Bacterial Immune Evasion Flashcards
What are common features of bacteria that our body can detect?
LPS in Gram-negative bacteria
LTA in Gram-positive bacteria
Flagella on certain bacteria
What are the three major stages that bacteria can evade?
Antibody opsonisation
Complement opsonisation
Neutrophil functions
What are our innate immune cells?
Neutrophils
Eosinophils
Basophils
Dendritic Cells
Macrophages
- the innate immune response is very efficient at detecting and killing invading microbes
What are facts about neutrophils?
Most abundant leukocyte (50-70%) in the blood
Recruited to areas of infection
Detect microbes
Perform effector functions-> kill microbes
Considered simple immune cells
What do neutrophils do?
Why must neutrophil responses be balanced?
Neutrophil responses must be balanced to prevent infection, but also, prevent damage (inflammation) to the host.
What is Staphylococcus aureus?
Gram-positive bacterium, that is a commensal and lives harmlessly in the nose of 30% of human population. S. aureus is an opportunistic pathogen able to cause minor skin infections to severe and life-threatening diseases.
- S.aureus has evolved many sophisticated mechanisms to evade neutrophils
What is Streptococcus pyogenes?
Gram-positive bacterium, that can live harmlessly in the throat of humans. S. pyogenes is an opportunistic pathogen able to cause a range of disease including cause pharyngitis (Strep throat), skin infections, scarlet fever and sepsis.
- S.pyogenes has evolved many sophisticated mechanisms to evade neutrophils
What is antibody opsonisation?
Antibodies bind bacterial antigens, allowing…
- the deposition of complement in the classical complement pathway
- neutrophils and other phagocytes the ability to detect invading microbes
How do bacteria evade antibody opsonisation?
Capsule polysaccharide hides the antigens
e.g., S.aureus and S.pyogenes
Surface proteins bind Fc region of antibodies
e.g., S.aureus (Protein A aka Spa) and S.pyogenes (M protein)
Proteases to degrade antibodies
e.g., S.pyogenes IdeS
Explain in more detail the capsule polysaccharide.
Bacteria can expresses capsule on their surface.
This helps to hide antigenic structures that can be detected by innate and adaptive immune components, such as complement and antibodies
Explain in more detail the surface proteins binding Fc region of antibodies.
Spa and M surface proteins bind antibodies via their Fc region not their Fab region.
This prevents normal opsonisation, and therefore neutrophils cannot detect S. aureus or S. pyogenes.
Explain in more detail proteases to degrade antibodies.
Proteases cleave or modify antibodies.
This prevents normal opsonisation, and therefore neutrophils cannot detect S. pyogenes.
Overall, what are the S.aureus and S.pyogenes antibody evasion methods?
Capsule expression
Inhibit antibody opsonisation- Spa and M protein
Degrade antibodies- ideS
What is special about the proteins involved in immune evasion?
They often perform the same function. they:
1) hide antigens
2) disrupt functions
3) prevent detection
4) degrade antibodies
5) modify antigenicity
This helps to ensure immune evasion is successful.
How do N.gonorrhoeae and S.pneumoniae evade?
antigenic variation
(altering surface antigens)
N.gonorrhoeae= OPA and LOS antigens
S.pneumoniae= Cap
Do bacteria only have one method of evading immunity?
No, many bacterial pathogens utilise multiple strategies to evade antibody opsonisation.
What is the complement opsonisation?
Complement system is composed of a large number of proteins that react with one-another to opsonise pathogens or to directly kill them by membrane attack complex (MAC) formation
What are the key steps of the complement cascade?
1) initiation
2) formation of C3 convertase
3) formation of C4 convertase
4) MAC formation
What are the 3 types of complement cascade?
Classical, MBL, Alternative
what are the strategies that bacterial pathogens have to disrupt the complement cascade?
1) degrade complement components
2) inhibit convertases
3) recruit host-derived regulators
4) inhibit complement components
Explain in more details how bacteria degrade complement components.
Bacteria degrade C3
e.g., S.aureus and S.pyogenes
S. aureus Aur and S. pyogenes SpeB are proteases that degrade C3
This prevents…
C3b deposition
C3a formation
C5a formation
Explain in more detail how bacteria inhibit convertases.
Bacteria inhibit C3 or C5 convertases
S. aureus SCIN protein binds C3bBb and inhibits formation of C3 convertase and C5 convertase (aka blocks complement cascade and its amplification)
This prevents…
C3b deposition
C3a formation
C5a formation
Explain in more detail how bacteria recruit host derived regulators.
Bacteria recruit negative regulators.
E.g., S.aureus (recruits factor H), S.pyogenes (recruits factor H, recruits C4BP)
How do bacterial proteins prevent C3b or MAC deposition?
1) Cleave complement factors
2) Inhibit C3/C5 convertases
3) Acquire host-derived complement regulators
4) Bind complement factors and prevent their processing
What inactivates C3b?
fH on bacterial surface
What degrades C2a from C3 convertases (C4b2a)?
