Immune Evasion by Lymphocytes Flashcards
How have microbes developed immune evasion?
- Bacteria are diverse
- Pathogens are diverse
- Some microbes have evolved mechanisms that enhance their survival in their host
- These immune evasion mechanisms contribute to bacterial pathogenesis
What is the insane immune response effective at?
Innate immune response very efficient at detecting and killing invading microbes
What are 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
- neutrophil response must be balanced to prevent infection by to also prevent damage (inflammation) to the host
What do bacteria do?
-Bacterial express surface and secreted proteins that interfere with innate immune response
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
Why do bacteria need to evade host defences?
- Arms race between our immune system and bacteria
- Successful bacteria can evade host defences:
- More likely to replicate and propagate their genes
- More likely to cause disease (their pathogenicity)
What is pathogenicity?
The ability of pathogen to cause disease?
What does pathogenicity depend on?
Virulence and infecitivity
What is virulence?
Features that enhance disease causation
What is infecitivty?
general features favouring disease causation
What are the three methods by which bacteria can evade host defence?
- Evade Antibody Opsonisation
- Evade Complement Opsonisation
- Evade neutrophil functions (i.e phagocytosis)
How do bacteria evade antibody opsonisation?
1) Hide antigens
2) Disrupt functions
3) Prevent detection
4) Degrade antibodies
5) Modify antigenicity
How do bacteria hide antigens?
Just coat the bacteria with a polysaccharide capsule- that way the antigens are hidden and cannot be recognised by the host immune system!
How do bacteria disrupt normal immune function?
- Express proteins that means the antibody binds to the pathogen incorrectly- i.e via Fc and not Fab
- Neutrophils and other components of the immune system recognise Fc- so if this isn’t shown- nothing happens as a result of antibody binding
How do bacteria inhibit detection?
Secrete proteins that ‘cover up’ Fc receptors
Play ‘hide and seek’ – Tuberculosis Bacterium
How do bacteria degrade antibodies?
Secrete enzymes (proteases) which chop up the antibodies- making them ineffective
What is antigenicity?
The capacity of the antigen to produce an immune response inside the body- determined by how it binds to Antibodies ( B cell response) or receptors ( T cell response)
How do bacteria modify antigenicity?
- Antigen variation
- Genetic mutations (i.e recombination)- to produce an antigen that is different in structure and cannot be recognised
- Gram-negative bacteria- particularly good at this
What do bacteria acid by evading antibody opsonisation?
- the deposition of complement in the classical complement pathway
- neutrophils and other phagocytes the ability to detect invading microbes
How do bacteria evade complement opsonisation?
Inhibit C3/C5 convertases
2) Bind complement factors and prevent their processing
3) Cleave complement factors
4) Acquire host-derived complement regulators
How do bacteria inhibit C3/C5 convertases?
Secrete proteins which inhibit C3 and C5 convertases
As a result of this:
This prevents
C3b deposition
C3a formation
C5a formation
-Therefore less chemoattraction of neutrophils and less inflammation
How do bacteria inhibit C3 processing?
Secrete proteins which prevent:
Binding of factor B to C3
C3dg binding CR2
How do bacteria cleave complement components?
secrete proteases which chop up C3 or C5
How do bacteria acquire complement regulators?
Genetic mutations- express copies of human complement regulators- which can turn off complement
What is the purpose of bacteria evading complement activation?
- Prevent complement opsonisation
- Also prevent the formation of the membrane attack complex- which otherwise would kill the bacteria directly.
What is normal function of a neutrophil?
- Cells of the innate response- first to arrive
- Kill pathogens (phagocytosis or form neutrophil extracellular traps)
How do bacteria evade neutrophil function?
- Secrete proteins which inhibit chemotaxis
2 .Secrete proteins that bind to Fc receptors on neutrophils- preventing phagocytosis
How do bacteria inhibit function of neutrophils?
- Kill neutrophils- by releasing toxins
- Express surface proteins that are stimulatory receptor antagonists
- Express surface proteins that activate inhibitory receptors
- Secrete molecules that neutralise toxins
- Manipulate intracellular signalling- Escape the endosome or phagosome
- Prevent fusion of the phagosome with lysosomes
- Survive well in the phagolysosome- mainly applies to I.C pathogens.
- Change their surface
What are immune privileged sites?
- Sites with reduced immune surveillance include the eye, CNS and testes
- Latency of HSV in Sensory Neurones
- Measles in CNS
What are escape mutations?
- Escape mutations- changes of amino acids in the peptide epitopes (the antigen) interfere with MHC binding (if at anchor residue) or T cell recognition if at contact residue
- Loss of MHC binding- therefore no antigen presentation
- No T cell recognition- hence no T cell activation
- Or may change the viral peptide so that the T cell becomes unresponsive instead of activated.
How do viruses down regulate MHC?
