lecture 13 immunology and disease: parasite antigenic diversity
TRANSCRIPT
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Lecture 13
Immunology and disease: parasite antigenic diversity
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Today:Today:
• Benefits and mechanisms of antigenic variation
• Antigenic variation that allows pathogens to persist in the individual host they’ve infected
• Antigenic variation that allows pathogens to infect hosts with prior exposure
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Benefits of antigenic variationBenefits of antigenic variation
1. Persist in infected host
Let’s look at some experimental results…
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Experimental evolutionExperimental evolution• Manipulates the environment of a population and
then looks at the resulting patterns of evolutionary change
• Allows for the direct study of the selective forces that shape antigenic diversity
• We’ll focus on CTL escape, which gets us down to the level of single amino acids changes that can mean life or death for both hosts and parasites
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Figure 1-27•The two main classes of MHC molecules present antigen from cytosol (MHC class I) and vesicles (MHC class II)
ReviewReview
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Figure 3-23MHC class I molecule presenting an MHC class I molecule presenting an
epitopeepitope
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Figure 1-30
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CTL escapeCTL escape• CTL pressure favors “escape mutants”, pathogens
with amino acid substitutions in their epitopes that make them escape recognition. Substitutions can lead to escape in three ways.
• They can interfere with processing and transport of peptides.
• They can reduce binding to MHC molecules.
• And they can reduce the affinity of TCR receptor binding.
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CTL escape: interfering CTL escape: interfering with processing/transportwith processing/transport
• A study of murine leukemia virus showed that a single amino acid substitution in a viral peptide can alter the cleavage pattern, and hence epitope presentation, and hence CTL response
• MuLV is an oncogenic retrovirus
• There are two main types (MCF and FMR)
• Both types are controlled in large part by CTL responses, but with different immunodominant epitopes
• The immunodominant CTL epitope for MCF is KSPWFTTL
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CTL escape: interfering CTL escape: interfering with processing/transportwith processing/transport
fmrmcf
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CTL escape: interfering CTL escape: interfering with processing/transportwith processing/transport
• Proteasomes are hollow multiprotein complexes. They are like meat-grinders for pathogen proteins found in the cytosol
• Cellular proteasomes continuously chop up proteins into smaller peptides, for presentation by MHC
• Proteasomal cleavage patterns determine which bits of pathogen peptides get to the cell surface
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CTL escape: interfering CTL escape: interfering with processing/transportwith processing/transport
• Changing KSPWFTTL to RSPWFTTL introduces a new cleavage site (the proteasome likes to chop after R)
• Viruses with RSPWFTTL are cleaved right within what would otherwise be a great epitope, leading to a huge reduction in the abundance of the R-containing epitope available for MHC presentation
• Inspection of the nucleotides reveals that this escape is mediated by a single point mutation!
• End result: that epitope is unavailable to MHC and the CTL response to FMR type is weak
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CTL escape: reducing CTL escape: reducing MHC bindingMHC binding
• Several studies report mutations that reduce peptide-MHC binding
• This can either prevent MHC from dragging the peptide successfully to the cell surface, or from holding on to it once there
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CTL escape: reducing CTL escape: reducing MHC bindingMHC binding
• Lymphocytic choriomeningitis virus (LCMV) is an RNA virus that naturally infects mice
• Infection can be controlled or eliminated by a strong CTL response
• Puglielli et al. used an LCMV system with transgenic mice that expressed an MHC molecule that binds a particular epitope of LCMV (GP33-43)
• After infection, an initial viremia was beaten down by CTL pressure
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CTL escape: reducing CTL escape: reducing MHC bindingMHC binding
• Later, virus titers increased. Were escape mutants to blame?
• The late viruses indeed had a V to A substitution at the 3rd site of the epitope.
• This substitution nearly abolished binding to the MHC molecule expressed by the mice
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CTL escape: reducing CTL escape: reducing MHC bindingMHC binding
• SIV/macaques is used as a model system for HIV since you can’t experimentally infect humans to study the arms race between HIV and humans
• Escape from CTLs appears to be a key component of the dynamics and persistence of infection within hosts
• Allen et al. (2000) studied 18 rhesus macaques infected with SIV
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CTL escape: reducing CTL escape: reducing MHC bindingMHC binding
• Ten of the monkeys expressed a particular MHC, and these all made CTLs to an epitope in the Tat protein in the acute phase of infection
• Shortly after, the frequency of these Tat-specific CTLs dropped off
• Sequencing showed that a majority of these animals had mutations in the Tat viral epitope that destroyed binding to the MHC
• There was little variation outside of the epitope
• End result: positive selection to block MHC binding
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CTL escape: reducing CTL escape: reducing TCR bindingTCR binding
• The LCMV system also shows examples of single amino acid changes that can lead to a decline in affinity for the TCR
• Tissot et al (2000) showed that a Y to F substitution in one immunodominant epitope obtained during experimental evolution in vivo caused a 100-fold reduction in affinity for the TCR
• End result: escape mutation that destroys the immune system’s ability to see that epitope
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Benefits of antigenic variationBenefits of antigenic variation
2. Infect hosts with prior exposure
• Hosts often maintain memory against prior infections, generating a selective pressure for parasites to vary
• Cross-reaction occurs when the host can use its specific recognition from a prior exposure to fight against a later, slightly different antigenic variant
• Good vaccines are ones that have excellent cross-reactivity (e.g. measles virus)
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Figure 11-1 part 1 of 3In the simplest case, each antigenic variant acts like a separate parasite that doesn’t cross-react with other variants
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Figure 11-1 part 2 of 3
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Figure 11-1 part 3 of 3
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Benefits of antigenic variationBenefits of antigenic variation
2. Infect hosts with prior exposure
• A more dynamic mechanism of antigenic variation is seen in influenza virus
• Antigenic drift is caused by point mutations in the genes encoding surface proteins
• Antigenic shift is caused by reassortments leading to novel surface proteins
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Figure 11-2 part 1 of 2
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Figure 11-2 part 2 of 2
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Benefits of antigenic variationBenefits of antigenic variation
2. Infect hosts with prior exposure
• Antigenic drift is caused by point mutations in the hemagglutinin and neuraminidase genes, which code for surface proteins
• Every 2-3 years a variant arises that can evade neutralization by antibodies in the population
• Previously immune individuals become susceptible
• Most individuals still have some cross-reactivity and the ensuing epidemic tends to be relatively mild (but still kills 100s of thousands per year!)
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Benefits of antigenic variationBenefits of antigenic variation
2. Infect hosts with prior exposure
• Antigenic shift brings in an all-new hemagglutinin or neuraminidase gene to a naïve population
• Can lead to severe infections and massive pandemics like the Spanish flu of 1918.
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Benefits of antigenic variationBenefits of antigenic variation
Why, fundamentally, is it of benefit to a parasite to extend the length of infection or re-infect hosts with prior exposure?
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