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PoM - Principles of Medicine Week 3 > Immune Evasion By Bacteria > Flashcards

Immune Evasion By Bacteria Flashcards

1
Q

How has our immune response adapted to detect such a diverse range of bacteria?

A

It can detect LPS found in gram negative bacteria and LTA found in gram positive bacteria
Flagella on certain bacteria

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2
Q

How have bacteria, in response, evolved to enhance their survival in host cells?

A

Developed immune evasion mechanisms - e.g. to protect them from being detected by our innate immune responses / phagocytes / from being killed

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3
Q

What are the 5 main innate immune cells?

A 
Neutrophils
Eosinophils
Basophils
Macrophages
Dendritic Cells
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4
Q

Which of the 5 innate immune cells is most abundant in our blood?

A

Neutrophils (make up 50 - 70% of all the innate immune cells in circulation)

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5
Q

What is the role of a neutrophil upon infection?

A

Usually the first to migrate to the site of infection
Detect microbes there, which activates them
Perform effector functions, which helps to kill those microbes

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6
Q

Neutrophil function must be balanced, why?

A

Too weak response = hosts susceptible to infections

Too strong response = unnecessary damage to host tissue and inflammation

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7
Q

What is the mechanism of a neutrophil?

A

Bacteria get opsonised by antibodies / complements
Gradient of bacterial proteins and complement components of C3a and C5a are produced
Activates endothelial cells lining the blood vessels - upregulation of the endothelial cell receptors (e.g. express ICAM)
Neutrophils flowing / rolling along surface of blood vessel, detect and migrate towards the microbe
Cross endothelial barrier
Migrate up the gradient via chemotaxis to the main site of infection
Become activated to perform effector functions

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8
Q

What are the effector functions of a neutrophil?

A
  1. Phagocytosis - kill the mincrobes within a phagolysosome
  2. Degranulation - release reactive oxygen species / antimicrobial molecules
  3. Iinflammation - recruit other immune cells
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9
Q

What are the 3 parts of the immune response bacteria evade?

A
  1. Bacterial evasion of antibody opsonisation
  2. Bacterial evasion of complement opsonisation
  3. Bacterial evasion of neutrophil functions
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10
Q

How do bacteria evade the immune system?

A

Express surface and secreted proteins that are inhibitors
Capsules to hide antigens
Enzymes

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11
Q

What is S. aureus?

A

Staphylococcus aureus
Gram-positive bacteriumlives harmlessly in the nose of 30% of human population
Opportunistic pathogen - causes minor skin infections to severe and life-threatening diseases
Has a diverse immune evasion strategies

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12
Q

What is antibody opsonisation?

A

Antibodies bind bacterial antigens, allowing:

  1. The deposition of complement in the classical complement pathway
  2. Neutrophils and other phagocytes the ability to detect invading microbes
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13
Q

How do bacteria prevent / suppress antibody opsonisation?

A
  1. Hide antigens - expression of a capsule
  2. Disrupt functions - bind to Abs via Fc region
  3. Prevent detection - secrete proteins that bind to Fc regions of the Ab
  4. Degrade Abs - release proteases that can cleave Abs
  5. Modify antigenicity - antigenic variation by switching / changing the expression of antigens regularly
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14
Q

How does expression of a capsule help evade antibody opsonisation?

A

e.g. The S. Aureus has 2 types of capsules. They hide antigens on the surface of the bacteria so Abs can no longer bind to the bacteria efficiently
Fewer bacteria are flagged to the rest of the immune system to be cleared up
Different bacteria have different capsule types

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15
Q

How does bacteria binding to Abs via Fc regions help evade antibody opsonisation?

A

e.g. In S. Aureus, protein SpA binds to the Fc region of IgG Abs (instead of the Fab region)
Complement cannot be deposited on the bacteria and Fc receptors on immune cells cannot detect the Fc region on the Ab as it is attached to the surface of the bacteria

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16
Q

How does bacteria secreting proteins that bind to Fc regions on the Ab help evade antibody opsonisation?

A

e.g. The S. Aureus secretes the SSL10 protein, which binds to the Fc regions on the Ab
Even if the bacterium is opsonised, the Fc regions cannot be detected by the Fc receptors on other immune cells, so little / no further immune action

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17
Q

Often there are multiple genes / molecules that code / do the same function, why?

