Bacterial Toxins Flashcards
What are bacterial toxins and what do they do?
Poisonous substances produced within bacteria and promote infection and disease by directly damaging host tissues and by disabling the immune system
Which strains of bacteria can produce toxins and are they general or specific to the species?
Virulent strains
Specific to the species
What are the effects of DT in vivo?
Inhibits protein synthesis leading to epithelial cell damage and myocarditis
What are the effects of CT in vivo?
Activates adenylate cyclase, elevates cAMP in cells leading to changes in intestinal epithelial cells that cause loss of water and electrolytes
What are endotoxins, typically what is the Gram stain, and what effects do they have?
The part of the bacteria that is toxic to the host
Gram-negative
Generalized effect
What are exotoxins, typically what is the Gram stain, and what effects do they have?
Secreted toxins with high potency that have specific effects
Mostly Gram-positive
What is an example of an endotoxin?
Bacterial LPS lipid A
Release of lipid A in small amounts overwhelms the TLR4 pathway which induces massive inflammation
What are the 3 main types of exotoxins?
AB toxins
Pore-forming toxins
Super antigens
How do bacterial toxins (exotoxins) resemble enzymes?
Protein-based
Denaturable
Catalytic activity
Have a degree of specificity
Which routes does DT use to enter host cells?
Direct entry and RME
What is direct entry and which toxins use it?
The binding of the B subunit of the toxin forms a pore to allow entry of the A subunit
Some AB toxins
How does DT enter a host cell via RME?
The B subunit binds endogenous receptors on the host
The entire toxin is internalized into a vesicle inside the host
The vesicle is transported to the endosomes where the low pH causes the A/B toxin to dissociate
The A subunit leaves the endosomes and enters the cytoplasm
What are AB toxins and what do they do?
Two-component protein complexes secreted by a number of pathogenic bacteria that interfere with internal cell function
What is an A+B toxin?
The toxin is synthesized and secreted as two independent subunits
What is an A-B toxin?
Components are synthesized separately but associate during secretion
What is a 5B toxin?
The B subunit is composed of 5 identical B subunits, synthesized separately
What is a 5B toxin?
The B subunit is composed of 5 identical B subunits, synthesized separately
What is an A/B toxin?
Components are synthesized as a single polypeptide then cleaved into subunits
What type of AB toxins are PT and CT and how do they enter the host?
5B, RME
What type of AB toxin is DT and how does it enter the host?
A/B, RME and to a lesser extent direct entry
Which receptor that DT bind to on the host cell?
HP-EGF receptor (growth factor)
What are the subunits of DT held together by and how are those bonds broken?
disulfide bridges and they are broken by host cell receptors
What does subunit A of DT do in the cytoplasm of the host cell?
Binds to and ADP-ribosylates E2F (elongation factor in transcription) which will halt protein synthesis and kill the cell
What is DT encoded by?
A prophage which is an integrated bacterial virus and only strains with the phage are virulent
What is ADP-ribosylation and what is it required for??
The addition of one or more ADP-ribose moieties to a protein required for the initiation of disease
What covalently links ADP-ribose to its target?
Subunit A
What disease does B. pertussis cause, what is it secreted by, and how can it enter the host?
Whooping cough
Type IV secretion system
RME or direct entry
What type of toxin is PT?
An ADP-ribosylating AB5-type toxin
What is the mode of action of PT?
A subunit ADP-ribosylates a regulatory G protein - target = inhibitory G protein
How does PT affect cAMP function and what does it cause?
It upregulates cAMP which causes insulin release (hypoglycemia) and cytokine release
How does PT enter the host and what does it do when it does?
A subunit can enter via RME or direct entry and PT ADP-ribosylates the alpha subunit of Gi
What does the B subunit of PT recognize?
Several different targets and acts independently as a functioning toxin
What is the main symptom of cholera and what is the toxin encoded by?
Watery discharge/diarrhea
Prophage
What do the 5B subunits associate into in CT?
A barrel structure that is often heavily glycosylated
What does heavy glycosylation allow?
Immune evasion and increased host range
What is CT secreted by?
Type II secretion system
What else does CT secrete?
A neuraminidase enzyme which removes sialic acid from the host cell receptor to facilitate CT binding
Where does cholera colonize?
The small intestine
What is CT produced in response to and which receptor does it associate with?
Infection and associates with a GMI receptor (ganglioside receptor localized in lipid rafts of enterocytes
How does CT move from endosomes to the ER?
Via retrograde transport
How does CT get to the cytoplasm?
CT is internalized by RME
At ER, A subunit leaves the endomembrane system and enters the cytoplasm via sec61 endogenous transporter
Unfolds during transport and refolds in the cytoplasm
Mode of action of CT?
Refer to notes
What is KDEL?
A 4 aa sequence in CT that acts as a euk endogenous ER retention signal
Where is KDEL located and where does it bind?
At the carboxyl terminus of the CT A subunit and it binds to Erd2 in the Golgi
What does binding at the KDEL sequence cause?
Euk host to traffic toxin from endosomes to ER
What are pore-forming toxins?
Protein exotoxins (secreted)
What do pore-forming toxins do?
They are cytotoxic and created unregulated pores in the membrane of targeted cells
What do PFTs insert into a host cell membrane?
A transmembranous pore
What do PFTs disrupt and what are they secreted by?
Disrupt selective permeability of the host
Secreted by the pathogen and assemble at the host cell membrane
What is a pre-pore intermediate and what does it do?
Pore components associate and assemble at the membrane prior to insertion
Beta-toxin
Causes an efflux of nutrients from the host
What is a partially-formed pore?
Assembly of the PFT is simultaneous with insertion
Alpha-toxin
What are examples of pre-pore intermediates and partially-formed pores?
Pre-pore = C. perfringens
Partial = S. aureus
How do partially-formed pores work?
PFT subunits bind to host cell membrane via specific interactions - lipids or proteins
What happens at an active PFT?
Toxin accumulates and oligomerizes
