Microbial triggers to innate immunity Flashcards
How do bacteria hang on?
Non-specific electrostatic interactions
Tethering via projections or pili
Attachment via special receptors on human cell surfaces (fibronectin binding proteins)
Internalisation into epithelial cell
What does the penetration of epithelial barriers/endothelial barriers consist of?
Artificial penetration (breach of epithelium) Entry into and through the cell Transit in between cell layers
What causes scalded skin syndrome?
S. aureus has an exfoliative toxin that cleaves desmosomes
What happens following host recognition of a pathogen?
There are danger signals and release of chemokines, cytokines and the complement kills Gram negatives
What does the recognition of pathogen actually lead to?
Transcriptional changes that lead to the production of cytokines
Why is there inflammation during infection?
Nitric oxide is released which leads to relaxation of blood vessels and characteristic features of inflammation- redness and swelling
What toll-like receptor detects lipoproteins from various bacteria?
TLR2 which is always in a heterodimer with TLR1 or TLR6
What does TLR 4 detect?
Endotoxins (LPS)- important for detection of gram-negative bacterial infections
What does TLR5 detect?
Flagellin- feature of some Gram-negative bacteria
What does activation of TLRs lead to?
Signalling inside the cell and transcriptional changes which causes release of inflammatory mediators and recruitment of innate immune response and clearance of bacteria
What are the pattern recognition receptors (PRRs) found inside the cells?
NOD and various TLRs
Give the triggers for the following receptors: TLR2/TLR1 TLR2/TLR6 TLR4 TLR5 NOD TLR9
TLR2/TLR1- Lipoproteins TLR2/TLR6- Mycoplasmal lipoproteins TLR4- LPS TLR5- Flagellin NOD- Peptidoglycan TLR9- Bacterial DNA
What will be found in the CSF of someone with bacterial meningitis?
Loads of neutrophils- responsible for characteristic stiff neck of meningitis
How are Gram-negative bacteria cleared?
Antibodies can opsonise the bacterium prior to phagocytosis
Complement can also opsonise bacteria
Chemotaxis of neutrophils (complex mediated- C5a)
Membrane attack complex (MAC) which results from complement activation can lyse certain Gram-negative bacteria
What is very important in dealing with meningococcal infection?
Complement
What is ineffective against Gram Positive bacteria and what is the result of this?
Complement can’t lyse Gram-positive bacteria, they don’t have lipopolysaccharide and this means that they must be phagocytosed
What components of Gram Positive bacteria trigger the immune system?
Peptidoglycan (through TLR2 or NOD)
Lipoteichoic acid
How are Gram-positive bacteria cleared?
Specific antibody opsonising Complement opsonising Chemotaxis of neutrophils Clearance by phagocytosis and then killing (Complement is insufficient on its own)
What is the general relationship between pathogens and PRRs?
Pathogens trigger multiple PRRs because they have multiple PAMPs
What does streptococcus pneumonia trigger?
TLR2- Lipoproteins
TLR4- Pneumolysin
TLR9- Bacterial DNA
What does legionella trigger?
TLR4- Lipopolysaccharide
TLR5- Flagellin
TLR9- Bacterial DNA
What does herpes virus trigger?
TLR9- DNA
TLR3- dsRNA
TLR2- Viral protein
What does influenza trigger?
TLR7/8 ssRNA
TLR3 dsRNA
What TLRs do viruses trigger?
Intracellular
How does staphylococcus aureus cause toxic shock?
Production of a superantigen (toxic shock syndrome toxin-1)
Streptococcus pyogenes also causes this
What happens normally to antigens?
They are taken up by antigen presenting cells, processed and presented on MHC class II to T cells (specific to that antigen)- antigenic peptides are loaded on MHC groove
How do superantigens work?
They trigger a much more powerful immune response, they deceive the immune system because they can bind to MHC class II outside of antigen binding groove. Around 20% of T cells will see super antigen stuck onto MHC class II and will think it is their peptide so will proliferate massively and there is massive production of cytokines- toxic shock syndrome
What defense system is there against toxic shock syndrome?
Antibodies
How does streptococcus pyogenes evade the immune system?
Anti-neutrophil strategies e.g. streptolysin
Anti-opsonisation strategies e.g. complement binding
Toxins that interfere with immune response e.g. superantigens
How does staphylococcus aureus evade the immune system?
Anti-neutrophil strategies e.g. panton valentine leukocidin
Anti-opsonisation strategies e.g. Ig binding proteins
Toxins that interfere with immune responses e.g. superantigens
How does Neisseria meningitides evade the immune system?
Anti-complement/Anti-MAC strategies e.g. capsule
What does mecA gene do?
Confers resistance to beta-lactams
Where do bacteria resistant to beta-lactams tend to be found?
In hospitals
What have clones of the resistant bacteria in the community been found to have?
Similar anti-biotic resistance element (mecA) but also they’ve acquired a phage that encodes a bacterial roxin called panton valentine leukocidin (PVL)
How does PVL exist?
It forms a heptamer that has a pore
What does the heptameric pore do at low and high concentrations?
Low- makes human neutrophils apoptose
High- Makes human neutrophils lyse
PVL producing staphylococci causes very nasty infections associated with abscesses that can’t be cleared by the patients
