Lecture 10 - Pathogens and viruses, avoiding immune system

Question 1

Why might bacteria become pathogenic?

Answer 1

1) encounter new area
2) result of new variants/strain/mutation
3) infected host not normal/ primary host

Question 2

what is the goal of an infectious organism?

Answer 2

1) multiply

2) secure route of transmission

Question 3

What are features of viruses?

Answer 3

1) compromised of nucleic acid and protein coat
2) obligate parasite - replication dependent on host cell
3) Intracellular existance
4) spread via extracellular stage - virion

Question 4

What methods of transmission do viruses have?

Answer 4

1) aerosols e.g. influenza, rhinovirus
2) ingestion e.g. enterovirus, polio
3) injection (insect/wound) e.g. yellow fever
4) mucosal e.g. papillomavirus, HIV

Question 5

What are the different types of receptor virus’ use to gain entry into host cell?

Answer 5

1) can use accessory receptor
2) has to use primary receptor
3) co receptors e.g. CCR5, CXCR4 used by HIV

Question 6

What do the host molecules a virus can use to can entry to a cell determine?

Answer 6

• host range e..g HIV humans, influenza lots
• tissue trophism
• pathology of disease

Question 7

What are accessory receptors?

Answer 7

• found on host cells v common
• used by some viruses (Herpes simplex)
• present at high diversity on cell surface
• binds with low affinity
• not required for entry but help

Question 8

What are properties of primary receptors?

Answer 8

• essential for viral entry into cell
• used for all viruses
• binds with high affinity
• same receptor used by all viruses

Question 9

What are the properties of co receptors for viral entry?

Answer 9

• on cell surface
• followed by binding of primary receptor
• essential for viral entry
• same receptor can be used by different virus’

Question 10

What is the poliovirus method of entry into host cell?

Answer 10

• capsid proteins bind to CDI55 (function in host unknown)
• species specific (only binds to primate CDI55)
• expressed on gut nasopharynx and CNS

Question 11

What is the HIV method of entry into host cell?

Answer 11

• binds initally to CD4 (primary receptor) on cell surface
• then binds to CXCR4 or CCR5 (chemokine receptors) as coreceptor
• highly species specific
• CCR5 found on macrophages,

Question 12

What is the mutation in CCR5 HIV coreceptor that leads to cells being resistant to HIV infection?

Answer 12

• insertion of stop codon in ORF

- 32bp deletion

Question 13

What does HIV do after inital infection?

Answer 13

• after infection HIV gp120 mutates to allow binding to CXCR4 (chemokine receptor SDF-1) in T lymphocytes
• HIV changes tropism from macrophages to CD4 and T lymphocytes, associated with rapid progression to severe disease

Question 14

What is the immune response to HIV?

Answer 14

Few weeks- virus is into macrophage population, macrophage is activated and released a range of cytokines and antibodies against HIV, acitvation of CTL
2-12 years - antibodies against HIV go down resulting in higher virus titre in plasma

Question 15

What are the different antibody functions in response to viruses?

Answer 15

espec. secretory IgA - blocks binding of virus to host cells preventing infection or reinfection
IgM, IgG, IgA - block fusion of viral envelope with host plasma membrane
IgG, IgM - enhances phagocytosis of viral particles (opsonization)
IgM - agglutinates viral particles
Complement activated by IgM - mediates opinisation by C3b and lysis of viral particles by membrane attack complex

Question 16

What are two ways by which cell mediated killing of viruses?

Answer 16

1) CTL releases toxic effector molecules in granule exocytosis, entry of granzymes through perforation holes, follwed by activation of caspases, apoptosis
2) Saf L to Fas binding on infected cell leads to apoptosis

Question 17

What are properties of Natural Killer cells?

Answer 17

• innate immune response
• killing by NK cells peak before CD8 cells
• only activated during infection

Question 18

What happens in natural killer cell interaction with a normal cell?

Answer 18

1) normal cell recognised by inhibitory receptors on NK cells as binds to MHCI, peptide and NK activating ligand
2) Inhibitory receptor inactivates the activating receptor on NK cell

Question 19

What happens in NK cell interaction with an abnormal cell?

Answer 19

1) Target cell, presenting abnormal MHCI peptide complex and NK cell activating ligand does not bind to MHCI molecule
2) positive activation towards NK cell leads to release of granzymes

Question 20

What is the process of immune response in a viral infection?

