotoxin part of the molecule
- A conserved polysaccharide core
- A highly variable O-antigen which consists of a repeating polysaccharide chain of varying length
What PRR does LPS eventually activate?
TLR4
What are the major effects of endotoxin?
- Activation of macrophages, complement, Haegman factor
- These lead to fever, hypotension, inflammation, vascular coagulation
- this is often called SIRS
What is the mechanism of action of LPS?
Binds to lipid binding protein → transfers it to CD14 on the cell membrane → transfers it to MD2 → this associates it with TLR4 → this is coupled to NFkB
Brief explanation of Shigella pathogenesis
- By translocation through M (microfold) cells
- M cells are specialised ECs that sample particles from gut lumen and present them to underlying mucosal lymphoid tissue
- After this, shigella is released from the M cell to get into the cytoplasm of the intestinal epithelial cells through basolateral side
- Once inside EC, it moves by directed polymerisation of actin to adjacent cells
- This elicits a strong inflammatory response
What mediates epithelial cell entry of Shigella?
- Secretion of effector proteins by a type 3 secretion system at the basolateral membrane of the EC
- This causes cytoskeletal rearrangement and lysis of vacuolar membranes for phagosome escape
Where does Shigella invade?
Colon
Where does Salmonella invade?
The small intestine epithelial cells in a similar manner to Shigella (translocation through M cells)
Where in the epithelial cells does Salmonella grow and survive?
In the phagolysome
Describe secretion systems of Salmonella
It has two T3SSs
- SPI-1 → entry into non-phagocytic cells - induction of intestinal inflammatory responses and diarrhoea
- SPI-1 → intracelular survival and replication (in macrophages) and induction of systemic disease
Do G+ or G- typically have a T3SS?
G-
What does the T3SS apparatus consist of?
Two rings that provide a continuous path across the inner and outer embranes, including the peptidoglycan layer
Also has a needle-like structure
Give examples of some bacteria that are associated with T3SSs
EPEC, EHEC, Shigella, Salmonella
Endotoxin is produced by…
G-
Draw endotoxin
Look at essay plan
What does LPS consist of?
- Conserved lipid A
- Conserved polysaccharide core (same within a genus of bacteria)
- A highly variable O-antigen which consists of a repeating polysaccharide chain of varying length
What are the effects of endotoxin?
Activation of macrophages → Hypothalamic temperature regulatory centre → fever
→ NO vasodilation → hypotension
Activation of complement → inflammation
Activation of Haegman factor → coagulation
What can endotoxin ultimately lead to?
Endotoxic shock → severe, generalized inflammatory response induced by bloodstream infection with G- bacteria
Give an example of an ADP-ribosylation toxin
- often the mechanism by which enterotoxins cause diarrhoea (e.g cholera toxin, hexamer of 5CTB and 1CTA)
- CTB binds enterocytes
- CTA ribosylate GPCR, ultimately leading to Cl- efflux
Example of toxin with protease activity
Botulinum
Cleaves SNARE
Example of protein causing cleavage of other substances
Alpha toxin from Clostridium perfringens
Cleaves cell membranes
Example of superantigen
TSST
Bind non-specifically to MHCII of APCs which then activate Th cells, without any need to undergo intracellular processing
Results in a massive release of cytokines (e.g. IL-1 and IL-2), causing symptoms of toxic shock such as hypotension and fever → cytokine storm
Give examples of invasins
EC enzymes which degrade tissue allow bacterial spread (collagenase, hyaluronidase, streptokinase)
What roles does LPS play?
- acts as a protective permeability barrier
- adhesion
- variations of LPS allow different antigenic strains, allow species to bypass immunity
What is the mechanism of LPS?
- Binds to liid binding protein
- LB in serum which transfers it to CD14
- transfers it to a non-anchored protein MD2
- this associates it with TLR4
- TLR4 is coupled with NFkB which is the source of the symptoms of shock
Where does BoNT primarily act?
NMJ → inhibits cholinergic transmission and leading to an instability of alpha motor neurons and muscles to communication and lead to contraction → flaccid paralysis
Where does TeNT act?
- retroaxonally transported from peripheral neurones to inhibitory neurons where cholinergic transmission is inhibited, leaving excitatory stimulation of motor neurons unoppsed and resulting in spastic paralysis
What toxins mediate diarrhoea in Clostridium difficile infection? What do these do?
Enterotoxin (toxin A) mediates apical entry
Cytotoxin (toxin B) enters basolaterally
What are the mechanisms of the two clostrium difficile toxins?
Both are glucosyltransferases which target and inactivate Rho GTPase
This impairs the cell funtions downstream from these
Main virulence factor of N.meningitidis
Capsule
What structure associted with the bacterial cell wall of certain strains of Streptococcus pneumoniae prevents phagocytosis?
Capsule
Examples of encapsulated bacteria
E coli (some strains) N.menigitidis Salmonella typhi Strep. pneumoniae and pyogenes S aureus
Capsule - more common in G+ or G-?
more common among G-
What is the capsule of S.pyogenes composed of?
Hyaluronic acid
What secretion system does shigella use?
T3SS
Where does salmonella invade?
The small intestine
Where does shigella invade?
colon
