Lecture 9 - Viral Immunity I Flashcards
Describe the first line of defence against viral pathogens
1. Physical barriers: • Keritanised epithelial cells • Tight junctions • Mucociliary escalator • Longitudinal flow of air and fluid • Tears
2. Chemical barriers: • Low pH on skin and stomach • Fatty acids on skin • Mucous • Lysozyme in tears • Pepsin in stomach
- Soluble proteins
• Defensins
• Collectins
• C’ - Cells
• Alveolar macrophages
• PMNs - Microbiological
• Normal flora occupying the niche
List the various routes of entry to viral pathogens, and list a few that exploit each route
Respiratory tract: • Influenza • Rubella • Mumps • Measles • Adenoviruses • RSV • Rhinoviruses
Conjunctiva:
• Adenoviruses
• HSV
UGT: • HIV • HBV • HSV • CMV • HPV
GIT: • Rotavirus • Norovirus • HAV • Caliciviruses • Adenoviruses
Skin:
• HSV
• HPV
• West nile virus
Describe the action of defensins
Two subtypes:
1. α-defensins
• Present in neutrophils
- β-defensins
• Present on epithelia
Amphipathic molecules
Insert into cell membranes, creating a pore
Result in lysis of cell
NB only good for enveloped viruses (HIV)
Describe the action of collectins
Give examples of collectins
Structure:
• Protein
• Carbohydrate binding group
Examples:
• Mannan-binding lectin
• Surfactant protein A
• Surfactant protein D
Function:
1. Aggregation of particles
• A type of opsonisation
- Neutralisation
What type of molecule are collectins?
Soluble PRRs
Belong to C-type lectin superfamily
Describe the action of C’
C’ components present in the serum
C’ binds to surface of pathogens and becomes activated
Effector function:
• Inflammation (C3a, C5a)
• MAC formation (C56789)
• Opsonisation (C3b)
Describe how the various subsets of macrophages protect against viral infections
Alveolar macrophages:
• Capture viruses in respiratory tract
Subcapsular sinus macrophages & Marginal zone macrophages
• Present in LNs
• Prevent further spread of viruses
Release IFN and cytokines that limit viral replication and prime immune response
What was observed in mice lacking sub-capsular sinus macrophages?
Viruses were able to spread from LNs to nerves
VSV (vesicular stomatitis virus) spreads to nerves and causes paralysis
Describe, in general, the role of innate immunity in viral infection
Type I IFN
NK cells
Stem the spread of viruses in the first few days while the adaptive immune response is being primed
Stems the spread, but cannot fully remove the infection
Describe the sensing of viruses
What does this trigger?
- PRR-PAMP ligation
PRRs:
1. NLRs
• Cytosolic
• Detect viral DNA/RNA
- RLR
• Cytosolic
• Detect viral DNA/RNA - TLRs
• Membrane associated
• Detect viral DNA/RNA - Signal transduction
• NFKB
• IRF - Transcription of type I IFN and pro-inflammatory cytokines
- Induction of the anti-viral state; inflammation
Which pro-inflammatory cytokines are produced in response to PRR-PAMP ligation?
IL-1 IL-6 IL-12 IL-18 TNFa
Describe the effects of type I IFN
‘Anti-viral state’
IFN binds receptors on the surface of all cells
S-T pathway through JAK/STAT
- Inhibition of viral protein synthesis
• Activation of PKR
• Inhibition of eIF2a (through phosphorylation) - Increased Ag presentation on MHC I
• Immunoproteasome - Degradation of viral RNA
• Activation of 2,5-Oligo A synthetase
• Activation of RNAseL - Inhibition of virion assembly
Describe the role of NK cells in viral infections
- Key mediators of viral immunity -
Inhibitory receptors:
• KIR
Activation receptors:
• NKG2D
• Ly49
• CD16
- Virus infected cells down regulate MHC I and express viral glycoproteins
- NK cells interrogate cells; do not receive inhibitory signals through KIR and receive activation signals (viral glycoproteins) through NKG2D
- NK cells become activated and kill infected cells (perforin dep.)
Which cytokine do NK cells predominantly produce?
IFN-gamma
Describe adaptive immunity to virus infections
T cells:
• CTLs recognise virus infected cells specifically and kill them (perforin dep.)
• ‘Helper’ T cells help CTLs and B cells
B cells:
• Generate Ab against virus
• Neutralisation of virus particles
• Agglutination of virus → phagocytosis
Describe how lymphocytes become activated in viral infections
Requires DCs
DCs must present viral Ag to lymphocytes in lymphoid tissues:
• Direct infection of DCs
• Cross-presentation
- DC activation in tissues
- Upregulation of CCR7 and down regulation of adhesion molecules
- Migration through lymphatics to lymphoid organs
- Entry into paracortex of LNs through afferent lymph
- Interaction with T cells; immunological synapse
Describe the immunological synapse
Interaction between DCs and T cells
Adhesion:
• LFA-1 and ICAM-1
Signal 1:
• MHC:Ag and TCR
• MHC II and CD4 T cells
• MHC I and CD8 T cells
Signal 2: Costimulation
• CD80/86 on DC
• CD28 on T cell
Signal 3:
• Cytokines released by DCs
• IL-2
Describe CD4 T cell help for B cells
Activated CD4 T cells express CD40L
Th cells stimulate B cells through CD40L-CD40 interaction
B cells now undergo the maturation events (SHM, CSR) to be able to generate an effective immune response
How do CTLs kill virus infected cells?
- Perforin & granzymes
- Cytokines
• IFN-gamma
• TNFa
The cytokines may result in purging cells of virus w/o killing it. This may be especially important in infection of neurons
Describe how Ab can play a role in viral immunity
- Neutralisation
- Opsonisation
- C’ activation
- ADCC
Compare Ab presence in serum and secretions
Serum: IgG
Secretions: IgA
Which cells have FcRs?
Macrophages
NK cells
PMNs
How is an individual protected against future infections of the same virus?
- Stable Ab titres in serum and secretions
- Pool of memory T cells:
• T(CM)
• T(EM)
• T(RM)
Compare the following features of the various subsets of memory T cells: • Location • Recirculation • Effector function • Proliferation
Location:
• T(CM): blood and 2° lymph. organs
• T(EM): blood and extra lymphoid tissues
• T(RM): skin and mucosae
Recirculation:
• T(CM): high
• T(EM): high
• T(RM): low
Effector function:
• T(CM): low
• T(EM): high
• T(RM): high
Proliferation:
• T(CM): high
• T(EM): low
• T(RM): low
What is the role of T(RM) cells?
Remain localised in the skin and mucosa
Capable of rapidly responding to invaders
May have an important role in localised infections
Which PRRs recognise viral Ags?
TLRs:
• 2, 3, 4, 7, 8, and 9
RLRs:
• RIG-I
• MDA-5
• LGP2
NLRs:
• NLRP3 inflammasomes
• AIM2
Which components of virus do the following detect: • TLR2 • TLR3 • TLR4 • TLR7 • TLR8 • TLR9?
TLR2: unknown ligand
TLR3: dsRNA
TLR4: glycoprotein F of RSV
TLR7 & 8: ssRNA
TLR9: CpG DNA
Which components of viruses do the following detect:
• RIG-I
• MDA-5
• LPG2?
RIG-I:
• Short dsRNA
• ssRNA
MDA-5: longer dsRNA
LPG2: facilitates MDA-5 and RIG-I
Which components of the following detect:
• NLRP3 inflammasomes
• AIM2?
NLRP3: large number of stimuli
AIM2: cytosolic dsRNA
