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MIIM30003 - Medical & Applied Immunology > Lecture 14 - Immunity to Bacterial I > Flashcards

Lecture 14 - Immunity to Bacterial I Flashcards

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USMLE® Step 1 flashcards
1
Q

Describe the generic structure of the bacterial cell

A

Cell wall

Cell membrane

+/- Capsule

Intracellular constituents:
• DNA
• Ribosomes
• RNA

+/- Flagella

+/- Pilli

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2
Q

Compare Gram + and - bacteria

A

Gram +
• One plasma membrane
• Thick outer wall of peptidoglycan

Gram -
• Inner and outer plasma membranes
• Thin layer of peptidoglycan in between membranes
• LPS on outer membrane

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3
Q

Describe the components of bacterial cell walls

A

Peptidoglycan

Teichoic acid

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4
Q

What is another name for pilli?

A

Fimbriae

Made of protein

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5
Q

Describe the structure of LPS

Where is it found?

A

(Lipopolysaccharide) aka endotoxin

Present on the outer membrane of Gram -ve bacteria

Core glycolipid
• Outer and inner oligosaccharides
• Lipid A (anchors LPS in the lipid membrane)

O-specific polysaccharide chain
• Variable length
• Repeats
• Part that induces Ab responses

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6
Q

List some general features of immune responses to microbes

A
  • Mediated by innate and adaptive immunity
  • Distinct and specialised responses to different microbes
  • Pathogenicity and survival of microbes influence by ability to evade immune system
  • Latency can occur
  • Tissue injury and disease can result from the host response against bacteria
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7
Q

Compare the features of extracellular and intracellular bacterial pathogens

Where do each reside?

Give an example each

A 
Extracellular:
 • Evade phagocytosis
 • Reside in interstitial spaces, blood, lymph, or on epithelial surfaces
 • Non-invasive, toxin producers
 • e.g. E. coli, V. cholerae

Intracellular:
• Resist intracellular killing
• Reside in either cytoplasm or vesicles
• e.g. Salmonella typhinurium

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8
Q

List the general mechanisms of Ab against extracellular bacteria

A

• Neutralisation

  • Preventing replication
  • Preventing adhesion to / invasion of host cells
  • Opsonisation and FcR-mediated phagocytosis
  • C’ activation
  • Phagocytosis of C3b coated bacteria
  • Inflammation
  • Lysis (MAC formation)
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9
Q

List some of the ligands on bacteria that trigger the C’ cascade

Which molecules are binding to these ligands on bacteria?

A

Gram -ve:
• LPS
• Proteins
• PS

Gram +ve:
• Phosphocholine
• Many proteins

Triggering molecules:
• C1q
• MBL

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10
Q

Give an overview of the pathways of C’ activation

A
  1. Classical
    • Ab binds surface of pathogen and triggers C’ activation
  2. Alternative
    • C’ proteins bind directly to molecules on the pathogen
  3. Lectin binding
    • MBL binds sugars on the surface of microbes
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11
Q

Describe T cell responses to extracellular bacteria

A

CD4+ ‘helper’ T cell responses are most important

  1. Inflammation
    • IL-17, TNF and other cytokine production
  2. Macrophage activation
    • IFN-γ production
    • Increased phagocytosis and intracellular killing
  3. Antibody response
    • Help for B cells
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12
Q

Which components of the immune system fight against extracellular bacteria?

A
  • Antibodies
  • C’ cascade
  • CD4+ ‘helper’ T cells
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13
Q

Which infections do people w/o Th17 responses suffer from?

A

Bacterial and fungal infections

Th17 produce IL-17 which is important for immunity against bacteria

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14
Q

Describe the roles of the various compartments of immunity against intracellular pathogens

A
  1. Innate immunity
    • Stems spread of infection in early stages
    a. Neutrophils
    • IL-12 for NK cell activation

b. NK cells
• IFN-γ production for macrophage stimulation

c. Macrophages
• Phagocytosis of bacteria
• IFN-γ signalling from NK cells is crucial

  1. Adaptive immunity
    • Needed for eradication of infection
    a. Th1
    • Help macrophages to clear the bacteria

b. CTLs
• Especially important against bacteria that escape into the cytoplasm
• eg. Listeria infections
• Perforin and granzyme dependent killing

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15
Q

Compare macrophages and neutrophils

A

Macrophages:
• Present in tissues
• Long lived
• Phagocytose bacteria

Neutrophils:
• Short lived
• Present in circulation
• Phagocytose bacteria

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16
Q

Are macrophages present in the spleen?

