Immunity to Viruses and Non-Viral Pathogens

Question 1

What are barrier to infection and innate response

Answer 1

• Chemical and physical barriers must be breached
• Epithelial linings of skin and gut (non-specific physical barrier)
• Secretions (contain antivirals, acidic pH, enzymes, fatty acids) are often toxic to pathogens
• Presence of normal microbiota make an inhospitable environment

Question 2

What are properties of viruses

Answer 2

• Contain DNA or RNA
• Contain a protein coat / envelope / spikes
• Infect specific types of cells in a host
• Multiply inside living cells through hijacking synthesising machinery
• Direct synthesis of viral proteins to enable replication and transmission
• Enter through surface receptors and undergo replication
• More likely to thrive if they don’t kill host

Question 3

How does the immune system respond to viruses

Answer 3

• Innate: Negotiate physical barriers, ciliated ECs, mucous / basement membranes
• Adaptive: CD4 / CD8 and B cells (effector / memory)

Question 4

What are interferons

Answer 4

• Protein released in response to the presence of viruses
• Occurs within first few hours of infection by plasmacytoid DCs
• Type 1 (IFNα, IFNβ), type II (IFNγ), type III(IFNλ1, IFNλ2, IFNλ3 = IL-29, IL-28a and IL-28b respectively)

Question 5

How are IFN-1 activated

Answer 5

1. Cytoplasmic PRRs (RIG-I) detect viral ssRNA / dsRNA
2. Stimulation of IRF3 and NF-kβ activation
3. Transcription of IFNα and IFNβ and cytokine genes
4. Plasmacytoid DCs detect virus and up-regulate type I IFN production (not infected)
5. Plasmacytoid DCs take up virions and viral nucleic acids detected by TLR7 (viral ssDNA) and TLR9 (DNA containing CpG motifs) in endosomal compartments
6. Stimulation of IFR7 and NF-kβ activation
7. Transcription of IFNα and IFNβ and cytokine genes

Question 6

What is the role of IFN-1

Answer 6

• Interfere with viral replication
• Signal preparation of uninfected cells to resist viral infection
• Activate macrophages and NK cells to enhance antiviral activity
• Promote adaptive responses (MHC presentation)

Question 7

What are the innate mechanisms of viral immunity

Answer 7

• IFNs: Up-regulate ISGs (innate), JAK-STAT signal transduction (increased transcription of immune relevant genes)
• 2’5’ Oligoadenylate Synthetase: Activates RNaseL (targets degradation of viral RNA)
• PKR: dsRNA dependent protein kinaseR, blocks translation of viral mRNA, initiates apoptosis via Bcl-2
• Mx Proteins: GTPases that interfere with viral replication
• NO / NOS2: Potent activators of antiviral pathways
• APOBEC: Editing enzyme that inhibits infection with retroviruses, catalytic polypeptide like

Question 8

What is the role of NK cells in viral immunity

Answer 8

• Kill virally infected cells
• Maintain / increase tissue inflammation (secrete cytokines)
• Activation state regulated by activating / inhibiting receptors

Question 9

What are the effector responses to viral infection

Answer 9

• Adaptive immune response begins a few days after innate
• T cells appear at site of infection (4 days)
• CD8 are critical for resolution of viral infection
• Abs detected 6-7 days post infection, establish immunological memory
• Abs provide barrier to spread of viral infection

Question 10

What are the humoral responses to viral infection

Answer 10

• Free Virus: Antibodies block binding, entry and uncoating of virus, complement damages virus envelope / blockade of virus receptor)
• Virus Infected Cells: Complement opsonisation of virus / infected cells are phagocytosed, Ab bound attracts NK, macrophages and neutrophils

Question 11

What is the role of Th cells in viral immunity

Answer 11

• Secrete cytokines that promote antiviral activity
• IFN-y induces antiviral state in adjacent cells
• Induce hypersensitivity response (accelerated clearance)
• Activate and recruit macrophages and neutrophils to site of infection
• Induce CD8 and memory responses through IL-2

Question 12

Whats the role of cytotoxic T cells in viral immunity

Answer 12

• Actively find and destroy virally infected cells
• Prevent production of virus particles
• Kill infected cells through the release of perforin, granzymes, and other cytolytic proteins
• Trigger death through binding of TNFa or FasL ligands (signal apoptosis)
• IFNy / TNFa ‘cure’ infection through eradication of virus

Question 13

What are viral evasion strategies

Answer 13

• Impair host immune response
• Avoid recognition and resist control by effector mechanisms
• Reduce circulating pDCs / infect pDCs and impair their function
• Disrupt chemokine network (affect leukocyte migration)

Question 14

How does HIV evade the immune system

Answer 14

• Latency program
• Mutates genome rapidly avoiding presentation on MHC
• Counteracts / inhibits immune response (protein coat)
• HIV vif (counteracts APOBECS)
• HIV nef (inhibits lysis of infected cells)

Question 15

What are PRRs

Answer 15

• Pattern recognition receptors
• Activated when pathogens override epithelial barriers
• Bind PAMPs expressed on pathogens
• Bind DAMPs released by damaged cells
• Located on plasma membrane / within cytosol
• TLR, MLR, SLR
• Recognise viral RNA / DNA / proteins

Question 16

How do bacteria evade the immune system

Answer 16

• Attach host cell (proteases prevent IgA binding)
• Proliferation (surface structures) induction of apoptosis in macrophages
• Invade (secrete elastase that inactivates C3a / C5a)
• Toxin induced damage (secretion of hyaluronidase which enhances bacterial invasiveness)

Question 17

What does pathogenicity of bacteria refer to

Answer 17

• Toxicity without invasiveness
• Invasiveness without toxicity
• Combined

Question 18

What is the innate response to +ve / -ve bacteria

Answer 18

• +ve: Lipopolysaccharides activate innate, bind LPS binding protein, signal pro-inflammatory cytokine cascade
• -ve: Peptidoglycan / lipoteichoic acids recognised by TLR2
• Mycobacteria / spirochete: Lipid bilayer susceptible to lytic complex, C3a / C5a attract neutrophils, causing opsonisation / phagocytosis

Question 19

What is the humoral response to bacteria

Answer 19

• Antibody dependent anti-bacterial defences
• Antibody-Dependent cell cytotoxicity
• Opsonisation, activation of complement
• Interfere with motility of bacterial flagellin
• IgA interferes with binding of bacteria to epithelial cells

Question 20

What is malaria (parasitic infection)

Answer 20

• Protist disease caused by Plasmodium spp.
• Life cycle moves through liver / RBCs, maturational changes allow Ag shifting, intracellular phases resist Ab-based responses
• Ab responses avoided by outer coat shedding

Question 21

What is leishmaniasis (parasitic infection)

Answer 21

• Vector borne disease
• Transmitted by sandflies
• Lives in macrophage phagosomes and produces localised cutaneous self-resolving lesions and systemic visceral leishmaniasis (spleen / liver)
• Body defends via complement system, neutrophil activation, NK cells and Th1 cells

Question 22

What are helminths (parasitic infection)

Answer 22

• Parasitic worms, enter hosts via intestinal tract, exclusively extracellular
• Don’t replicate in hosts (limit immune engagement)
• Immunity may proceed via induction of IgE production and recruitment of eosinophils
• Induction of TH1 IFN-γ macrophage activation is more effective

Question 23

What are fungal infections

Answer 23

• Based on site of infection, route of acquisition and virulence
• PRRs respond and secrete antimicrobial peptides
• Induction of phagocytosis destroys fungal cells
• Capsules can prevent PRR binding and fungi-induced expulsion from macrophages