Bacterial Pathogens and Disease - EXOTOXINS Flashcards
What is a pathogen?
A microorganism capable of causing disease
What is pathogenicity?
The abillity of an infectious agent to cause disease
What is virulence?
The quantitative abillity of an agent to cause disease
What is toxigenicity?
The abillity of a microorganism to produce a toxin which contributes towards the development of diseases
List some virulence mechanisms
- Adherance factors
- Biofilms
- Invasion of host cells and tissues
- Toxins - endotoxins and exotoxins
What are exotoxins?
Exotoxins are a group of hetergeneous proteins which are produced and secreted by gram + and gram - living bacterial cells
- Cause disease symptoms in the host
- Act via a variety of diverse mechanisms
What is the purpose of bacteria having exotoxins?
- Exotoxins will cause disease → However in a severe disease may cause death meaning bacteria will not be able to replicate and cause an evolutionary dead end
- However, with many toxins the disease causing activity may not be the primary function others include:
- Evade immune response of host
- Enable biofilm formation
- Enable attachment of host cells
- Escape from phagosomes
What can functions such as evading immune response, biofilm formation, attachment of host cells and escape of phagosomes result in?
- Allow for colonisation, niche establishment and carriage = Evolutionary advantage
Looking at Staphylococcus aureus what toxin does it produce and what are their functions?
-
HAEMOLYTIC TOXINS = Causes cells to lyse by forming pores
- Important feature of S.aureus disease
- α,β,δ, toxins ,Panton Valentine Leukocidin (PVL), LukAB, LukED, LukMF
- Important feature of S.aureus disease
- PHENOL SOLUBLE MODULINS (PSM) = Causes lipid bilyaer of host cells to break down through aggregation - lysis
What happens when these toxins are released in the nose?
- Alpha toxins and PSMs prevent phagolysosome formation by blocking fusion of the lysosome with the phagosome
- PSMs will kill any cohabiting bacteria in the nose giving S.aureus an advantage by reducing competition
- PSMs will have surfactant properties and allow S.aureus to slide across surfaces (as its not too motile on its own)
- Biofilm formation → Alpha toxins enable bacteria to attach to a surface and grow, beta toxins aid in secondary structure formation, PSMs allow for further growth and detachment so bacteria can go and disperse to new sites of infection
Expand on the genetics of exotoxins
- Can be encoded by chromosomal geens
- Shinga toxin in Shingella Dysenteriae, TcdA and TcdB in C.dificile
- Many toxins are also encoded by extrachromosomal genes
- Plasmids – Bacillus anthracis toxin, tetanus toxin
- Lysogenic bacteriophage e.g. streptococcal pyrogenic exotoxins in Scarlet Fever, Diphtheria toxin
How can exotoxins be classified?
- Membrane Acting Toxins = Type I
- Membrane Damaging Toxins = Type II
- Intracellular Toxins = Type III
Describe Type I Exotoxins
These are MEMBRANE ACTING
They act from without the cell and interfere with host signalling by inappropriate activation of host cell receptors on membrane
Give some examples of target receptors that type I exotoxins receptors activate
Target receptors include:
- Guanylyl cyclase increase intracellular cGMP
- Adenyl cyclase increase intracellular cAMP
- Rho proteins
- Ras proteins
See notes for E.Coli heat stable toxin
Heat stable toxin binds to the GC-C receptor and producing cGMP acts on CFTR which increases electrolyte secretion (Cl-,HCO3-) = secretory diarrhoea
Describe type II Exotoxins
- These are MEMBRANE DAMAGING
1) Insert channels into host cell membrane - β sheet toxins e.g S.aureus α-toxin, γ toxin, PVL
- α helix toxins à e.g diptheria toxin
2) Enzymatic damage e,g S. aureus β-haemolysin, PSM
These can either be receptor mediated or receptor independant
Describe type III Exotoxins
- These are INTRACELLULAR TOXINS
There are usually two components one with allows toxin entry and one which causes damage
- Receptor binding and translocation function - B
- Toxigenic (enzymatic) – A
- May be single or multiple B units e.g. Cholera toxin AB5
Some bacteria will also contain a needle like system through which they can directly insert the toxin inside the cell without receptor interaction e.g CagA in H.Pylori
Expand on superantigens and cytokines
Exotoxins are able to induce inflammatory cytokine release IL1, IL1β, TNF, IL 6,δ interferon, IL18
MECHANSIMS:
1) Superantigen – nonspecific bridging of the MHC Class II and T- cell receptor leading to cytokine production.
E.g. Staphylococcal Exfoliative Toxin A, Toxic Shock Syndrome Toxin 1 (TSST1)
2) Inflammasome which will detect damage to cells and results in activation of the different inflammasome leading to the release of IL1β and IL18 e.g. S. aureus toxin A, PVL.
Describe the mechanism of the TcdA and TcdB toxin
- Toxin will bind to specific host cell receptors
- The toxins are internalised by the cell
- The endosome in which the toxin is in is acidified
- There is pore formation on the endosome
- GTD is released from endosome to the host cell cytoplasm
- Rho GTPases are inactivated by glycosylation
- Down stream effects (cytopathic and cytotoxic effects)
Describe the mechanism of the Shigatoxin
- Toxin will bind to receptors on the surface Gb3 and Gb4
- Bound toxin is internalised by receptor mediated endocytosis
- Carried by retrograde trafficking via the Golgi apparatus to the ER
- The A subunit (active component) is cleaved off by membrane bound proteases
- Once in cytoplasm A1 and A2 dissociate
- A1 will bind to the 28S RNA subunit → Blocking protein synthesis
