Lecture 19: Immune Evasion Flashcards
What 3 host immune responses can bacteria evade?
- antibody opsonisation
- complement opsonisation
- neutrophil functions
What common features of bacteria can be detected by our immune response?
- LPS in Gram-negative bacteria
- LTA in gram-positive bacteria
- flagella on certain bacteria
What are the innate immune cells?
- neutrophils
- eosinophils
- basophils
- dendritic cells
- macrophages
What is the most abundant leukocyte in the blood?
neutrophils
What is the function of neutrophils?
- recruited to areas of infection
- detect microbes
- perform effector functions –> kills microbes
- considered ‘simple’ immune cells
Why must neutrophil responses be balanced?
To prevent infection, but to also prevent damage (inflammation) to the host
Outline how neutrophils are activated when bacteria enters the body.
- Bacteria that has entered body gets opsonised by innate immune components (e.g. antibodies, complement)
- Gradient of complement proteins C3a and C5a produced, alongside gradient of bacterial proteins
- results in activation of endothelial cells lining blood vessels
- Upregulation of endothelial cell receptors like ICAMs
- neutrophils roll along surface (adhesion), migrate across endothelial barrier (transmigration)
- Become primed by gradient of proteins
- Migrate towards complement components and bacterial proteins up the gradient (chemotaxis)
- Become activated
- Can now perform effector functions (phagocytosis, degranulation, inflammation)
What 3 effector functions do neutrophils have?
Phagocytosis - ingestion, killing within phagosome by antimicrobial molecules
Degranulation - release reactive O2 species, antimicrobial molecules
Inflammation - recruit other immune cells
What is antibody opsonisation?
Antibodies bind bacterial antigens, allowing:
1) deposition of complement in the classical complement pathway
2) neutrophils and other phagocytes w/ability to detect invading microbes
How do bacteria evade antibody opsonisation?
1) hides antigens
2) disrupt functions
3) prevent detection
4) degrade antibodies
5) modify antigenicity
How can bacteria hide antigenic structures that would normally be detected by innate and adaptive immune components?
By expression of a capsule (polysaccharide) on surface which hides antigens
What does a capsule surrounding a bacterium do?
Make antibodies less efficient/they don’t bind
How can the SpA protein (S. aureus protein A) disrupt antibody function?
SpA binds antibodies via Fc region not Fab region - back to front binding so immune cells can’t detect antibodies on surface
How does S. aureus SSL10 work to inhibit detection and prevent opsonisation?
Secreted protein that binds to Fc region of IgG - prevents Fc receptors on neutrophils from detecting IgG on surface of S. aureus
How can antibodies be degraded by bacteria?
Proteases cleave antibodies into Fab and Fc regions, no stimulation of immune response
What is an example of a group of bacteria that degrade antibodies?
Group B streptococcus (IdeS protein)
What is antigenic variation and how it does it allow bacteria to evade opsonisation?
Switch expression of antigen to another variant so it’s no longer recognised by antibody
How can bacteria evade complement opsonisation?
1) inhibit convertases
2) inhibit complement components
3) degrade complement components
4) recruit host-derived regulators
What is complement opsonisation?
System 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 C5 convertase
4) MAC formation
What does a Membrane Attack Complex (MAC) do?
Produces pores in bacterial cell membrane leading to lysis
What does the S. aureus protein SCIN do?
Binds C3bBb and inhibits formation of C3 and C5 convertase which prevents:
- C3b deposition
- C3a formation
- C5a formation
What does the S. aureus protein Efb do?
Binds C3d in C3 which induces conformation change, prevents:
- binding of factor B to C3
- C3dg binding CR2
Inhibit C3 processing
What S. aureus protein inhibits MAC formation?
SSL7
How may bacteria cleave complement complements?
Using proteases to cleave C3 into 2 non-functional forms etc.
E.g. S. pyogenes (SpeB)
How can bacteria evade complement using acquired host derived complement regulators?
Recruit regulators of complement via surface proteins and then inactivate C3b:
Surface proteins include fH (S. aureus)
Or protein fI - degrades C2a from C3 convertases (C4b2a)
How can bacteria dysregulate neutrophil functions?
1) Inhibit chemotaxis
2) Inhibit detection of bacteria
3) Kill neutrophils
4) Stimulate inhibitory receptors
5) Disrupt intracellular signalling
How do neutrophils sense and respond to their environment?
Express hundreds of different immune receptors at surface or in secretory vesicles (SVs) and granules
Immune receptors allow neutrophils to sense and respond to their environment.
What does PRRs stand for?
Pathogen recognition receptors - directly detect microbes or microbial products to prime/activate neutrophils
Which receptors detect conserved microbial structures?
TLR receptors
Which receptors detect microbial carbohydrates?
CLEC receptors
Which receptors detect formylated peptides?
FPR receptors
How can immune receptors indirectly detect bacteria?
Neutrophils detect opsonised microbes through Fc receptors or complement receptors
What do activatory receptors do?
Enhance immune cell activity
What do inhibitory receptors do?
Suppress immune cell activity
How does the S. aureus protein CHIPs inhibit chemotaxis and activation?
Inhibits chemotactic receptors by binding to C5aR which usually detects C5a and binding to FPR1 which usually detects formylated peptides (fMLP)
Therefore neutrophils don’t migrate to sites of infection and don’t become activated
How does S. aureus inhibit phagocytosis?
FLIPr inhibits Fc gamma receptors (IgG)
SSL5 inhibits Fc alpha receptors (IgA)
Prevents detection of IgG-opsonised bacteria
Reduces antibody mediated phagocytosis and killing of bacteria = enhanced survival
How can S. aureus kill neutrophils (and other immune cells)?
With toxins
How can S. aureus bind and inhibit functions of activatory receptors?
By expressing molecules that are receptor antagonists
How else can bacteria evade the immune system?
- bind inhibitory receptors
- inhibit effects of antimicrobials
- manipulate intracellular signalling
- modify bacterial surface