A

Yes, they are very abundant in the red pulp

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17
Q

How do macrophages recognise bacteria?

A 
Various receptors:
 • C' receptors
 • C1q receptor
 • FcR
 • Mannose receptor
 • Scavenger receptors
 • PRRs
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18
Q

Describe the process of opsonisation and phagocytosis

A
  1. Opsonised bacterium:
    • C3b and Abs on surface
  2. Macrophage recognises opsonised bacterium
    • C3b binds CR1
    • Ab Fc region binds FcR
  3. Triggering of phagocytosis
  4. Opsonised bacterium taken up into phagosome
  5. Lysosomes fuse with the phagosome to produce a phagolysosome, in which the bacteria are killed and degraded
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19
Q

Why don’t macrophages constantly bind Ab in the serum?

A

Need cross-linking of FcR for activation of the macrophage

This only happens when Ab are aggregated on a bacterium

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20
Q

Outline how macrophages and neutrophils kill ingested organisms

A
  1. Acidification
    • pH 3.5-4.0 in lysosomes
    • This is bactericidal or bacteriostatic
  2. Toxic oxygen-derived products
    • Superoxide, 02-
    • Hydrogen peroxide, H2O2
    • Hydroxyl radical, OH-
  3. Toxic nitrogen oxides
    • NO
  4. Antimicrobial proteins
    • Cathelicidin in macrophages and neutrophils
    • α and β defensins in neutrophils
  5. Enzymes
    • Lysozyme
    • Acid hydrolases (e.g. elastase)
  6. Competitors
    • Lactoferrin in neutrophils
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21
Q

Describe the action of lysozyme

A

Digests cell walls of some Gram positive bacteria

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22
Q

Describe the mechanism of respiratory burst

A

Neutrophils have receptors that recognise peptides (fMLP) that are only produced by bacteria (prokaryotic cells)

  1. fMLP on bacteria activates receptor, resulting in activation of Rac2
  2. Rac2 is instrumental in the formation of the NADPH oxidase complex
  3. NADPH oxidase complex on membrane of secondary granules in neutrophils
  4. NADPH oxidase complex generates oxygen radicals
    • Superoxide
    • Hydrogen peroxide
  5. Granules fuse with phagosomes (containing pathogen) and lysosomes
  6. Bacteria killed
23
Q

Describe how neutrophils can kill extracellular bacteria

A

Neutrophil Extracellular Traps (NETs)

“NETosis”

Composition:
 • DNA
 • Anti-bacterial proteins:
- Myeloperoxidase
- Serine proteases
- Elastase

Function:
• NETs are exocytosed
• Helps to immobilise and ultimately kill the bacteria

24
Q

What molecules are present in the granules of neutrophils?

A

ROS
• OH-
• O2-
• H2O2

Defensins
Cathelicidins
Myeloperoxidase

25
Q

Which cytokines and chemokines do macrophages produce?

A
  • IL-1β
  • TNF-α
  • IL-6
  • CXCL8
  • IL-12
26
Q

What is the role of IL-1β from macrophages?

A

Activates vascular endothelium

Activates lymphocytes

Local tissue destruction → increased access for effector cells

Systemic effects:
• Fever
• IL-6 production

27
Q

What is the role of IL-6 from macrophages?

A

Lymphocyte activation (Th17)

Increased Ab production

Systemic effects:
• Fever
• Induces acute phase response; CRP production in liver

28
Q

What is the role of TNF from macrophages?

A

Activation of vascular endothelium

Increased vascular permeability

Increased entry of IgG, C’, and effector cells

Systemic effects:
• Fever
• Shock

29
Q

What is the role of CXCL8 from macrophages?

