Transcript Sept 16 Lecture 7 Diversity of infectious agents

Lecture 11
Immunology and disease:
parasite antigenic diversity
RNAi interference video and tutorial (you are
responsible for this material, so check it out….)
http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html
http://www.nytimes.com/2006/10/03/science/03nobel.html?em&ex=1160107200&en=7cbf3cd9027a96ea&ei=5087%0A
Benefits of antigenic variation
•
To understand why parasites vary in the ways they
do, it helps to break down the potential benefits
provided by variation
•
But first, what about the potential disadvantages?
(think in terms of trade-offs)
So, what are the benefits?
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?
Benefits of antigenic variation
1. Extend the length of infection
•
Initial infection stimulates immune response
against dominant antigens
•
In some cases (e.g. measles virus) this response
is sufficient to clear infection
•
If the parasite can evolve new variants, it can stay
one step ahead of the immune response and
maintain a vigorous infection
•
The host must generate a new response against
each escape mutant (parasite with altered
genotype that allows for immune escape)
Benefits of antigenic variation
1. Extend the length of infection
•
There are a variety of mechanisms parasites use
to generate novel antigens or evade immune
response:
-Mutation
-Recombination
-Differential expression of archived variants
-Latency
-Subversion of immune response
Benefits of antigenic variation
1. Extend the length of infection
•
Some viruses, like HIV, escape by changing their
dominant epitopes to evade CTL response.
•
Even though such changes may arise only rarely
in each replication, the huge population ensures
that the “epitope space” is efficiently explored
•
Both mutation and recombination may play a role
in immune escape. We’ll explore HIV evolution in
detail later…
Figure 11-29
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
epitope
Figure 3-23
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
CTL escape: interfering
with processing/transport
mcf
fmr
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 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 Rcontaining 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
1. Extend the length of infection
•
Other viruses, like hepatitis C virus, escape by
evading the host antibody response
•
In most cases, a persistent infection is
established, with high variability in the envelope
protein indicating positive selection
•
Both HIV and HCV make use of high mutation
rates to stay ahead of the adaptive immune
responses in the host-parasite arms race
Benefits of antigenic variation
1. Extend the length of infection
•
Antigenic variation in trypanosomes allows them
to escape immune surveillance
•
Trypanosoma brucei, the agent of sleeping
sickness changes its dominant antigenic surface
glycoprotein about once every hundred cell
divisions
•
This occurs not through mutation, but through
differential expression of a huge pool of variant
genes already present in the genome
•The surface of a
trypanosome is
covered with variantspecific glycoprotein
(VSG)
•There are about 1000
different VSG genes
•Upon initial
infection, antibodies
are raised against the
VSG initially
expressed
• A small number of
trypanosomes
spontaneously change
VSG via gene
conversion, and the new
variant grows
•As the new variant
grows, the whole cycle is
repeated, leading to
successive waves of
parasitemia and clearance
•Wears out your immune
system and leads to coma
Benefits of antigenic variation
1. Extend the length of infection
•
Several other important pathogens also sample
from a pool of archival genomic variation
•
Borrelia hermsii, the spirochete that causes
relapsing fever, swaps expression sites of a
surface lipoprotein leading to waves of fever
•
Plasmodium falciparum expresses the var gene
within erythrocytes. The gene product is
expressed on cell surface influencing recognition
by host immunity. Clones switch between pool of
var variants
Benefits of antigenic variation
1. Extend the length of infection
•
Some viruses persist in vivo by ceasing to
replicate until immunity wanes
•
During latency the virus is not transcriptionally
active, and causes no disease
•
Because it’s not producing viral peptides, it cannot
be disposed of because it cannot be recognized
• Initial infection by herpes
simplex virus in the skin is cleared
Figure
11-4
by an effective immune response
•But residual infection persists in
sensory neurons
•When the virus is reactivated, the
skin is re-infected. This can be
repeated endlessly
Benefits of antigenic variation
1. Extend the length of infection
•
•
•
•
Why do sensory neurons remain infected?
First, because the virus remains quiescent, few
viral proteins are produced and hence there are
few virus-derived proteins to present on MHC
class I
Second, neurons carry low levels of MHC class I
molecules making it harder for CTLs to recognize
and kill them.
Why would neurons have low MHC I expression?
Benefits of antigenic variation
1. Extend the length of infection
•
Low level of MHC I expression may be beneficial
to the host since it reduces the risk that neurons,
which cannot regenerate, will be attacked
inappropriately by CTLs.
Benefits of antigenic variation
1. Extend the length of infection
•
Some pathogens resist destruction by host
defense mechanisms or even exploit them
•
Mycobacterium tuberculosis, for example, is
taken up by macrophages but prevents the fusion
of the phagosome with the lysosome, effectively
hiding from antibody-mediated immunity
•
Many viruses, particularly DNA viruses, subvert
various arms of the immune system
•
How would you do this if you were a virus?
Benefits of antigenic variation
1. Extend the length of infection
•
One way is through inhibiting MHC class I
synthesis or assembly…
Figure 11-5 part 3 of 3
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 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
•
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.