Lecture 10 - Viral Immunity II Flashcards
What are the key principles of viral evasion of the immune system?
- Avoid recognition
2. Interfere with the function of the immune system
In particular, which class of viruses have acquired strategies for immune evasion?
Large complex DNA viruses
e.g.
• Herpesviruses
• Poxviruses
List the various mechanisms of immune evasion by viruses
- Antigen variation
- Blocking / interfering with Ag presentation
- Blocking / interfering with host cell function
- Viral mimicry
- Infecting immune cells
- Persistence
• Latency
• Chronic infection
Describe the structure of the influenza virion
Envelope:
• HA
• NA
• M1 (membrane protein)
8 strands of RNA
NS-1: Non-structural protein
Polymerase complex: • PB1 • PB2 • PA • NP
Describe how viruses employ antigenic variation to avoid the immune system
- Influenza antigenic shift
• Recombination of RNA strands of different strains of influenza within a ‘mixing vessel’ (e.g. pig)
• Generates a strain of influenza that is different enough not to be recognised by the immune system - Antigenic drift
• Slow changes in antigenic sequences
• Due to error-prone viral RNA polymerase (no proof reading mechanism)
• Can result in antigenic sites that are no longer recognised by Abs in population - Glycosylation
• Addition of carbohydrate groups to antigenic molecules means that Abs do not have access to epitopes
Describe how viruses interfere with antigen processing and presentation to avoid the immune system
- Inhibition of proteasome
• EBV
• CMV - Inhibition of TAP
• HSV - Removal of MHC I from ER
• CMV - Inhibition of MHC I synthesis
• Adenovnirus
• hCMV - Trapping of MHC I in ER
• Adenovirus
• hCMV - ‘Decoy’ MHC I-like molecules
• Expressed on surface of host cells
• ‘Distracts’ T cells
• mCMV
Describe how viruses interfere with host cell functions to avoid the immune system
(Use an illustrative example)
e.g. Influenza NS-1
NS-1 functions:
1. Inhibition of type I IFN production (through inhibition of RIG-I), thus interference with induction of anti-viral state
- Blocks processing of anti-viral mRNAs
- Enhances viral protein production
• Inhibition of PKR; activation of eIFα2
• Inhibition of RNAse L - Limits apoptosis of host cells
Describe normal PKR function
- Type I IFN activates PKR, which becomes phosphorylated
- Activated PKR phosphorylates eIFα2 to render it inactive
- eIFα2 can no longer promote translation (of both cellular and viral proteins)
Describe normal 2,5-oligo A synthetase activity
- Type I IFN activates 2,5-OAS
- 2,5-OAS activates RNAse L
- RNAse L chops up viral RNA
Describe normal RIG-I function in viral immunity
- Viral RNA ligates with RIG-I in cytosol
- RIG-I associates with IPS-1 on mitochondria
- Activation of NFKB and IRF signalling
- Transcription of type I IFN
What is the function of active eIFα2?
Promotes translation of proteins
Describe how NS-1 interferes with the following:
• RIG-I
• PKR
• 2,5-OAS
RIG-I:
• Inhibits activation
• Inhibits production of type I IFN
PKR:
• Inhibits activation
• eIFα2 does not become inactivated
• No blocking of protein synthesis
2,5-OAS:
• Inhibits activation
• RNAse L does not become activated
Describe how poxviruses deal with type I IFN
Poxviruses produce soluble and membrane bound molecules that ‘mop up’ type I IFN
Describe how viral mimicry can avert the immune system
Give specific examples
Viruses can generate molecules that mimic host cytokines
This confuses the host immune system, resulting in dampening down of the effector function
Cytokines:
• IL-10
• EBV
Chemokines:
• CXC1 (like IL-8)
• Recruits neutrophils
• hCMV
Cytokine receptors:
• TNF
• Herpesvirus and Poxvirus
Soluble cytokine receptors • Mop up pro-inflammatory cytokines • TNF receptors • IL-1 receptor • IL-18 binding protein
Chemokine receptors
• US28
• hCMV
Give examples of viruses infecting cells of the immune system
How does this give the virus an advantage?
Infection of immune cells interferes with their function
CD4+ T cells
• HIV
• Results in death of CD4+ T cells
B cells:
• EBV
• Results in latent infection
DCs: • Poxviruses • Herpesviruses • Measles virus • Alters their function
Lymphoid stromal cells
• Ebola
• LCMV
• Death / altered function of lymphoid tissues
What determines the outcome of viral infection?