- Endocytosis of MHC molecules once they are expressed
- Retention of MHC in ER
- Essentially, could block any step in the pathway
What is antibody opsonisation?
1)the deposition of complement in the classical complement pathway
2)neutrophils and other phagocytes the ability to detect invading microbes
Bacteria have evolved many mechanisms
to evade antibody detection
What is antibody evasion?
Antibody opsonisation:
1)the deposition of complement in the classical complement pathway
2)neutrophils and other phagocytes the ability to detect invading microbes
-Bacteria have evolved many mechanisms
to evade antibody detection
How does S.Aureus capsule hide antigen?
S. aureus expresses capsule on its surface:
This helps to hide antigenic structures that can be detected by innate and adaptive immune components, including complement and antibodies
What other bacteria expression capsule?
- E. coli (many K types, 80 types)
- S. pyogenes
- Pseudomonas aeruginosa
- S. pneumonia (91 capsule types)
- S. agalactiae (9 capsule types)
How do S.Aureus protein A (SpA) bind IgG Fc region?
Spa surface protein binds antibodies via their Fc region not their Fab region: Spa prevents normal opsonisation, and therefore neutrophils cannot detect S. aureus
What other bacteria express surface proteins that bind antibodies?
SSL10 is a secreted protein that binds to the Fc region of IgG: SSL10 prevents the Fc receptors on neutrophils from detecting IgG on the surface of S. aureus
Describe S.aureus antibody evasion?
Multiple proteins often perform the same function. They:-
1) Hide antigens
2) Disrupt functions
3) Prevent detection
- This helps to ensure immune evasion is successful
What are other antibody evasion strategies?
- Multiple proteins often perform the same function. They:-
1) Hide antigens
2) Disrupt functions
3) Prevent detection
4) Degrade antibodies
5) Modify antigenicity - This helps to prevent or hide antibody opsonisation.
What is 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 complement cascade?
1) Initiation
2) Formation of C3 convertase
3) Formation of C5 convertase
4) MAC formation
What does S.aureus SCIN bind to and inhibit? What does this prevent?
S. aureus SCIN protein binds C3bBb and inhibits formation of C3 convertase and C5 convertase: This prevents 1)C3b deposition 2)C3a formation 3)C5a formation
What does S.aureus Efb bind to and prevent?
- S. aureus Efb protein binds C3d in C3, which induces conformation change
- This prevents
1) Binding of factor B to C3
2) C3dg binding CR2
What is S..aureus complement evasion?
Bacterial proteins prevent C3b or MAC deposition. They:-
1) Inhibit C3/C5 convertases
2) Bind complement factors and prevent their processing
3) Cleave complement factors
4) Acquire host-derived complement regulators
What are other complement evasion strategies?
Bacterial proteins prevent C3b or MAC deposition. They:-
1) Inhibit C3/C5 convertases
2) Bind complement factors and prevent their processing
3) Cleave complement factors
4) Acquire host-derived complement regulators
How do neutrophils function through receptors?
-Neutrophils sense and reason to their environment by:
1. Neutrophils express hundreds of different immune receptors, at their surface or in their secretory vesicles (SVs) and granules
2/ Immune receptors allow neutrophils to sense and respond to their environment. They detect microbes, microbial products or self proteins
How do immune receptors detect bacteria?
-Pathogen recognition receptors (PRRs)
directly detect microbes or microbial
products:
-Neutrophils are primed or activated
How do immune receptors indirectly detect bacteria?
-Microbes can become opsonised by antibodies or complement: -Neutrophils detect opsonised microbes through Fc receptors or complement receptor
How do immune receptors modulate function?
- There is a diverse range of immune receptors involved in generating and modulating a balanced immune response
- Activatory receptors enhance immune cell activity
- Inhibitory receptors suppress immune cell activity
How does S.aureus CHIPs inhibit chemotaxis and activation?
- CHIPs binds C5aR and FPR1 and prevents binding of their agonists (C5a and formylated peptides)
- Neutrophils do not migrate to sites of infection and do not become activated through C5aR or FPR1
What. are chemotactic receptor and which do S.aureus inhibit?
- Chemotactic receptors:
1. C5aR detects C5a
2. FPR1 detects formylated peptides (fMLP) - S. aureus inhibits chemotactic receptors:
1. CHIPs binds C5aR
2. CHIPs binds FPR1
How does. S.Aureus FLIPr and SSl5 block Fc repceotrs?
1.. FLIPr inhibits Fc g receptors (IgG)
2. SSL5 inhibits Fc a receptors (IgA)
3. FLIPr binds Fc g Receptors preventing the detection of IgG-opsonised bacteria
4. Reduces antibody
mediated phagocytosis and killing of
S. aureus
What are some additional mechanisms of S.aureus neutrophil evasions?
Additional mechanisms.
1) Bind and inhibit functions of activatory receptors
2) Kill neutrophils (and other immune cells) with toxins.
