Transcript Oct. 11 Lecture 13: Parasite antigenic diversity

Lecture 13
Immunology and disease:
parasite antigenic diversity
Today:
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Benefits and mechanisms of antigenic variation
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Antigenic variation that allows pathogens to
persist in the individual host they’ve infected
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Antigenic variation that allows pathogens to infect
hosts with prior exposure
Benefits of antigenic variation
1. Persist in infected host
Let’s look at some experimental results…
Experimental evolution
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Manipulates the environment of a population and
then looks at the resulting patterns of evolutionary
change
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Allows for the direct study of the selective forces
that shape antigenic diversity
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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
Review
Figure 1-27
•The two main classes of
MHC molecules present
antigen from cytosol
(MHC class I) and
vesicles (MHC class II)
MHC class I molecule presenting an
epitope
Figure 3-23
Figure 1-30
CTL escape
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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.
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They can interfere with processing and
transport of peptides.
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They can reduce binding to MHC molecules.
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And they can reduce the affinity of TCR
receptor binding.
CTL escape: interfering
with processing/transport
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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
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MuLV is an oncogenic retrovirus
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There are two main types (MCF and FMR)
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Both types are controlled in large part by CTL
responses, but with different immunodominant
epitopes
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The immunodominant CTL epitope for MCF is
KSPWFTTL
CTL escape: interfering
with processing/transport
mcf
fmr
CTL escape: interfering
with processing/transport
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Proteasomes are hollow multiprotein complexes.
They are like meat-grinders for pathogen proteins
found in the cytosol
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Cellular proteasomes continuously chop up
proteins into smaller peptides, for presentation by
MHC
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Proteasomal cleavage patterns determine which
bits of pathogen peptides get to the cell surface
CTL escape: interfering
with processing/transport
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Changing KSPWFTTL to RSPWFTTL introduces a
new cleavage site (the proteasome likes to chop
after R)
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Viruses with RSPWFTTL are cleaved right within
what would otherwise be a great epitope, leading
to a huge reduction in the abundance of the Rcontaining epitope available for MHC presentation
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Inspection of the nucleotides reveals that this
escape is mediated by a single point mutation!
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End result: that epitope is unavailable to MHC and
the CTL response to FMR type is weak
CTL escape: reducing
MHC binding
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Several studies report mutations that reduce
peptide-MHC binding
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This can either prevent MHC from dragging the
peptide successfully to the cell surface, or from
holding on to it once there
CTL escape: reducing
MHC binding
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Lymphocytic choriomeningitis virus (LCMV) is an
RNA virus that naturally infects mice
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Infection can be controlled or eliminated by a
strong CTL response
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Puglielli et al. used an LCMV system with
transgenic mice that expressed an MHC molecule
that binds a particular epitope of LCMV (GP33-43)
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After infection, an initial viremia was beaten down
by CTL pressure
CTL escape: reducing
MHC binding
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Later, virus titers increased. Were escape
mutants to blame?
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The late viruses indeed had a V to A substitution
at the 3rd site of the epitope.
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This substitution nearly abolished binding to the
MHC molecule expressed by the mice
CTL escape: reducing
MHC binding
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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
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Escape from CTLs appears to be a key
component of the dynamics and persistence of
infection within hosts
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Allen et al. (2000) studied 18 rhesus macaques
infected with SIV
CTL escape: reducing
MHC binding
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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
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Shortly after, the frequency of these Tat-specific
CTLs dropped off
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Sequencing showed that a majority of these
animals had mutations in the Tat viral epitope that
destroyed binding to the MHC
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There was little variation outside of the epitope
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End result: positive selection to block MHC
binding
CTL escape: reducing
TCR binding
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The LCMV system also shows examples of single
amino acid changes that can lead to a decline in
affinity for the TCR
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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
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End result: escape mutation that destroys the
immune system’s ability to see that epitope
Benefits of antigenic variation
2. Infect hosts with prior exposure
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Hosts often maintain memory against prior
infections, generating a selective pressure for
parasites to vary
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Cross-reaction occurs when the host can use its
specific recognition from a prior exposure to fight
against a later, slightly different antigenic variant
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Good vaccines are ones that have excellent crossreactivity (e.g. measles virus)
In the simplest case, each antigenic variant acts like a separate
parasite that doesn’t cross-react with other variants
Figure 11-1 part 1 of 3
Figure 11-1 part 2 of 3
Figure 11-1 part 3 of 3
Benefits of antigenic variation
2. Infect hosts with prior exposure
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A more dynamic mechanism of antigenic variation
is seen in influenza virus
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Antigenic drift is caused by point mutations in the
genes encoding surface proteins
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Antigenic shift is caused by reassortments
leading to novel surface proteins
Figure 11-2 part 1 of 2
Figure 11-2 part 2 of 2
Benefits of antigenic variation
2. Infect hosts with prior exposure
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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!)
Benefits of antigenic variation
2. Infect hosts with prior exposure
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Antigenic shift brings in an all-new hemagglutinin
or neuraminidase gene to a naïve population
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Can lead to severe infections and massive
pandemics like the Spanish flu of 1918.
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?