A

If one of the proteins is not expressed / if host finds an immune response mechanism against one of the proteins, there is still another protein to continue the same function

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18
Q

How does bacteria secreting proteases help evade antibody opsonisation

A

Proteases cleave Abs into Ffc and Fab regions, so even if the Fab region of the Ab binds to the bacteria, there is no stimulation of a further immune response

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19
Q

How does bacteria switching the expression of antigens regularly help evade antibody opsonisation?

A

Even if Abs were previously produced against this pathogen, they currently are not complementary to the antigens being expressed, and so cannot bind (lowered amount of opsonisation)
Further immune response is not triggered

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20
Q

What is complement opsonisation?

A

A system comprised of a large number of proteins that react with one-another to opsonise pathogens so they are recognised by phagocytes to be killed, or to directly kill them by forming the membrane attack complex (MAC)

21
Q

What are the 3 different pathways to start the complement cascade?

A
  1. Classical - deposition of Abs and the C1qrs formation, then activation of the C4bC2b C3 convertase
  2. MBL - also leads to the activation of the C4bC2b C3 convertase
  3. Alternative - production of C3bBb C3 convertase, and so deposition of C3b onto the surfaces of microbes
22
Q

What are the 4 main steps of the complement cascade?

A
  1. Initiation (via one of the 3 paths)
  2. Formation of the C3 convertase
  3. Formation of the C5 convertase
  4. Deposition of C6 - C9, and MAC formation
23
Q

What does the MAC do?

A

Produces pores in the bacterial cell membranes, resulting in lysis

24
Q

How do bacteria evade complement opsonisation?

A
  1. Inhibit convertases - production of proteins that bind to molecules to prevent the formation of C3 and C5 convertase
  2. Inhibit complement components - produce proteins that bind the components of the complement cascade
  3. Inhibit MAC formation - bacteria do not undergo lysis via MAC
  4. Degrade complement components - enzymes to cleave complement components
  5. Acquire host-derived complement regulators - recruit regulators of the complement to the surface of the bacteria
25
Q

How does bacteria producing proteins to inhibit the formation of the convertases / help evade complement opsonisation?

A

e.g. The S. Aureus produces the protein SCIN which binds to C3bBb, preventing the formation of C3 and C5 convertases - stops them having their normal function
Therefore MAC is not formed, hence bacteria do not undergo lysis
It also prevents the formation and so deposition of C3b onto the surface of the bacteria, and formation of important immune stimulants e.g. C3a and C5a
Therefore, cannot signal to phagocytes to kill the bacteria

26
Q

How does bacteria producing proteins to inhibit the function of other complement components help evade complement opsonisation?

A

e.g. S. Aureus also produces EfB, which binds to C3, and prevents the cleaving of C3 to C3b, so C3 and C5 convertases are not formed, hence MAC is not formed

27
Q

How does bacteria producing proteins to inhibit the formation of the MAC help evade complement opsonisation?

A

MAC is no longer able to make holes in the cell membrane of the bacteria and cause lysis

28
Q

How does bacteria producing enzymes to cleave complement components help evade complement opsonisation?

A

Forms non-functional proteins that are unable to communicate with the rest of the components of the complement cascade, so the cascade does not flow (it is stopped)

29
Q

How does bacteria recruiting complement regulators to their surface help evade complement opsonisation?

A

e.g. Express surface proteins that recruit the regulator fH, which inactivates C3b, so the convertases and consequently the MAC is not formed, so the bacteria do not undergo lysis
Express other proteins which recruit the regulator C4BP

30
Q

How does a neutrophil perform its functions?

A

Via receptors - hundreds of different cell surface receptors to detect and respond to its environment and microbes
Has granules that contain anti-microbial factors and secretory vesicles

31
Q

What are the two broad types of the immune receptors on the neutrophil that detect bacteria?

A
  1. Receptors to detect bacteria directly

2. Receptors to detect bacteria indirectly

32
Q

What are some examples of receptors on neutrophils that detect bacteria directly and where are they found?

A

Pathogen Recognition Receptors (PRRs) to directly detect microbes / microbial products:
TLR receptors - recognise conserved microbial structures (e.g. LPS in gram negative, LTA in gram positive bacterial cell walls, and flagella)
CLEC receptors - recognise microbial carbohydrates
FPR receptors - formulated peptides released by bacteria
Found on activated neutrophils

33
Q

What are some examples of receptors on neutrophils that detect bacteria indirectly and what does it result in when those receptors are used?

A

Fc receptors - detect Ab opsonised bacteria / pathogens y binding to the Fc region of Abs
Complement receptors - detect complement opsonised bacteria / pathogens by binding to complement molecules
Phagocytosis / degranulation

34
Q

How do the Fc receptors know to carry out phagocytosis when they bind to the Fc region of the Ab?

