Lecture 1-3: Immune Response to and Immune Evasion by Bacteria Flashcards

1
Q

What is a pathogen ?

A

A microbe that can cause disease in its host

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2
Q

What are the goals of pathogens ?

A
  1. Invade host and gain a foothold
  2. Multiply and persist
  3. Disseminate through the body
  4. Cause disease and transmit to new hosts
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3
Q

What are the functions of the immune system ?

A
  1. Recognition of bacteria
  2. Clearance of bacteria
  3. Resolution of inflammation
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4
Q

What does microbial invasion initially encounter ?

A

Innate immune defences

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5
Q

What have pathogens evolved to overcome innate immunity ?

A

Mechanisms

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6
Q

What is adaptive immunity required for ?

A

Clearance of pathogens and prevention of re-infection

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7
Q

What have successful pathogens evolved ?

A

A range of anti-immune strategies to overcome both innate an acquired immunity

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8
Q

What does immunity of bacteria depend on ?

A

The nature of bacteria and the mechanism of pathogenicity

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9
Q

What are some examples of the nature of bacteria ?

A
  1. Intracellular verses extracellular
  2. Gram positive or negatiive
  3. Toxicity or invasiveness
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10
Q

What is virulence factor ?

A

A quantative measure of pathogenicity

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11
Q

What are some virulence factors ?

A
  1. Colonisation of a niche in host
  2. Immune evasion
  3. Entry and exit out of cells
  4. Obtain nutrient from host
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12
Q

Where do extra-cellular bacteria live ?

A

Outside cell

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13
Q

How do extracellular bacteria replicate ?

A

Quickly to avoid elimination

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14
Q

What are extracellular bacterias immune response targeted to ?

A

Eliminate bacteria and neutralise toxins

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15
Q

What are some examples of extra-cellular bacteria ?

A
  1. Straphylococcus aureus
  2. E. coli
  3. Streptococcus pneumoniae
  4. ” pyrogenes
  5. Pseudomonas aeruginosa
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16
Q

What are the immune responses in extra-cellular bacteria ?

A
  1. Complement
  2. Anti-microbial peptides
  3. Phagocytes
  4. Antibodies
  5. T-helper cell
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17
Q

Where do intracellular bacteria live ?

A

Lives inside host cells

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18
Q

What are intra-cellular bacteria capable of ?

A

Avoiding many host immune strategies

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19
Q

How do intracellular bacteria enter cells ?

A

Phagocytosis

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20
Q

What must intracellular bacteria evade ?

A

Lysosomal killing

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21
Q

What are common host cells of intracellular bacteria ?

A

Macrophages and epithelial cells

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22
Q

What are some examples of intracellular bacteria ?

A
  1. M. Tuberculosis
  2. Listeria
  3. Salmonella enterica
  4. ” typhimurium
  5. ” trachomatis
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23
Q

What are the immune responses of intracellular bacteria ?

A
  1. Phagocytes
  2. Cytotoxic T cells
  3. NK cells
  4. T helper cells
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24
Q

What type of immunity are extracellular bacteria ?

A

Humoral

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25
Q

What type of immunity is intracellular bacteria ?

A

Cellular immunity

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26
Q

What is the bacterial cell wall PAMPs ?

A

Bacterial surface that the host immune system sees

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27
Q

What are appendages ?

A

Proteins attached to cell surface

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28
Q

What is a capsule ?

A

Carbohydrate coating

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29
Q

What is the structure of bacteria ?

A
  1. Bacteria cell wall PAMPs
  2. Appendages
  3. Capsule
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30
Q

What is gram negative target for ?

A

Outer lipid membrane target for membrane lysis eg. complement

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31
Q

What does gram positive bacteria require ?

A

Killing requires uptake by phagocytes

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32
Q

What are the pathogen recognition receptors ?

A
  1. TLRS
  2. NLRS
  3. CLRS
  4. DNA sensors
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33
Q

What do CLRs do ?

A

Bind carbohydrates in a ca+2 dependent manner

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34
Q

What does TLR5 recognise ?

A

Flagella

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35
Q

What are exotoxins ?

A

Proteins secreted by bacteria, act at sites removed from bacteria

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36
Q

What are endotoxins ?

A

Cell associated moleucles, structural molecules of the bacteria. Maybe released from growing bacteria or cells that are lysed

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37
Q

Where do endotoxins act in the vicinity of ?

A

Bacterial growth or presence

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38
Q

What can inhibit opsonisation ?

A

Carbohydrate coating

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39
Q

What are the functions of endotoxins ?

A
  1. Protective permeability barrier
  2. Barrier to lyozyme and antimicrobial agents
  3. Impedes destruction of the bacterial cells by serum components and phagocytic cells
  4. Role as an adhesin
  5. Variations in LPS result in antigenic variation
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40
Q

What are the most powerful human poisons ?

A

Bacterial toxins

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41
Q

Where does enterotoxin target ?

A

Intestines

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42
Q

Where does Neurotoxin target ?

