Immunology 5: Immune evasion

Question 1

Why are pathogens able to evade the immune system

Answer 1

The host environment is predictable

Question 2

Strategy overview

Answer 2

Speed: in and out before adaptive immunity is effective.

Inhibition: producing molecules that interfere with immune pathways

Avoid detection (innate or adaptive)

Change rapidly: keeping one step ahead of the response

Smoke-screen effects
-> Induce huge responses against non-protective antigens

Stimulate the “wrong type” of response.

Question 3

Speed

Answer 3

In, replicate + out before adaptive immunity is effective (quick hit)

• Eg. Influenza, Salmonella -> mucosal surface infections where rapid transmission is favoured

Question 4

Inhibition with immune pathways

Answer 4

Viruses:
- Decoy receptors that bind/ block cytokine activity (e.g. Poxviruses contain a viral IL18 binding protein)
- Inhibitors of antigen presentation pathways (e.g. Down reg MHC transcription, Inhibit proteases that chop up virus)
- > BUT NK detect reduction in MHC so some viruses use CMV to mimic
- Inhibors of apoptosis
- interferance with signalling pathway (e.g. degrade adaptor proteins in TLR signalling)

Example: HIV
- targets CD4+ T cells first which are cells which would recognise and control it
- Downregulates MHC-1 complex
- frequenct antigenic drift due to low fidelity reverse transcriptase
- Hides within cells
- CD4 reduction leads to CD8 reduction
- Eventually leads to AIDs

Bacteria and parasites:
- proteases digest antibodies stuck to surface
- complement components degraded by proteases (e.g Pseudomonas aeruginosa- Produces elastase that inactivates C3b and C5a )
- coagulation cascades disrupted – proteases break up clots so pathogen can move
- antibody binding molecules eg. protein A
- slippery capsule of bacteria to prevent phagocytosis
- Escape from phagosome into cytoplasm (e.g. listeria monocytogenes -> hijack host cytoskeleton to drive bacteria forward in projection to adjacent cell)
- Block phagosome-lysosome fusion (e.g. M.tuberculosis which also avoids acidic phagosome environment)

Question 5

Avoid detection

Answer 5

hide somewhere w/ low response or disguise yourself

Induce tolerance by deleting cells
- > e.g. being present in the thymus during T cell developement (gap in T cell repetoir)
- > e.g. using super antigen to delete family of T cells (Murine Mammary Tumour Virus)

Replicate away from immune activity
-> In brain eg. Toxoplasma gondii
-> In outer keratinised skin eg. Papilloma virus
-> Intracellular – away from antibodies
-> In red blood cells w/ no MHC pathways eg. Plasmodium

Coat surface w/ host or mimic host proteins
- > e.g. lipooligosaccharide of Campylobacter jejuni mimics the human GM1 ganglioside

Obscure coat
- > e.g. carbohydrate capsules to mask antigens (pneumococcus)
-> But key molecules like flagella cannot be covered

Latency
- > Herpes virus spreads to sensory neurone to persist inlatent state (low MHC levels)

Question 6

Change in the face of immune attack

Answer 6

Change antigens to escape antibodies and T cells

1) Multiple serotypes circulating at once so harder for host to adapt

Example: 84 known serotypes of Streptococcus pneumoniae)

2) host dynamically change during infection

Chance:
-> Antigenic drift (mutation)
-> antigenic shift (reassortment of segments)

Example: Influenza

Programmed:
- programmed rearrangements of the pathogen DNA

Example: African Trypanosomes
- 1000 Variable Surface Glycoproteins VSGs
- sequentially expressed via rearrangement into expression sites

Question 7

Smoke screen effect

Answer 7

Induce strong response against non-protective epitopes / antigens so the immune system is less effective against actual antigen

Can involve super antigens to proliferate the non-effective response
- Super antigens cross link the MHC with the TCR creating huge proliferation of T cells, limiting the amount of response possible against the pathogen.

Example: Toxic shock syndrome
- releases toxin-1 which acts as a superantigen leading to T cell proliferation and death

Question 8

Stimulate wrong response

Answer 8

Pathogens can stimualte the wrong response (e.g produce mimicing chemokines, cytokines)

Example: Trichuris nematode
- make IFNγ mimics that drive Th1 response which is ineffective against them and inhbits the Th2 response required

Question 9

Cross host effects

Answer 9

Immune evasion can be harder when the pathogen has many hosts with different immune systems

Example: SARS coronavirus hypothesis
- coronaviruses evolved to interfere w/ type I IFN responses
- Some bats:
o High basal IFN responses
o Low inflammation from PPRR activation
o Less intense adaptive responses
- Human have:
o Lower basal IFN system
o Higher inflammation
- Virus easily combats early IFN response as it is low compared to bats, and can lead to uncrolled inflamation -> get severe immunopathology