Answer 20

1) as virus titre increases, IFN-alpha, IFN-beta, TNF-alpha and IL-12 produced
2) then get a peak in action of NK cell mediated killing of infected cells
3) after 7 days followed by activation and response of T cell-mediated killing of infected cells, severly decreases virus titre

Question 21

What strategies do viruses use to evade the immune system?

Answer 21

1) inhibition of humoural immunity
2) inhibition of inflammatory response
3) blocking of antigen processing and presentation
4) Immunosupression of host

Question 22

How might viruses inhibit humoral immunity?

Answer 22

1) virally encoded Fc receptor blocks effector functions of antibodies bound to infected cells e.g. herpes simplex and cytomegalovirus
2) Virally encoded complement receptor blocks complement mediated effector pathways e.g. herpes simplex

Question 23

How might viruses inhibit the inflammatory response?

Answer 23

Viral inhibition of adhesion molecule expression e.g. LFA-3, ICAM-1, blocks adhesion of lymphocytes to infected cells e.g. Epstein barr virus

Question 24

How might viruses block antigen processing and presentation?

Answer 24

Inhibition of peptide transport by TAP

-blocks association with MHCI herpes simplex virus

Question 25

How might viruses immunosupress a host?

Answer 25

Virally encoded cytokine homolog of IL-10, inhibits Th1 lymphocytes, reduces interferon-y production e.g. Epstein Barr virus

Question 26

What specific viral evasions are involved in the viral blocking of antigen presentation?

Answer 26

Viral evasions US6 and ICP47 block antigen presenting by preventing peptide movement though TAP peptide transporter

Question 27

What are the 4 types of adhesin moecules?

Answer 27

1) Integrins
- B1 -mediated cell-cell and cell-ECM interactions, binds to fibronectin, collagen, lamanin in ECM
- B2 - binds complement e.g. CR3 to CD11b/CD18
2) Cadherins e.g. E-cadherin
3) Immunoglobulin superfamily e.g. ICAM
- mediate cell-cell interactions and attachment of moving lymphocytes
4) Selectins e.g. L-selectin, P-selectin, E-selectin
- mediate attachment of moving lymphcytes

Question 28

What is type III secretion system?

Answer 28

• induction of intimate adhesions
• Enteropathogenic E.coli, EPEC
• Initial contact mediated by pilli but cell contact initiates a specialised secretary apparatus (typeIII secretion)
• Induced pedestal type adherance
• in GUT

Question 29

What are strategies for invasion and invasins?

Answer 29

1) Endo cytosis
2) Lipid rafts
3) Phagocytosis

Question 30

What are properties of invasion by endocytosis?

Answer 30

• receptor mediated

- independent of actin rearrangement in host cells

Question 31

What are properties of invasion by Lipid rafts?

Answer 31

1) bacteria that express FilmB adhesin (e.coli) can enter via lipid rafts = rich in cholesterol and GPO linked proteins
2) Caveolae = lipid rafts that form a pit, rich in adhesion molecules e.g. CD48 = GPI-linked receptor for FilmB

Question 32

What are the properties of invasion by phagocytosis?

Answer 32

-via professional phagocytes (macrophages and neutrophils)
-requires substantial membrane rearrangement
-can operate via opsonins:
Type I: via receptors for antibody Fy chain
Type II: via CR3 (complement receptor), C3bi component binds to bacteria and then CR3 on phagocyte

Question 33

What occurs in the process of invasion by phagocytosis using Type II opsonins?

Answer 33

1) Bacteria bound to antibody
2) complement activation occurs, C3bi attaches to cell surface
3) C3b binds to CR3 on cell surface antibody binds to Fc receptor
4) bacterium, receptor and attached molecules are phagocytised into vesicle, leads to phagosome formation and recruitment of lysosomes
5) phagosome lysosome fusion -> phagolysosome

Question 34

What strategies can a bacteria use to avoid killing and phagocytosis?

Answer 34

1) Avoid contact
- remaining inaccessible
- inhibit phagocyte chemokines
- coat with host like material
2) Inhibit phagocytic engulfment
- make surface resistance to phagocytosis
- inhibit opsonisation by secretion of protein A (bocks IgG binding)
- M protein prevents binding of complement
3) escape from phagosome
4) Interfere/avoid immune defenses
- hit and run, excretion
- induce wrong antibody
- destroy antibody
- Fc receptors on microbe
- Antigenic variation
- antibodies mopped up by mucus