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Lecture 13 Immunology and disease: parasite antigenic diversity. 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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Presentation Transcript
slide2

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
slide3

Benefits of antigenic variation

  • Persist in infected host

Let’s look at some experimental results…

slide4

Experimental 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
figure 1 27
Figure 1-27

Review

  • The two main classes of MHC molecules present antigen from cytosol (MHC class I) and vesicles (MHC class II)
figure 3 23
Figure 3-23

MHC class I molecule presenting an epitope

slide8

CTL 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.
slide10

CTL escape: interfering with 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
slide12

CTL escape: interfering with 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
slide13

CTL escape: interfering with 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
slide14

CTL escape: reducing MHC 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
slide16

CTL escape: reducing MHC 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
slide17

CTL escape: reducing MHC 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
slide19

CTL escape: reducing MHC 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
slide20

CTL escape: reducing MHC 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
slide21

CTL escape: reducing TCR 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
slide22

Benefits 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)
figure 11 1 part 1 of 3
Figure 11-1 part 1 of 3

In the simplest case, each antigenic variant acts like a separate parasite that doesn’t cross-react with other variants

slide26

Benefits 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
slide29

Benefits 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!)
slide30

Benefits 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.
slide31

Benefits 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?