A

They have an activatory motif (iTAM) at the base of the receptor / at their cytoplasmic tails
When the ligand is made with the Fc region, and crosslinks are formed
It stimulates an activatory signal, causing the neutrophil to perform its function

35
Q

Can some receptors on the neutrophils be inhibitory?

A

Yes - has an iTIM motif, so if they are stimulated, the neutrophil does not perform its function as it is suppressed

36
Q

What are some examples of inhibitory receptors on neutrophils and why are they important?

A

e.g. LAIR receptors and SIGLEC receptors
Prevents the neutrophil from becoming activated at the wrong time / place so host healthy tissue is not damaged
Prevents neutrophil from getting overactivated

37
Q

What are some other receptors expressed on the neutrophil surface?

A
  1. Cytokine receptors - detect the cytokines produced in our immune responses
  2. Chemoattractant receptors - detect the immune signals that tell the neutrophil to migrate to the site of infection
38
Q

Are there families of receptors with activatory and inhibitory properties and why?

A

Yes, e.g. LILR receptors and CEACAM receptors

Helps modulate the strength / amount of immune cell activity

39
Q

What are the 4 main types of receptors on the neutrophil?

A
  1. Activatory - stimulate immune cell activity
  2. Inhibitory - suppress immune cell activity
  3. Cytokine
  4. Chemoattractant
40
Q

How do neutrophils migrate to the site of infection?

A

By detecting formulated peptides released by bacteria or complement signalling (e.g. C3a or C5a) and following them

41
Q

What are 2 important chemotaxis receptors on neutrophils?

A
  1. C5a receptors (binds to C5a)

2. FPR receptors (binds to fMLP - formulated peptides)

42
Q

What are the different ways bacteria can evade neutrophil function?

A
  1. Inhibit chemotaxis - release chemotaxis inhibitory proteins that bind to the chemotaxis receptors
  2. Inhibit detection of bacteria - express proteins that bind to Fc receptors on the neutrophil to prevent detection of opsonised bacteria
  3. Kill neutrophils - antagonist receptors or toxins released
  4. Stimulate inhibitory receptors - molecules bind to inhibitory receptors, activating them and so suppressing neutrophil function
  5. Inhibit effects of antimicrobials - release proteins that inhibit the enzymes and antimicrobial products in the phagolysosome so they survive phagocytosis
  6. Disrupt intracellular signalling
  7. Modify their surface - expression of capsules or different proteins
43
Q

How can bacteria target chemotaxis to evade neutrophil functions?

A

e.g. The S. Aureus secretes CHIPs, a chemotaxis inhibitory protein, which binds with a higher affinity to C5a and FPR receptors
This prevents neutrophils from migrating to the site of infection via chemotaxis so they do not get activated

44
Q

How can bacteria target detection to evade neutrophil functions?

A

e.g. S. Aureus express a protein called FLIPr, binds to Fc receptors with a high affinity so cannot detect Fc regions on IgG Abs. Also express a protein called SSL5, binds to Fc receptors, inhibiting detection of Fc regions on IgA Abs
Reduces antibody mediated phagocytosis and killing of the bacteria

45
Q

How can bacteria target activation to evade neutrophil functions?

A

Prevent them from becoming activated by expressing molecules that are receptor antagonists, so bind to activatory receptors and inhibit them
Release toxins to kill the neutrophils

46
Q

How can bacteria target inhibitory receptors to evade neutrophil functions?

A

Molecules released by bacteria to bind the inhibitory receptors, cross-linking them
Phosphorylation of the inhibitory motifs in the cytoplasmic tails
Induces inhibitory signals, prevents activation of the neutrophil (suppresses neutrophil function)

47
Q

How can bacteria target phagocytosis to evade neutrophil functions?

A

Release proteins that inhibit effects of enzymes / antimicrobial products present within the granules when they enter the phagolysosome
Allows them to survive phagocytosis
Or degranulation of the neutrophil allows for survival of the bacteria from the compounds released locally
e.g. In S. Aureus, protein called SPIN binds to MPO, to inhibit its toxic effects

48
Q

How can bacteria target intracellular signalling to evade neutrophil functions?

A

Manipulate intracellular signalling to prevent activation of immune cells, etc.

49
Q

How can bacteria modify their surface to evade neutrophil function?

A

Bacteria can express capsules / proteins to prevent detection from activated neutrophils at the site of infection

PoM - Principles of Medicine Week 3 (9 decks)

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