L15- Immunity to Bacteria

Question 1

What is bacterial pathogenesis?

Answer 1

Types of pathogenesis include microbial infection, inflammation, malignancy and tissue breakdown. For example, bacterial pathogenesis is the mechanism by which bacteria cause infectious illness. Most diseases are caused by multiple processes.

 Attachment to host tissue colonisation

 Invasion into deeper host tissues and production of toxins

 Inflammation at the site of invasion

Question 2

Immune responses to pathogenic bacteria are determined by?

Answer 2

• Bacterial surface chemistry
• Mechanisms of pathogenicity
• Whether they are extracellular or intracellular

Question 3

Immune responses to pathogenic bacteria are determined by surface chemistry. Provide some examples.

Answer 3

 Bacteria have an inner cytoplasmatic membrane and peptidoglycan wall.

 Gram-negative bacteria also have an outer lipid bilayer in which LPS is embedded.

 Lysosomal enzymes and lysozymes are active against the peptidoglycan layer.

 Cationic proteins and Gram-positive cell wall complement are effective against the outer lipid bilayer of Gram-negative bacteria.

 Fimbriae or flagellum, or outer capsule, can impede function of phagocytes or complement.

Question 4

Explain the layers of Gram+ve cell wall

Answer 4

Thick peptidoglycan layer with teichoic acid and lipoteichoic acid sticking out

Periplasmic space

Plasma membrane and integral proteins

Question 5

Explain the layers of Gram-ve cell wall

Answer 5

Outer membrane and O-specific side chains sticking out. Porins stick out

Thin peptidoglycan layer sandwiched between periplasmic space with Broun’s lipoprotein extending out to outer-membrane

Plasma membrane and integral proteins

Question 6

Immune responses to pathogenic bacteria are determined by mechanisms of pathogenicity. Name some.

Answer 6

Exotoxin production- E.g. Staphylococcus aureus

Endotoxin- E.g. Escherichia coli

Direct cytoplasmic effect- E.g. Hepatitis B virus (HBV)

Immune complexes- E.g. Malaria

Anti-host antibody- E.g. Streptococcus pyogenes

Cell-mediated immunity - Mycobacterium tuberculosis

Question 7

Immune responses to bacteria are determined by whether they are extracellular or intracellular. Provide an example for Extracellular pathogens affecting epithelial surfaces

Answer 7

Epithelial surfaces;

Neisseria gonorrhoea
Helicobacter pylori
Candida albicans
Vibrio cholerae

Question 8

Immune responses to bacteria are determined by whether they are extracellular or intracellular. Provide an example for intracellular pathogens affecting cytoplasm

Answer 8

Cytoplasmic;

Viruses
Chlamydia spp.
Rickettsia spp.
Protozoa

Question 9

Immune responses to bacteria are determined by whether they are extracellular or intracellular. Provide an example for intracellular pathogens affecting vesicular

Answer 9

Vesicular;

Mycobacterium spp.
Yersinia pestis
Legionella pneumophila
Leishmania spp.

Question 10

Immune responses to bacteria are determined by whether they are extracellular or intracellular. Provide an example for Extracellular pathogens affecting interstitial spaces, blood, and lymph

Answer 10

Interstitial spaces, blood. Lymph;

Viruses
Bacteria 
Protozoa 
Fungi
Worms

Question 11

What are the immune cells that protect the interstitial spaces, blood and lymph?

Answer 11

Complement
Phagocytosis
Antibodies

Question 12

What are the immune cells that protect epithelial surfaces?

Answer 12

Antimicrobial peptides

Antibodies especially IgA

Question 13

What are the immune cells that protect the cytoplasm?

Answer 13

NK cells

Cytotoxic T cells

Question 14

What are the immune cells that protect vesicular?

Answer 14

T cell and NK dependent

Macrophage activation

Question 15

Our skin is the first line of defence against bacteria does not depend on antigen recognition. List some mechanical and chemical mediators

Answer 15

 Skin and exposed epithelial surfaces have non-specific protective systems which limit entry of potential invasive bacteria.

 Skin is “impenetrable”; also, fatty acids produced by skin are toxic to many organisms.

 Epithelial surfaces are cleared by ciliary action in the trachea or by flushing of urinary tract.

 Most bacteria are killed by low pH of stomach and vagina.

 Normal microbiota (bacteriocins)

Question 16

Some bacteria with an outer bilayer susceptible to the lytic complex can be killed via…

Answer 16

The complement system (C5b-C9) i.e. Gram-ve bacteria

Question 17

Production of C3b of complement is important for…?

Answer 17

Opsonin

Question 18

Which part of complement is involved with inflammation?

Answer 18

C3a and C5a

• Attract and activate neutrophils
• Activates mast cells – release of histamine and leukotriene contributes to increased vascular permeability.

Question 19

What is opsonisation?

Answer 19

Opsonisation is the process by which a microorganism is coated by serum components, thereby enhancing recognition and ingestion by phagocytic cells.

Question 20

Explain the process of opsonisation

Answer 20

a. Intrinsic ability of a phagocyte to bind a microorganism is enhanced is the microorganism is coated with antibodies; the Fc receptor on the phagocyte.
b. If the microbe is coated with the complement protein C3b, binding to the phagocyte, via the C3b receptor, is further enhanced.
c. If the microbe is coated with antibody and C3b, binding to the phagocyte is maximal.

Question 21

What are 2 acute-phase proteins that are mainly secreted by hepatocytes, that assist the host in eliminating bacteria?

Answer 21

C-reactive protein and Mannosebinding protein

They activate complement and act as opsonins; CRP recognises altered self and non-self molecules.

