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

Benefits of antigenic variation

1. Persist in infected host

Let’s look at some experimental results…

•

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

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

Figure 1-30

•

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.

•

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

mcf fmr

CTL escape: interfering with processing/transport

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

CTL escape: interfering with processing/transport

• Changing

K

SPWFTTL to

R

SPWFTTL introduces a new cleavage site (the proteasome likes to chop after

R

) • Viruses with

R

SPWFTTL 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

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

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

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

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

•

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

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

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)

In the simplest case, each antigenic variant acts like a separate

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

• 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

Figure 11-2 part 1 of 2

Figure 11-2 part 2 of 2

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!)

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.

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?