C4BP, it’s associated with fI
How do neutrophils sense and respond to their environment?
Neutrophils express hundreds of different immune receptors, at their surface or in their secretory vesicles (SVs) and granules.
Immune receptors allow neutrophils to sense and respond to their environment. They detect microbes, microbial products or self proteins.
What are PRRs?
pathogen recognition receptors
they directly detect microbes on microbial products- leading to neutrophils to be primed or activated
What detects conserved microbial structures?
TLR (toll-like) receptors
What detects microbial carbohydrates?
CLEC receptors
What detects formylated peptides?
FPR receptors
How do immune receptors indirectly detect bacteria?
Microbes can become opsonised by antibodies or complement
Neutrophils detect opsonised microbes through Fc receptors or complement receptors
What detects antibody opsonised microbes?
Fc receptors
(there are activatory motif (ITAM) below the cell membrane attached to the receptors)
What detects complement opsonised microbes?
Complement receptors (e.g., CR1, CR3, CR4)
What immune receptors modulate function?
Cytokine receptors (e.g., TNFR1, IL4R, IFNAR, etc.) and chemoattractant receptors (e.g., C5aR, PAFR, BLT1,2)
What receptor enhances immune cell activity?
activatory receptors
How does S.aureus inhibit chemotaxis and activation?
CHIPs
How does CHIPs work?
1) C5aR (chemotactic receptors on neutrophils) detects C5a
2) S.aureus inhibits chemotactic receptors by CHIPs binding to C5aR
- CHIPs binds C5aR and prevents binding of C5a
3) neutrophils do not migrate to sites of infection and do not become activated through C5aR
How does S.pyogenes inhibit chemotaxis?
SpyCEP
How does SpyCEP work?
1) CXCR1 and CXCR2 (chemotactic receptors) detect CXCL8
2) SpyCEP cleaves CXCL8 (S.pyogenes modifies CXCL8)
- SpyCEP cleaves CXCL8 and prevents binding to CXCR1/2
3) Neutrophils do not migrate to sites of infection and do not become activates through CXCR1/2
How does S.aureus inhibit phagocytosis?
FLIPr and SSL5 blocking Fc receptors
How does FLIPr and SSL5 work?
FLIPr inhibits Fcy (Fc gamma) receptors (IgG)
SSL5 inhibits Fca (Fc alpha) receptors (IgA)
1) FLIPr binds Fcy receptors preventing the detection of IgG-opsonised bacteria
2) reduces antibody mediated phagocytosis and killing of S.aureus
How do bacteria kill neutrophils?
They release toxins
1) fewer neutrophils at the site of infection that can detect and kill bacteria
2) reduces phagocytosis and killing of S.aureus and S.pyogenes
What are the toxins that S.aureus and S.pyogenes release to kill neutrophils?
S.aureus
- PVL toxin
- LukAB
- LukDE
S.pyogenes
- SLS
- SLO
What are the overall broad ways bacteria immune evade?
Inhibit effects of antimicrobials
Manipulate intracellular signalling
Modify bacterial surface
- phagocytosis
- opsonisation
- activation
- chemotaxis
What is a pyogenic disease?
one that causes pus to be produced
What are pyogenic diseases mediated by?
Hydrolytic enzymes and cytotoxins
What are systemic diseases mediated by?
Toxins
What protein binds to C3bBb and prevents the formation of C3 convertase and C5 convertase?
SCIN
All three complement pathways result in what?
The formation of C3 convertase
What is a key step in the complement system?
The deposition of C3b on the surface of the microbe
What does the deposition of C3b on the microbe allow?
The detected of the microbe by certain receptors on neutrophils / phagocytes
Why are C3a and C5a so essential?
They are chemoattractants and therefore attract the components needed for MAC complexes - C6. C7, C8, C9
How do C3a and C5a result in neutrophils arriving at the site?
They bind to their respective receptors on the epithelial cells, which causes the epithelial cells to increase the expression of ICAM which results in neutrophils recruited to the area
What primes neutrophils?
The complement gradient
Why is S. aureus a common cause of food poisoning?
Because they are able to grow in high salt concentrations
What does coagulase do?
Converts fibrinogen into fibrin so that blood clots can form
What does enterotoxin do?
Causes food poisoning as it is heat stable and acid resistant
Describe neutrophil action during an infection?
- Pathogen enters blood stream
- Pathogen opsonised by antibodies and complement
- This triggers the complement cascade
- Results in the formation of C3a and C5a which forms a gradient
- C3a binds to C3aR and C5 binds to C5a receptors, on endothelium
- This triggers the endothelium to increases the expression of ICAM
- This causes neutrophils to be recruited to the site - they bind to the lining and migrate through
- Then activated and perform effector functions
What does factor H do?
Inhibit C3 convertases
What is protein G and what expresses it?
It is an antibody binding protein like SpA that is expressed by S. dysgalactiae
What is special about the proteins involved in immune evasion?
They often perform the same function. they:
1) hide antigens
2) disrupt functions
3) prevent detection
This helps to ensure immune evasion is succesful.
