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Year 1 POM > Immune Evasion by Lymphocytes > Flashcards

Immune Evasion by Lymphocytes Flashcards

1
Q

How have microbes developed immune evasion?

A
  • 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
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2
Q

What is the insane immune response effective at?

A

Innate immune response very efficient at detecting and killing invading microbes

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3
Q

What are neutrophils?

A
  • 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
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4
Q

What do bacteria do?

A

-Bacterial express surface and secreted proteins that interfere with innate immune response

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5
Q

What is staphylococcus aureus?

A
  • 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
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6
Q

Why do bacteria need to evade host defences?

A
  • 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)
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7
Q

What is pathogenicity?

A

The ability of pathogen to cause disease?

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8
Q

What does pathogenicity depend on?

A

Virulence and infecitivity

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9
Q

What is virulence?

A

Features that enhance disease causation

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10
Q

What is infecitivty?

A

general features favouring disease causation

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11
Q

What are the three methods by which bacteria can evade host defence?

A
  1. Evade Antibody Opsonisation
  2. Evade Complement Opsonisation
  3. Evade neutrophil functions (i.e phagocytosis)
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12
Q

How do bacteria evade antibody opsonisation?

A

1) Hide antigens
2) Disrupt functions
3) Prevent detection
4) Degrade antibodies
5) Modify antigenicity

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13
Q

How do bacteria hide antigens?

A

Just coat the bacteria with a polysaccharide capsule- that way the antigens are hidden and cannot be recognised by the host immune system!

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14
Q

How do bacteria disrupt normal immune function?

A
  • 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
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15
Q

How do bacteria inhibit detection?

A

Secrete proteins that ‘cover up’ Fc receptors

Play ‘hide and seek’ – Tuberculosis Bacterium

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16
Q

How do bacteria degrade antibodies?

A

Secrete enzymes (proteases) which chop up the antibodies- making them ineffective

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17
Q

What is antigenicity?

A

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)

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18
Q

How do bacteria modify antigenicity?

A
  • 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
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19
Q

What do bacteria acid by evading antibody opsonisation?

A
  • the deposition of complement in the classical complement pathway
  • neutrophils and other phagocytes the ability to detect invading microbes
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20
Q

How do bacteria evade complement opsonisation?

A

Inhibit C3/C5 convertases

2) Bind complement factors and prevent their processing
3) Cleave complement factors
4) Acquire host-derived complement regulators

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21
Q

How do bacteria inhibit C3/C5 convertases?

A

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

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22
Q

How do bacteria inhibit C3 processing?

A

Secrete proteins which prevent:
Binding of factor B to C3
C3dg binding CR2

23
Q

How do bacteria cleave complement components?

A

secrete proteases which chop up C3 or C5

24
Q

How do bacteria acquire complement regulators?

A

Genetic mutations- express copies of human complement regulators- which can turn off complement

25
Q

What is the purpose of bacteria evading complement activation?

A
  • Prevent complement opsonisation

- Also prevent the formation of the membrane attack complex- which otherwise would kill the bacteria directly.

26
Q

What is normal function of a neutrophil?

A
  • Cells of the innate response- first to arrive

- Kill pathogens (phagocytosis or form neutrophil extracellular traps)

27
Q

How do bacteria evade neutrophil function?

A
  1. Secrete proteins which inhibit chemotaxis

2 .Secrete proteins that bind to Fc receptors on neutrophils- preventing phagocytosis

28
Q

How do bacteria inhibit function of neutrophils?

A
  1. Kill neutrophils- by releasing toxins
  2. Express surface proteins that are stimulatory receptor antagonists
  3. Express surface proteins that activate inhibitory receptors
  4. Secrete molecules that neutralise toxins
  5. Manipulate intracellular signalling- Escape the endosome or phagosome
  6. Prevent fusion of the phagosome with lysosomes
  7. Survive well in the phagolysosome- mainly applies to I.C pathogens.
  8. Change their surface
29
Q

What are immune privileged sites?

A
  • Sites with reduced immune surveillance include the eye, CNS and testes
  • Latency of HSV in Sensory Neurones
  • Measles in CNS
30
Q

What are escape mutations?

A
  • 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.
31
Q

How do viruses down regulate MHC?

A
  • Endocytosis of MHC molecules once they are expressed
  • Retention of MHC in ER
  • Essentially, could block any step in the pathway
32
Q

What is antibody opsonisation?

A

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

33
Q

What is antibody evasion?

A

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

34
Q

How does S.Aureus capsule hide antigen?

A

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

35
Q

What other bacteria expression capsule?

A
  • E. coli (many K types, 80 types)
  • S. pyogenes
  • Pseudomonas aeruginosa
  • S. pneumonia (91 capsule types)
  • S. agalactiae (9 capsule types)
36
Q

How do S.Aureus protein A (SpA) bind IgG Fc region?

A

Spa surface protein binds antibodies via their Fc region not their Fab region: Spa prevents normal opsonisation, and therefore neutrophils cannot detect S. aureus

37
Q

What other bacteria express surface proteins that bind antibodies?

A

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

38
Q

Describe S.aureus antibody evasion?

A

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

39
Q

What are other antibody evasion strategies?

A
  • 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.
40
Q

What is complement opsonisation?

A

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

41
Q

What are the key steps of complement cascade?

A

1) Initiation
2) Formation of C3 convertase
3) Formation of C5 convertase
4) MAC formation

42
Q

What does S.aureus SCIN bind to and inhibit? What does this prevent?

A 
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
43
Q

What does S.aureus Efb bind to and prevent?

A
  • 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
44
Q

What is S..aureus complement evasion?

A

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

45
Q

What are other complement evasion strategies?

A

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

46
Q

How do neutrophils function through receptors?

A

-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

47
Q

How do immune receptors detect bacteria?

A

-Pathogen recognition receptors (PRRs)
directly detect microbes or microbial
products:
-Neutrophils are primed or activated

48
Q

How do immune receptors indirectly detect bacteria?

A 
-Microbes can become opsonised
by antibodies or complement:
-Neutrophils detect opsonised microbes
through Fc receptors or complement
receptor
49
Q

How do immune receptors modulate function?

A
  • 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
50
Q

How does S.aureus CHIPs inhibit chemotaxis and activation?

A
  • 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
51
Q

What. are chemotactic receptor and which do S.aureus inhibit?

A
  • 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
52
Q

How does. S.Aureus FLIPr and SSl5 block Fc repceotrs?

A

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

53
Q

What are some additional mechanisms of S.aureus neutrophil evasions?

A

Additional mechanisms.

1) Bind and inhibit functions of activatory receptors
2) Kill neutrophils (and other immune cells) with toxins.

Year 1 POM (39 decks)

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