Bacterial exotoxins- Lecture 20 Flashcards
Stages of Infection
Colonization and entry into host cells, evade the immune system and damage the host
Patterns of pathogenesis
(1) produce investable toxins
(2) proliferate at mucous membranes and inject effectors (toxins) into the host cell
(3) Evade the immune system to live inside cells
(4) Enter cells and release toxins inside
Primary mechanisms of adhesion
Adhesion are proteins found on the tips of pili
also, use T6SS to inject effectors to mediate uptake
Ways of penetrating the mucous membranes
(1) direct uptake into epithelial cells
(2) Transverse M cells to mediate being eventually uptake into M cells
How are M cells transversed by bacteria?
(1) Use a section system, i.e. (T3SS) to generate membrane ruffling
(2) Use cell-damaging proteins to enter cells and subsequently enter nearby cells (epithelial cells)
How does Shigella enter M cells?
(1) Enters into M cells
(2) Macrophages engulf the shigella
(3) pathogen is released from macrophages and has broken mucous membrane giving ability to infect epithelial cells
Exotoxins
Typically secreted upon lysis of bacteria into the surrounding fluid, toxins that can be effective with or without the pathogen present
Targets of exotoxins
(1) Neurotoxins: Neurons and nervous system
(2) cytotoxins: organs throughout the body
(3) Enterotoxins: gastrointestinal toxins
How does the immune system react to toxins?
produces antibodies, but may be too slow to react to fast-acting toxins
Toxoid
Used for vaccines, a non-toxic version of the toxin that is highly antigenic
Classes of toxins
(1) AB toxins: B subunit mediates entry of the A subunit (toxin)
(2) Hemolysins: includes phospholipase, pore-forming and detergent toxins
(3) Superantigens: causes over-activation of the immune system and cytokine storms, since it leads to over-recruitment of T-cells
Botulinum toxin
(1) A neurotoxin that causes paralysis, produced by Clostridium botulinum under anaerobic conditions (i.e., canned foods), heat-labile so heating is insufficient
(2) Toxin enters cells through receptor-mediated endocytosis
(3) Acidification of the Endsome triggers the release of A subunit
(4) A subunit (peptidase) cleaves SNARE proteins, prevents exocytosis of vesicles that carry neurotransmitters, blocks acetylcholine release from pre-synaptic nerves and prevents innervation of muscle tissue
What activity does the A subunit of botulinum toxin have?
Peptidase activity, cleaves SNARE proteins
Tetanospasmin toxin
Neurotoxin produced by Clostridium tetani, Enters neurons in muscles through receptor-mediated endocytosis, travels back to CNS through retrograde axonal flow from motor neurons to the spinal cord
Cleaves SNARE proteins in inhibitory neurons usually lead to suppression of involuntary muscle contractions but SNARE cleavage prevents exocytosis of vesicles, resulting in continuous muscle contraction
Cholera toxin
Enterotoxin AB, produced by Vibrio Cholera (aquatic bacteria), the toxin is produced following colonization of intestinal epithelial and adherence using pili
Entry into cells: the five B subunits bind microvilli receptors on enterocytes, creating portal for A subunit entry
ADP-ribosyltransferase (A subunit) transfers the ADP-ribose group to the G-proteins, keeps it on indefinitely, leads to overproduction of CAMP, turns off CFTR (cystic fibrosis transmembrane conductance regulators), causes loss of water and ions from infected enterocytes leads to watery diarrhea
Self-limiting infections
if host hydrates well enough they can survive without the use of antibiotics since the pathogen cannot survive for a long-time inside the host
Anthrax
AB cytotoxin produced by bacillus anthracis, spore-forming bacteria, lies dormant until access to epidermis, lung or intestinal tissue, produces two virulence plasmids pOX1 and pOX2
pXO1 plasmid activity
(Anthrax toxin) contains B-Subunit: protective antigen, and A-subunit: edema factor and lethal factor
B subunit binds anthrax toxin receptor, monomer B Is cleaved by Furin (protease) to produce heptamer that allows for A-subunit receptor-mediated endocytosis
B-subunit forms pores in the end-some following acidification
Edema factor: adenyl cyclase, increases CAMP levels leading to loss of water and ions
Lethal factor: metalloprotease, inactivates mitogen-activated protein kinase kinases, kinases are essential for cell growth leads to apoptosis
Diphtheria toxin
Produced by Corynebacterium diphtheria, infects the throat and releases the exotoxin, mild sore throat and fever lead to malaise and fatigue
Toxin leads to tissue destruction after some time leads to a whiteish and gray appearance of tonsils
ADP-ribosyltransferase halts translation in specific tissues
How does the Diphtheria toxin halt protein translation
B-subunit binds to heparin-binding epidermal growth factor receptor, triggers receptor-mediated endocytosis
Endocytosis followed by acidification of the endsome stimulates proteolytic processing of the A subunit, (cleaves key disulphide bond) and releases catalytic domain into the cell
A subunit targets translation elongation factor 2 (ETF 2), required for polypeptide elongation during translation
A subunit (ADP-ribosyltransferase) adds ADP-ribose group to EF2 to inactivate it
Gas Gangrene
Membrane-degrading phospholipase enters open wounds and germinates when the environment is sufficiently anaerobic enough to produce a toxin
Toxin Is a metallophospholipase, with similar activity to phospholipase C (hydrolysis of head groups of phospholipids) and required zinc for activity
Produces diacylglycerol as a product of lysis, can act downstream activating cell pathways: arachidonic acid and thromboxane A2, resulting in tissue damage (Edema) and swelling
Causes muscle tissue breakdown and gas ferments amino acids and muscle glycogen which causes infection to spread quickly and no specific antibiotics or vaccines are available.
