Pathogens (Jeremy Lecture 3) Flashcards
Describe the characteristics of the innate immune response to a virus
1) Does not require previous viral exposure
2) Activated and responds in minutes to hours following infection
3) Involves pattern-recognition receptors and other innate signalling pathways
What components produce the antiviral state and how does this occur?
- Interferons
- Produced by innate immune activation
- Secreted interferons (INF) bind to INF receptors on uninfected cells
- Binding causes synthesis from over 1000 genes (ISG: INF stimulated genes)
- Interferons induce the cellular antiviral state
How do viruses inhibit interferon activation and function?
1) Prevention of signalling pathway activation (blocking interferon activation)
- dsRNA binding proteins, such as influenza virus NS1
2) Inhibition of signalling pathway
- PKR inhibitors
- STAT inhibitors
What are the main products of the innate immune system that cause inflammation?
Cytokines
- TNF-alpha in main early stage cytokine causing inflammation
What do cytokines cause?
- Increased blood flow (vasodilation)
- Increased blood vessel permeability (endothelial cell tight junctions)
- Influx of immune cells from blood to tissue
What are the main disease symptoms caused by inflammation?
- Redness
- Pain
- Heat
- Swelling
Why do viruses inhibit the inflammatory response?
Inflammation inhibits viral replication and infection
What is the name for viruses that do not cause an inflammatory response?
Non-cytopathic viruses
- Harder to cure
Describe the characteristics of the adaptive immune response in relation to viral infection?
- Activated days after initial infection
- Activated by innate immune system
- Cell mediated and humoral immunity
- Memory response
What are the effectors of cell mediated immunity and what does each do?
IFN-gamma secreted by Th and CTLs induces antiviral state
Cytotoxic T cells destroy virus infected cells
NK cells and macrophages destroy virus infected cells too
What are the effectors of humoral immunity and what does each do?
Primary secondary IgA - inhibits virion attachment
Primary IgG - inhibits fusion of enveloped viruses to PM
IgG and IgM antibodies - Opsonisation and complement activation
What is immunopathology?
Immune response to a disease
Name some viruses associated with CD8+, CD4+ and B-cell mediated immunopathology
CD8+:
- HIV-1
- Hepititis B
CD4+:
Measles
Herpes simplex
B-cell mediated:
Dengue virus
Name the different responses in viral-induced immunopathology
- Innate immunity killing
- Inflammation
- CD4+ cell mediated
- CD8+ cell mediated
- B cell mediated
- Molecular mimicry/autoimmunity
- Immunosuppression
How and what free radicals are produced during the inflammatory response?
- Nitric oxide (NO) is produced by nitric oxide synthase, a IFN-inducible enzyme
- Superoxide (O2-) is also produced
- Low NO is protective, high NO causes tissue damage
What is autoimmunity?
Host immune response directed against its own tissue
By what 2 main mechanisms can viruses cause autoimmunity?
1) Directly trigger autoimmunity
- cytolysis can lead to release of cellular antigens and then autoimmunity
2) Molecular mimicry
Viruses can mimic components of the hosts immune system
How can viruses cause molecular mimicry?
- Some viral and host proteins share sequence homology and may have similar antigenic regions
Name some epitopes that are shared between specific viruses and the host
Poliovirus VP2
Acetylcholine receptor
HIV p24
IgG contant regions
Papilloma virus E2
Insulin receptor
Name some ways in which viruses change the immune system to benefit themselves
- Evasion (latency, antigenic variation, blocking innate recognition
- Inhibition of innate pathways
- Inhibition of complement
- Immune cell killing
- Modulation of apoptosis/autophagy
- Blockage of apadtive immunity
What does interferon signal to the nucleus and what does it cause?
- IFN-alpha binds to the IFN alpha/beta receptor (IFNAR) and causes intracellular JAK/STAT signalling
- Requires the dimerisation of STAT1 with STAT2
- IFN-gamma binds to IFNGR
- Causes JAK/STAT signalling via STAT1 dimerisation with STAT1
- STAT signalling activates ISGs (INF stimulated genes): over 1000 genes
- Induces an anti viral state
How does influenza virus inhibit INF JAK/STAT signalling?
Influenza protein NS1 blocks STAT phosphorylation and activation thus preventing STAT signallinh
How can Influenza induce INF activation?
- Temporary intermediate dsRNA activates Protein Kinase R (PKR)
- PKR activates INF
What does influenza do to prevents PKR mediated INF activation?
NS1 protein binds dsRNA and prevents it from activating PKR
How does Ebola induce large scale inflammation that leads to serious disease?
- Ebola virus infects macrophages, resulting in large scale production of cytokines (cytokine storm) that increase vascular leakage
- Production of some cytokines i.e IL-10 associated with fatal disease
- Cytokines also signal for the recruitment of other inflammatory cells
What is Apobec? What does it do?
- An anti-viral RNA editing protein
- It is produced from an INF stimulated gene
- Deaminated C to U in the RNA genome of viruses - kills the virus
- Blocks HIV replication
How does HIV evade killing via Apobec?
Encodes Vif which binds to Apobec and targets it to the proteasome
In what 2 ways does HIV use Nef to evade the adaptive immune system?
1) Nef binds to MHC class I in the trans-Golgi network
- Traffics MHC to the lysosome instead of the PM
- MHC degraded by lysosomal enzymes
- Cell not recognized as infected
2) Nef binds CD4 on the plasma membrane
- Also traffics CD4 to the lysosome
Name another 2 ways that HIV can evade the immune system
1) Changing its antigens
- HIV RNA genome replicates and induces copying errors
- Changes in antigenic regions on the cell surface - harder to retain memory to HIV infection
2) Dormant CD4+ T cells
- Some CD4+ cells become memory CD4+ cells and are therefore dormant
- Not expressing antigens and not replicating
- HIV can become latent in these cells and survive