A

Neurons

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43
Q

Where does leukocidin target ?

A

Leukocytes

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44
Q

Where does hemolysin target ?

A

Red blood cells

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45
Q

What are the exotoxins mechanisms of action ?

A
  1. Enzyme activity
  2. Pore forming
  3. Super antigens
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46
Q

What do invasins do ?

A

Degrae tissue

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47
Q

What can intracellular enymati activity ie needs to be taken up into cell occur by ?

A
  1. Type 3 secretion system
  2. Receptor mediated endocytosis
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48
Q

How does Pertussis toxin work ?

A

Inhibits G protein coupling thus interfering with adenylate cyclase activity resulting in build up in intracellular cAMP which interferes with cell signalling pathways that regulate eg. phagocytosis

49
Q

What happens during pore forming ?

A

Inserts a transmembrane pore into cell membrane disrupting influx and efflux of ions across the membranes

50
Q

What is an example of bacteria which work by enyzymatic activity ?

A
  1. Staphylococcus aureus
  2. Streptococcus pyogenes
51
Q

What bacteria pore forms ?

A
  1. Streptolysim
  2. alpha toxin- s.aureus
  3. Listeriolysin - lysteria
52
Q

How do superantigens work ?

A

Hyper stimulation of the immune system - bind MHCII directly resulting in massive T cell proliferation and associated cytokine production

53
Q

Example of bacteria with superantigens ?

A

Pyrogenic exotoxins produced by staphlocooci and streptococci cause high fever and rash associated with toxic shock

54
Q

What is the complement system ?

A

An important humoral component of the innate immune system

55
Q

What does the complement system help do ?

A

Helps phagocytes and antibodies to clear infection

56
Q

What does the complement system consist of ?

A

Small proteins found in blood, generated in the liver

57
Q

How is the amplified enzyme cascade activated ?

A

Proteases activated by cleavage by other proteases in the system

58
Q

What are the functions of complement system ?

A
  1. Opsonisation - enhacing phagocytosis of antigens
  2. Chemotaxis - attracting phagocytes
  3. Lysis of bacteria - rupturing membranes of foreign cells
59
Q

What are the three pathways of the complement system ?

A
  1. Classical
  2. Mannose binding lectin
  3. Alternative
60
Q

What are the components involved in the classical pathway ?

A

C1, C2, C4

61
Q

What is the classical pathway triggered by ?

A

Antibody antigen complexes binding to C1 (C1Qq, C1r, C1s)

62
Q

What does the classical pathway form ?

A

C3 convertase (C4bC2a)

63
Q

How is the mannose binding lectin pathway activated ?

A

MBL binding directly to mannose resiues on the bacterial surface

64
Q

What does the binding of MBL to mannose activate ?

A

MBL associated serine proteases MASP-1 and MASP-2 which activates C4 and C2

65
Q

How does the alternative pathway work ?

A

Involves various factors B, D, H, I which interact with C3B to form an alternative C3 convertase. Functions to amplify pathway

66
Q

What is the lytic pathway ?

A

Initiated by the splitting of C5 and attachment of C5b to C6, C7, C8 and C9 to form the membrane attack complex, which inserts into the outer membrane of some bacteria causing lysis

67
Q

What are antimicrobial peptides ?

A

Cationic host defense peptides

68
Q

What type of molecule are antimicrobial peptides ?

A

Small positively charges amphipathic molecules

69
Q

How long are antimicrobial peptides ?

A

6 to 100 aa

70
Q

How are antimicrobial peptides grouped ?

A

Secondary protein structures

71
Q

What can antimicrobial peptides target ?

A

Bacteria, viruses, fungi and even cancerous cells

72
Q

What are the most prominent antimicrobial peptides ?

A
  1. Cathelicidians
  2. Defensins
73
Q

What are the antimicrobial mechanisms of action ?

A
  1. Selectively target bacterial cell membranes
  2. Destruction of target cell
74
Q

What do defensins and cathelicidins do ?

A

Form pores which promote lysis

75
Q

How does lysozyme work ?

A

Disrupts bacterial membranes through enzymatic digestion which targets peptidoglycan backbone

76
Q

What is LL37 ?

A

Cathelicidins

77
Q

What does LL37 do ?

A

Chemotactic activity that can attract neutrophils, monocytes, mast cells and T cells

78
Q

What can LL37 supress ?

A

TLR signalling by binding LPS or LTA

79
Q

How can LL37 promote inflammation ?

A

By binding nucleic acids to facilitate recognition of self DNA, self RNA, DSRNA

80
Q

What are the roles of phagocytes ?

A
  1. Recruitment to site of infection
  2. Recognition of infecting organism
  3. Ingestion of invading organisms
  4. Killing of ingested organism
  5. Clearance of activated phagocyte from site of infection
  6. Activation of adaptive immune response
  7. Presentation of antigen
81
Q

What are pathogens recognised by on the surface of phagocyte ?

A

Receptor

82
Q

How can optimal recognition by phagocytes occur ?