Balance between inflammatory and immunosuppressive signals
Preponderance of inflammation:
• Results in excessive damage of host tissues
Preponderance of immunosuppression
• Virus not properly cleared
To adequately clear the infection whilst not causing excessive tissue damage required a delicate balance between inflammation and immunosuppressive signals
Describe latent infections with an illustrative example
e. g. HSV
1. HSV virions get into sensory nerves in the area of skin where they caused infection
2. Move up sensory nerve into cell body in dorsal root ganglion
- Persist in the cell body even after the local infection in the skin is cleared
• Little gene expression
• No production of virions - Can remain latent for very long period of time and cause infection again in the skin when the individual becomes immune suppressed:
• Stress
• UV etc.
Describe the role of the host immune system in HSV latency
Host immune response is vital in maintaining a latent infection
CD8+ T cells remain in the latently infected trigeminal ganglia
‘Monitor’ for reactivating virus
Produce IFN-gamma, perforin and granzymes which do not kill the neurons
Describe immune exhaustion
When does it occur?
Describe specific features in T cells
Occurs with chronic infection; viral Ag persists
Mechanisms: • Expression of inhibitory receptors • Immunoregulatory cytokines • Altered APCs • Tregs
Changes to T cells over time: • Decreased cytokine production • Decreased proliferative potential • General loss of effector function • Increased apoptosis
What is the correlation between antigen load and immune exhaustion?
Viruses that persist at high levels induce more pronounced defects
• e.g. HIV, HCV, LCMV
• T cells are more exposed to Ag, for longer periods
Viruses that persist at low levels do not cause such profound exhaustion:
• EBV, CMV
APCs can contribute to this
Describe how the various components of the adaptive immune system can cause immunopathology
CTLs:
• Killing of host cells (perforin dep.)
• Cytokines
CD4+ T cells:
• Cytokines
Antibody:
• Glomerulonephritis
• Haemorrhagic fever
Describe the role of immunopathology in the 1918 H1N1 pandemic
Immunopathology is through to be responsible for much of the mortality
W curve: • Preponderance of deaths in: - V. young - Healthy young adults - Elderly
The healthy young adults had very robust immune responses to the infection
So robust, that it was very detrimental to the host:
• Pulmonary oedema
• Alveolar haemorrhage
• Inflammatory infiltrate in airways
It is thought that the robust immune response generated a cytokine storm in the infected people
Describe the correlation of PAMP load with outcome of influenza infection
- Low PAMP load
• Limited neutrophil activation
• Sublethal infection
2. High PAMP load • Extensive neutrophil activation • Chemokine feedforward loop • Increased inflammation • Vascular and pulmonary damage
Implication:
• More neutrophil activation, more damage
Describe the immunopathology induced by Ebola virus
- Dysregulated inflammation
* Poor immune responses
Describe the immunopathology associated with HSV infection
Herpetic stromal keratitis
- CD4+ T cells release cytokines
• IL-1, IL-6, IL-12, IL-17 - Inflammatory cells are recruited to the cornea
• Monocytes & PMNs - Neovascularisation of the cornea
Describe the immunopathology associated with Theiler’s virus
- Theiler’s encephalomyelitis virus persists in neurons
- CD4/8+ T cells respond to latent infection and release cytokines
- Cytokines damage oligodendrocytes
- Demyelination of nerves
Which cells are primarily responsible for the immunopathology in the following:
• Herpetic stromal keratitis
• Demyelinating syndrome
Herpetic stromal keratitis
• CD4+ T cells
Demyelinating syndrome
• CD4+ T cells
• CD8+ T cells
How does EBV interfere with Ag presentation?
Produces a molecule which inhibits the proteasome
How does HSV interfere with Ag presentation?
Produces a molecule which blocks TAP
How does CMV interfere with Ag presentation?
Produces a molecule which removes MHC I from the ER
How does murine CMV interfere with Ag presentation?
Produces molecules which act as decoy MHC I-like molecules which interfere with TCR recognition
How do adenoviruses interfere with Ag presentation?
Block MHC I synthesis / stop it from leaving the ER
How does human CMV interfere with Ag presentation?
Block MHC I synthesis / stop it from leaving the ER
Inhibits the proteasome
