Staphylococcus aureus: A super bug Flashcards
Staphyloccus aureus
Its a classical organism first identified by Robert Koch.
Its gram positive so has a thick cell wall around the outside. It means a bunch of grapes - forming clusters which is important for its pathogenicity. Its golden because of a pigment found in its membrane, giving it its colour.
It has the capacity to divide in 3 different planes and for the daughter cell remain stuck together- becomes important in pathogenesis.
S. aureus Lifecycle
Its an opportunist pathogen. It will try and inhbait anywhere and will cause disease
In doing so, it causes a wide range of different infections. For example nosocomial infections (that you pick up in hospitals). It forms biofilms because the cells stick together and can stick to surfaces, therefore its quite difficult to eradicate. Its also antibiotic resistant
What diseases can it cause
Many are initiated via wounds
- Furnacles (boils): superficial, self limiting infections- they then have the capacity to spread around your own body of someone else
-Pyomyositis: This is when an abscess forms underneath the skin - easiest way to treat this is to be an incision and release the bacteria. In itself isn’t life threatening but the bacteria can spread to cause other things - Endocarditis: This is on the heart valve- it degrades the heart valve.
- Indwelling devices: Many S. aureus infections you pick up in hospital, because the bacteria are there and because you might in a situation where your skin might be being breached.
- Toxic shock syndrome: S. aureus can also cause TSS. This is mostly prevalent in younger children
All of these can spread, leading to septicemia in the blood
How can one organism cause so many diseases?
- Highly adaptable- its an opportunist pathogen. It finds itself in a particular pathogen, it will try and survive and grow- it responds to environment conditions
- It has multiple virulence determinants
Infection-associated dynamics
- Interaction with specific target tissue: needs to recognise that environment.
- Then needs to proliferate and it needs to avoid our host defences - our primary line of defence against it- avoid innate
- It needs to cause local damage
- It then needs to disseminate of product or pathogen which can lead to systemic disease
Importance of the immune system
We can survive against S. aureus because of our innate immune system. Initial abscess leads to acute inflammatory reactions. Without these, we would be dead
Neutrophils are produced 10 to the 9/ day/ kg in a human - they are the gatekeepers for infection.
What is chronic granulatomous disease
Its a fatal hereditary defect - neutrophils fail to make H2O2 so no oxidative killing. These individuals have frequent serious S. aureus infections - primary defence.
Neutrophils
Neutrophils are important in the ability to control S. aureus
They have to be recruited via signals such as IL8, C5A, LTA and formyl peptides.
Neutrophils then need to kill off the bacteria they find e.g. phagocytosis (for example, opsonisation involves complement and antibodies)
Killing: reactive oxygen dependent (HOCL) and oxygen independent (cathespin, antimicrobial peptides etc.)
Neutrophil recruitment
TLR-2 recognises lipoproteins - s. aureus component that binds to it and inhbits it.
PSGL1 in migration of neutrophils
CD47 is involved in the migration of neutrophils
C5AR is the complement receptor involved in the opsonisatoon receptor
FPR1 is involved in recognising formyl peptides
CXCR2 is involved in binding chemokines and migration.
Phagocytosis
Complement activation leads to assembly of C3 convertase on the outside of the cell. The C3a cleaves bits to it. C3b is the marker (becomes covalently bound to bacterial surface for opsonisation)
This process has a lot of S. aureus components to prevent opsonisation.
Virulence factors that are needed to interact with environment
Cell wall anchored (sortase)- specific signal that sortase regocnises and covalently binds them.
ISD proteins- Iron acquisiation and innate defences resistance.
Protein A - (Spa) binds IgG prevents opsonisation- because opsonisation if its binding immunoglobulins - spa binds them in a way where they’re non functional
ClfA, FnBP etc- adhesions (bind host ligands).
Toxins
Hemolysins (over 3 types)
Alpha hemolysin- A heptameric pore forming toxin
As its becomes more and more prevalent - it has more than one function.
- It lyses red blood cells
- On the epithelial cells Hla interacts with ADAM10 (protease) and enhances its activity. It cleaves a protein called E-cadherin and destroys adherens junctions. It disrupts the epithelial barrier (important for getting in).
TSST- super antigen
This antigen is worse. It leads to IL-2 and other proinflammatory cytokines, fever and shock (death)
Children are suseptible to reoccuring bouts of it
MHC binding site, forms a bridge between the two. Leading to lesions leading to shock and death
Exfoliative toxins A and B. They are proteases and lead to the sloughing of the skin (scalded skin syndrome- mostly prevalent in children)
Leukocidin
Damages white blood cells.
There are a couple of classic toxins e.g. phanton valentine leukocidin.
Another leukocidin known as LukED
Phenol soluble modulins
They are associated with community acquried MRSA. - hospital acquried MRSA
Community acquried MRSA became prevelent - its not a fitness cost. - if someone gets those antibiotics, they might not work
Small peptides- PSM
Coagulase
It can clot your plasma
Used as a test for S. aureus. Coagulase reactions clots plasma - makes a fibrin clot. Fibrin is produced in order to clot wounds. Can tell the difference between S. aureus etc.
They convert Prothrombrin to Staphylothrombin
Staphylothrombin converts fibrinogen to fibrin (insoluble matrix).
This prevents neutrophil access and protects the bacteria in abscess.
Regulation of virulence determinant production
Organism has to be highly adaptable in order to produce these virulence determinant’s at appropriate amounts and modulate their expression in different scenarios.
- In response to environmental stimuli that it gets from that environment
- Specific virulence determinants expressed - doesn’t make them all at the same time. Not only does it control the virulence determinants individually etc.
- It allows adaptation to that specific niche
Growth phase in exponential phase into stationary phase
you get production of Surface Proteins (+++), Exoproteins (-) and as they go into stationary phase, they switch: They stop making Surface Proteins- adhesens and invasins (-), and they start to make toxins- Exoproteins (+++)
Surface proteins: Spa, Fnbp etc
Exoproteins: Hla, TSST etc
How many DNA binding proteins are there
There are 194 putative DNA binding proteins in S. aureus which bring about this regulation. All coordinate the production of virulence determinants
What is agr
accessory gene regulator- virulence determinants are accessory genes (not required for the life of the organism, they’re required for virulence) - are required to cause disease
key pivotal regulator- switch that leads from making immuno invasins during the exponential phase to switch to making toxins. Important regulator. Agr is a positive regulator of toxin production as they enter post exponential growth. Its a negative regulator of surface proteins
Agr kicks in in the interface between exponential phase and post exponential phase