Question 22

How are acute-phase proteins activated?

Answer 22

Bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins.

Question 23

What does C-reactive proteins do?

Answer 23

C-reactive protein binds phosphocholine on bacterial surfaces acting as opsonin, and also activating complement.

Question 24

What does mannose-binding lectin do?

Answer 24

Mannose-binding lectin binds mannose residues on bacterial surfaces acting as opsonin, and also activating complement.

Question 25

Second line of defence is mediated by recognition of bacterial components such as...?

Answer 25

Many bacterial PAMPs activate cells via Toll-like receptors.

Question 26

Where do TLR come from?

Answer 26

TLRs are preferentially expressed on phagocytes, DCs and epithelial cells at sites of bacterial entry

Question 27

What does TLR’s do?

Answer 27

TLR activation leads to expression of costimulatory molecules on phagocytes, and has an important role in production of inflammatory cytokines

Question 28

What do NOD-like receptors do?

Answer 28

Nucleotide-binding oligomerisation domain (NOD)-like receptors recognise bacterial degradation product in the cytoplasm.

Question 29

What kills most bacteria and who comes in second?

Answer 29

Most bacteria are killed by phagocytes. Few bacteria are killed by complement (mostly Gram-negative).

Question 30

Where would you find neutrophils?

Answer 30

Neutrophils are found almost entirely in blood.

Question 31

Where do macrophages arise from and where do they hang out?

Answer 31

Macrophages are differentiated from blood monocytes and are resident in tissues (i.e. alveolar macrophages, osteoclasts, histiocytes, etc.)

Question 32

What are phagocytes attracted (chemotaxis) by...?

Answer 32

* Bacterial structural components * Complement products such as C5a, also C3a (to a lesser extent) * Locally released cytokines and chemokines derived from resident macrophages and epithelial cells

Question 33

Explain the stages of phagocytosis

Answer 33

1. Chemotaxis 2. Attachment/ adherence 3. Engulfment/ ingestion 4. Digestion/phagosome maturation 5. Destruction and exocytosis

Question 34

Do macrophages promote leukocyte adhesion and migration? Explain.

Answer 34

Yes. TNF and IL-1 released by macrophages and dendritic cells upregulates adhesive molecules on endothelial cell and facilitates passage of more phagocytes into inflamed tissue.  Activated macrophages and dendritic cells act as APC to activate effector cells.

Question 35

Bacteria are taken up by binding to opsonic receptors including the Fc receptor; complement receptors; mannose receptor (MR). The antigen is taken up by phagocytes which present antigen to and activate CD4+ T cells. Explain this process further.

Answer 35

1. An APC encounters and ingests a microorganism. Antigen fragments of small peptides combine internally with MHC (self molecules) and the complex of MHC molecules and and antigen fragments are presented on the surface of the APC. 2. A helper T cell receptor binds to the complex, stimulating the APC to secrete interleukin-1. 3. Interleukin-1 stimulates the helper T cell to produce interleukin-2, which then stimulates that helper T cell to form a clone of helper T cells. 4. The cells of this clone in turn produce cytokines, stimulating cells of both immune systems.

Question 36

Explain how T cells mediate protection against Mycobacterium tuberculosis.

Answer 36

 IFN-γ and TNF-α, produced by TH 1 cells, contribute to the recruitment of monocytes and granulocytes and activate the anti-microbial activity of macrophages - phagosome maturation, production of reactive nitrogen intermediates and antigen presentation.  T cells also participate in granuloma formation, the pathologic hallmark of tuberculosis.  CD4 T cells deficiency (i.e. HIV+) dramatically increases susceptibility to both primary and reactivation tuberculosis.  Growing evidence suggesting that CD8+ T lymphocytes play an essential in controlling TB.

Question 37

CD4 T cells deficiency (i.e. HIV+) dramatically increases susceptibility to both primary and reactivation tuberculosis.. T or F?

Answer 37

True

Question 38

How do antibodies provide protection against toxins?

Answer 38

* Neutralises diphtheria toxin by blocking attachment to target cells. * Blocks locally acting toxins or extracellular matrix-degrading enzymes, which act as spreading factors.

Question 39

What other ways do antibodies provide antigen-specific protection against pathogens?

Answer 39

 Bind to flagellum and interfere with motility  Prevent bacteria binding to epithelial cells (secretory IgA);  For non-toxogenic bacteria, capacity of Ab to activate complement is important (IgM>IgG3>IgG1);  Opsonise pathogens via FcR.  Neutralises diphtheria toxin by blocking attachment to target cells.  Blocks locally acting toxins or extracellular matrix-degrading enzymes, which act as spreading factors.

Question 40

What are some ways in which bacteria evade the immune system?

Answer 40

 Invasion mechanisms - Type III secretion system, toxins, neuraminidases, etc.  Inhibition of complement activation - polysaccharide capsule, toxins, proteases.  Preventing phagocytosis;  Preventing phagosome maturation; • Fusion with lysosome • Acidification • Reactive oxygen and nitrogen species  Biofilm

Question 41

What are some mechanisms used by Neisseria gonorrhoea to avoid the effects of antibody?

Answer 41

1. Fails to evoke a large antibody response 2. Secreted an IgA protease to destroy antibody 3. Membrane vesicles (blebs) are released- these appear to absorb and so deplete local antibody levels. (Decoys) 4. Alter antigenic composition; - LPS May be sialyated: more closely resemble mammalian oligosaccharides - Organism may undergo phase variation - expressing an alternative set of surface molecules - Pilin gene undergoes homologous recombination to generate variants.