Bacterial pathogens and disease Flashcards
Define pathogen, pathogenicity, virulence, toxigenicity
Pathogen: A microorganism capable of causing disease
Pathogenicity: The ability of an infectious agent to cause disease
Virulence: the quantitative ability of an agent to cause disease
Toxigenicity: the ability of a microorganism to produce a toxin that contributes to the development of disease
What mechanisms give virulence to bacteria?
Adherence factors, proteins and molecules that allow bacteria to attach to surface
Biofilm, allows bacteria to produce 3D communities and structures
Invasion of host cells and tissues, allowed by mechanisms – allows colonisation
Toxins – endotoxins and exotoxins
What are exotoxins?
Heterogenous group of proteins produced and secreted by living bacterial cells
Produced by both gram negative and gram-positive bacteria
NOT the result of breakdown products, produced by living bacteria.
Cause disease symptoms in host during disease
Act via a variety of diverse mechanisms
What selective advantage does having exotoxins give to the bacteria?
Cause disease? May help transmission of disease by promoting carriage, however in severe disease host may be a literal and evolutionary dead end.
Evade immune response
Enable biofilm formation
Enable attachment to host cells
Escape from phagosomes
allow for colonisation, niche estabilishment and carriage - evolutionary advantage
What do exotoxins produce in the case of staphylococcus aureus?
Haemolytic toxins
- Cause cells to lyse by forming pores on the membrane
- Important cause of features of S.Aureus disease
- a, B, Y toxins, Panton Valentine leukocidin (PVL), LukAB, LukEF, LukMF
Phenol soluble modulins PSM
- Aggregate the lipid bilayer of host cells – causes cell lysis, damages lipid bilayer
Majority of S.aureus in humans is asymptomatic carriage in the nose and respiratory tract, and skin.
How does PSM help bacteria, starting cell cell phagocytososing bacteria
A. Cell, phagocytosing bacteria. PSMs allow bacteria to escape from phagosome. Alpha toxins block the binding of lysosomes to the phagosome, avoiding the destruction by acidification and enzymes released by lysosomes.
B. PSM useful at helping S.aureus in displacing other bacteria in the environment. By killing all the bacteria, it can find a niche and be dominant.
C. S.Aureus releases PSM as it allows it to slide through certain media like throats and mucosal sites.
D. Alpha toxins, beta toxins and PSM help initiate formation of biofilms, a community of bacteria that first need to find a niche and attach, accumulate and then interact with other molecules and different organisms to form a secondary structure.
Alpha and beta toxins allow this process. PSM helps chunks of that biofilm move and aids carriage.
What can exotoxins be encoded by?
Encoded by chromosomal genes Shiga toxin in Shigella dysenteriae, TcdA and TcdB in C.difficle.
Many toxins coded by extrachromosomal genes :
- Plasmids – Bacillus anthracis toxin, tetanus toxin
- Lysogenic bacteriophage (viruses of bacteria) – e.g streptococcal pyrogenic exotoxins in Scarlet Fever, Diphtheria toxin
toxins can be transferred, species that could not cause disease now cause disease
Toxins can be classified by the toxins activity
What are the issues with this classification?
- Membrane acting toxins – type 1
- Membrane damaging toxins – type 2
- Intracellular toxins – type 3
2.
Many toxins may have more than one type of activity
As mechanisms better understood by this classification tends to break down
Where do type 1, mechanism activating toxins:
Act
Interfere
Target
Act:
- Act from without the cell
Interfere:
- Interfere with the host cell signalling by inappropriate activation of host cell receptors
Target:
Target receptors include
- Guanylyl cyclase – increased intracellular cGMP
- Adenyl cyclase – increased intracellular cAMP
- Rho proteins
- Ras proteins
acting on cGMP and cAMP messes up central signalling pathways of host cells + conserved pathways, potential to cause severe diseases as most cells rely on production of cGMP and cAMP.
How do type 2, membrane damaging toxins cause damage to the host cell membrane?
1.
- Insert channels into the host cell membrane, disrupting the potential and transport of ions
- Beta sheet toxins e.g S.aureus a-toxin, y toxin, PVL
- Alpha helix toxins e.g diphtheria toxin
- Enzymatical damage that damages the cell e.g S.aureus Beta – haemolysin, PSM
Or
- Receptor mediated
- Receptor independent
Where are intracellular toxins, type 3 active?
What two components is it made of?
- Active within the cell – must gain access to the cell
Usually 2 components – AB toxins
- Receptor binding and translocation function – B
- Toxigenic (enzymatic) - A
- May be single or multiple B units e.g Cholera toxin AB5 – 5 B subunits.
Component B is the one that binds to the cell surface receptor to allow for internalisation of the toxin.
A is toxic and has enzymatic activity or tampers with metabolism of the cell – acts within cell.
Enzymatic component A of type 3 toxins has a wide variety of activities
ADP – ribsoyl transferases e.g Exotoxin A of Pseudomonas aeruginosa, pertussis toxin
Glucosyltransferases e.g TcdA and TcdB of Clostridium difficile
Deamidase e.g dermonecrotic toxin of Bordetella pertussis
Protease e.g Clostridial neurotoxins: botulism and tetanus
Adenylcyclase e.g EF (edema factor) toxin Bacillus antrhacis
Bacteria have different types of secretory mechanisms
Give examples
Secretions
And toxin injections
Multi-molecule complexes that act like needles.
Can have multi-meric secretory system, a pump of toxins like toxin CagA in Heliobacter pylori
On the left is an inner and outer membrane of a cell, a subunit protrudes and interacts with the host membrane to inject toxin.
e.g YopE in Yersinia species
What do exotoxins induce the release of?
Induce release of inflammatory cytokines
IL1, IL1B(beta), TNF, IL6, interferon y, IL18
How do supernatigens interact with the immune system and cause disease?
Superantigen: non-specific bridging of the MHC class II and T-cell receptor leading to cytokine production
e.g Staphyloccal Exfoliative Toxin A, toxic Shock Syndrome Toxin I (TSST1)
Via activation of the different inflammasome leading to release of IL1 Beta and IL18 e.g S.aureus toxin A, PVL
What is the pathogenesis of C.difficile?
What two effects does GTD binding to Rho GTPases lead to?
Receptor binding domain binds to receptor, toxin internalised
Endosome acidifies, allows for increase in activity of CPD (cysteine protease domain)
and interaction of DD (delivery hydrophobic domain) allows for the release of the toxin from the endosome
GTD (glucotransferase domain) released from the endosome to the host cell cytoplasm thanks to protease activity of CPD
Binds to Rho GTPases, leading onto two effects
- Cytopathic effects – cytoskeleton breakdown, loss of cell-cell contacts, increased epithelial permeability - and other functions that depend on cytoskeleton like renewal of cells, division of stem cells etc. Prolonged damage.
- Cytotoxic effects – activation of the inflammasome, increase in ROS levels (causes bystander damage) , induction of programmed cell death