A

Recruits:
• Neutrophils
• Basophils
• T cells

to site of infection

30
Q

What is the role of IL-12 from macrophages?

A

Activation of NK cells

Induces differentiation down the Th1 lineage

31
Q

Which T cells play a role in anti-bacterial immunity?

A 
CTLs
Th1
Th2
Th17
Treg
32
Q

Describe the role of CTLs in anti-bacterial immunity

A 
Cytotoxicity against infected cells:
 • Perforin
 • Granzymes
 • Granulysin
 • FasL

Cytokine production:
• IFN-γ
• LT-α
• TNF-α

33
Q

Describe the role of Th1 in anti-bacterial immunity

A

Activation of macrophages:
• IFN-γ
• CD40L

Killing of chronically infected cells
• FasL
• LT-β

Stimulation of monocytes in BM:
• IL-3
• GM-CSF

Activation of endothelium
• TNF
• LT-α

Accumulation of macrophages at site of infection:
• CXCL2

Stimulation of T cells:
• IL-2

34
Q

Describe the role of Th2 in anti-bacterial immunity

A 
Stimulate B cell responses & barrier immunity:
 • IL-4
 • IL-5
 • IL-13
 • CD40L
35
Q

Describe the role of Th17 in anti-bacterial immunity

A

Neutrophil recruitment:
• IL-17
• IL-6

36
Q

Describe the role of Tregs in anti-bacterial immunity

A

Immune suppression:
• IL-10
• TGF-β

• GM-CSF

37
Q

Compare different diseases caused by Mycobacterium leprae

A

M. leprae can cause two different types of diseases based on the host immune response (esp. Th response)

  1. Lepromatous disease:
    • Destructive lesions in skin and underlying tissue
    • Large n° of bacteria growing in macrophages
    • Inadequate macrophage activation (due to their infection)
    • High Ab titres
    - the bacterium is intracellular, so Ab responses aren’t helping to clear the infection
    • Weak cell-mediated immunity
    • Th2 response predominates
2. Tuberculoid disease:
 • Granulomas; less tissue destruction
 • Low n° of bacteria
 • Low Ab titres
 • Strong cell-mediated immunity
 • Th1 response predominates
38
Q

Describe the growth of the microbe in the following situations:
• Lacking innate immunity
• Lacking adaptive immunity
• Normal (immunocompetent)

A

Lacking innate immunity:
• Rapid growth of infection in early stages
• Infection not controlled

Lacking adaptive immunity:
• Innate immunity stems early growth
• Infection can not be cleared, and persists

Normal, immunocompetent:
• Growth of infection in early stages, but immune system eventually clears the bacteria

39
Q 
Describe the effect of the following conditions on anti-bacterial immunity:
 • Neutropaenia
 • MBL deficiency
 • Perforin
 • IL-12R deficiency

Also: intra- / extracellular infection

A

*

Perforin:
• Lacking CTL responses
• Susceptible to intracellular bacterial infections (esp. Salmonella typhimurium)

IL-12 deficiency:
• NK cells respond to IL-12
• Suffer from intracellular bacterial infections

40
Q

Which bacteria commonly causes intracellular (cytosolic) infections?

A

Salmonella typhimurium

41
Q

Which injuries can occur from immune response to bacteria (intra- and extracellular)

A

– Extracellular bacteria –
1. Inflammation
• Temporary
• Chronic (H. pylori)

  1. Septic shock
    • aka Endotoxic shock
  2. Superantigen-induced shock
  3. Disease producing Abs mediated
    • Intracellular bacteria –
      1. Delayed type hypersensitivity
      2. Granuloma formation
42
Q

Describe how bacteria can cause chronic inflammation

A

Helicobacter pylori

Resides in the mucous lining the epithelium of the stomach

Bind to host cells triggers a host Th1 response

Th1 produce IFN-γ, which recruits many macrophages

Macrophages can not eliminate the bacteria

IFN-γ results in chronic gastritis

43
Q

Describe how septic shock occurs

A

In response to LPS, hence endotoxic shock

Large amounts of LPS in the blood stream

Normally:
1. LPS released when bacteria are lysed

  1. LPS mopped up by LBP (LPS-binding protein)
  2. LBP/LPS complex binds CD14:
    • Soluble
    • Bound to macrophages and PMNs
  3. mCD14-LBP/LPS complex associates with TLR4
5. Signal-transduction, resulting in release of:
 • Cytokines:
- IL-1
- IL-6
- TNF
 • Tissue factor
  1. When there is a large amount of LPS, this happens at a great level, resulting in vast amounts of these cytokines being produced