A

Opsonisation

83
Q

What is opsonin independent recognition ?

A

Direct recognition of targets on microbe

84
Q

What is the function of PRRs ?

A

Facilitate recognition and enhance this process by activation of signalling pathways in phagocyte

85
Q

What does activation of signalling in phagocytosis do ?

A

Leads to actin polymerisation and cytoskeleton rearrangement

86
Q

What is the fundamental process of phagocytosis ?

A

Rearrangement of actin cytoskeleton

87
Q

What are the intracellular signalling pathways triggered upon receptor activation ?

A
  1. Src family kinases
  2. SYK tyrosine kinases
88
Q

What are Rho GTPases ?

A

Binding proteins - molecular switches which control various cellular processes

89
Q

When does cell shape change ?

A
  1. Migration
  2. Phagocytosis
  3. Using pseudopods
90
Q

What are endosomes ?

A

Intracellular membrane mound storage organelles

91
Q

What is endocytosis ?

A

Uptake and transport of extracellular material through the formation of membrane bound vesicles

92
Q

How can intracellular killing by phagocytes occur

A
  1. Reactive oxygen species
  2. Reactive nitrogen species
93
Q

What do reactive oxygen species do ?

A

Oxidising agents adversely effect cellular structures including membranes and nucleic acids

94
Q

What do reactive nitrogen species do ?

A

React with various biological targets and components of the cell including lipids, thiols, amino acid residues

95
Q

What does phagocytosis of apoptic neutrophils result in ?

A
  1. Increase TGF-beta, IL10
  2. Decrease in TNF-alpha, IL23
96
Q

How can antimicrobial peptides be blocked ?

A
  1. Proteolytic cleavage
  2. Alteration of cell surface net charge
97
Q

What does proteolytic cleavage result in ?

A

Bacteria secrete proteases and peptidases

98
Q

How are alterations of cell surface net charge occur ?

A

Modification of membrane structures to reduce anionic charge

99
Q

How is s. aureus modified to block antimicrobial peptides ?

A
  1. LTA modified by D-alanine
  2. Phospholipids with L-lysine
100
Q

How is s.entricas modified to block antimicrobial peptides ?

A

Modifies lipid A of LPS by deacetylation

101
Q

What are the targets of bacterial evasion of complement cascade ?

A
  1. Inhibition of C1q binidng to Ig molecules on bacteria
  2. Modulation of C3 convertase
  3. Targeting C3b
  4. Targeting C5a
  5. Inhibition of membrane attack complex
102
Q

How does C1q binding to Ig molecules be inhibited ?

A

Molecules such as protein A (s.aureus) and M.protein (Group A streptococcus) binding to Ig

103
Q

What happens in modulation of C3 convertase ?

A

Molecules such as staphylococcal complement inhibitor can target C3 convertase

104
Q

How does targeting C3b work ?

A

Proteases expressed by bacteria cleave C3b from surface of bacteria therefore preventing opsononophagocytosis

105
Q

What does targeting C5a do ?

A

Inhibit neutrophil recruitment

106
Q

What does inhibition of membrane attack complex ?

A

Prevents lysis

107
Q

What do all forms of phagocytosis require ?

A

F-actin to be recruited beneath the surface bound particle into 3d structures which then resolve to allow membrane extension

108
Q

What is actin re-organisation controlled by ?

A

Rho GTPase

109
Q

What does RhoA stimulate ?

A

Acto-mysoin contraction and F-actin stabilisation and formation of stress fibres

110
Q

What does Rac1 promote ?

A

Assembly of branched F-actin network and formation of lamellipodia

111
Q

What does Cdc42 promote ?

A

Short actin filaments

112
Q

What is bacterial evasion of phagocytic killing ?

A
  1. Inhibiton of phagosomal maturation
  2. Inhibition of killing mechanisms
  3. Escape from phagosome
113
Q

How does m.tuberculosis inhibit phagolysosome maturation ?

A
  1. Ingested into phagosome but maturation to phagolysosome fails
  2. No accumulation of EEA1 or hVPS34
  3. Effect dependent upon component of cell wall phosphoinositide lipoarabinomannan which prevents increase in CA2+
114
Q

How does m.tuberculosis inhibit intracellular killing by counteract acid accumulation?

A
  1. Stimulation of macrophages with IFN-Y promotes killing by overcoming block on phagosome maturation
  2. m.tuberculosis expresses thick waxy cell wall to resist low pH
  3. rV3571c gene encoding an enzyme important in peptidoglycan synthesis - absence bacteria becomes susceptible to acidification
    4.
115
Q

What does listeriolysin O do ?

A

Create pores in phagosome membrane

116
Q

What is L.monocytogenes effect restricted to phagosome ?

A

pH dependent

117
Q

How do bacteria become motile ?

A

Hijack cells actin cytoskeletal machinery

118
Q

What does actin assembly inducing protein which is produced by L.monocytogenes do ?

A

Mimics host protein WASP involved in initiating actin polymerisation