(LPS can also act directly on endothelial cells, resulting in cytokine production)

  1. Inflammatory response brought about by the cytokines
    • Neutrophil recruitment
    • Superoxide production
    • Degranulation
  2. Tissue factor triggers coagulation cascade:
    • Thrombin activation
    • Fibrin activation
    • Formation of a thrombotic and fibrinolytic response
9. Damage:
 • Endothelial damage
 • Loss of fluid in tissues
 • Drop in BP
 • Circulatory collapse
  1. Multiple organ failure
    • Nearly always fatal
    • V. difficult to reverse
44
Q

What is mCD14?

A

Protein bound to surface of macrophages and PMNs that binds LBP/LPS

45
Q

What are superantigens?

Which bacteria produce them?

Describe how they induce damage

A

Ags that bind MHC class II molecules and TCR

Do not require processing

  1. Binds to:
    • Conserved regions of Vβ region of TCR
    • Conserved residues on MHC II
  2. Results in activation of many T cells (not just those specific for a particular epitope)
  3. T cells and macrophages produce vast amounts of cytokines
    • TNF
  4. Results in:
    • Disseminated vascular coagulation
    • Cardiovascular shock

Bacteria:
• Staph. aureus produced Staphylococcal enterotoxins

46
Q

Describe what is happening during the late stages of super antigen induced shock

A

Monocytes release cytokines that act on endothelial cells

Intravascular co-agulation of blood

Loss of fluid from vasculature into tissues (through leaky endothelium)

47
Q

Give an example of how antibodies can produce disease

A

e. g. Streptococcus pyogenes (Group A strep.)
1. Group A strep infection in throat or skin

  1. Cross-reactivity of anti-bacterium antibodies with ‘self’
    • anti-M protein Abs react w/ Myocardial proteins
  2. Antibodies bind to proteins in heart, triggering C’
  3. Inflammation and carditis
  4. Immune complexes can also deposit in the kidney, causing nephritis
    • Immune complexes formed during an infection, if not properly removed
48
Q

What is the Mantoux test?

A

Test to determine if an individual has been exposed to M. tuberculosis

  1. Tuberculin (purified protein derivate) injected

If there has been prior exposure:
2. Formation of a DTH response:
• Tuberculin antigen is taken up, processed by DCs and presented to T cells

  1. Presence of CD4+ T cells in skin where injected

Size of the reaction is measures

49
Q

Describe granuloma formation

What causes this?

A

Caused by intracellular bacteria that resist killing

  1. Intracellular bacterial infection resists killing, persists
  2. Chronic Ag stimulation of T cells and macrophages
  3. Macrophages form giant multinucleate cells containing bacteria
  4. Influex of activated macrophages and surrounded by T cells
  5. May result in tissue necrosis and fibrosis
  6. Localises infections and prevents spread of microbes
50
Q

Which pathogen classically causes granuloma formation?

A

M. tuberculosis

51
Q

How is it possible that superantigens can activate 2% of T cells?

A

Superantigens bind conserved regions between the β chains of TCRs

2% of T cells will share certain regions in the Vβ domain

e.g. Staphylococcal enterotoxin B binds Vβ3, which is present in roughly 2% of TCRs

52
Q

Describe the structure of a granuloma

A

Centrally:
• Giant multinucleate macrophages containing the bacteria
• Activated macrophages

• CD4+ T cells around the outside

53
Q

Outline the various roles of macrophages in anti-bacterial immunity

A
  1. Release of cytokines and chemokines

2. Phagocytosis of pathogens

54
Q

Which cytokine is vitally important for NK cell activation?

Where does this cytokine come from?

A

IL-12

Released by macrophages that have sensed pathogens

MIIM30003 - Medical & Applied Immunology (30 decks)

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