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Evolution and Human Health
Chapter 13
1
Evolving Pathogens: Evasion of
the host’s immune response
Influenza A virus
2
Influenza A virus – 1
• Responsible for annual flu epidemics and
occasional global pandemics (1918, 1957,
1968)
• Kills ~20,000 Americans per year
• 1918 pandemic sickened ~20% of world
population, killed 50 – 100 million people
3
Influenza A virus – 2
• Genome of 8 RNA strands, that encode 10
proteins
• Predominant coat protein is hemagglutinin:
– responsible for binding to host cell
– major viral protein that is recognized, attacked
and remembered by host immune system
– Antigenic sites are those specific parts of
hemagglutinin that are recognized and
remembered by the immune system
4
Influenza A virus (Fig. 13.3)
5
Evolution of hemagglutinin genes in influenza A
(Fitch et al. 1991) – 1
• Strains isolated from humans between 1968 and
1987 and stored in freezers
• Virus evolves about 1 million times faster than
mammals
• 109 amino acid replacements observed
– In surviving (1987) strain 33 amino acid replacements
were in antigenic sites vs. 10 replacements in nonantigenic sites
– In extinct lineages, the ratio of antigenic to nonantigenic site replacements was 31 to 35
6
Evolution of hemagglutinin genes in influenza A
(Fitch et al. 1991) – 2
• 18 codons in the hemagglutinin gene showed an
excess of nonsynonymous over synonymous
substitutions – evidence of positive selection for
viral fitness (pathogenicity)
• This fact allows prediction of the flu strain that is
most likely to cause the next annual outbreak look for the circulating strain that has the most
mutations in the 18 codons known to be under
positive selection
– correct 9 of 11 times
7
Evolution of hemagglutinin genes in influenza A
(Fitch et al. 1991) (Fig. 13.4)
8
The origin of pandemic flu strains
• Influenza strains are designated by the groups to which
their hemagglutinin and neuraminidase coat proteins
belong
• H3N2 mean hemagglutinin-3, neuraminidase-2
• Before 1968 was H3 was unknown in human flu strains —
where did it come from?
• Evidence strongly supports the idea that flu strains can
move between humans, birds and pigs.
• When two strains simultaneously infect a cell, they can
“recombine” their RNA genomes
• H3 gene apparently entered humans from birds and this
new human strain was responsible for the 1968 pandemic
9
Phylogeny of influenza A viruses based on the
nucleoprotein gene (Fig. 13.5) – 1
Letter and numbers in parentheses indicate subtypes based on groups of hemagglutinin
and neuraminidase, e.g., H2N3 is hemagglutinin-2, neuraminidase-3
10
Phylogeny of influenza A viruses based on the
nucleoprotein gene (Fig. 13.5) – 2
Letter and numbers in parentheses indicate subtypes based on groups of hemagglutinin
and neuraminidase, e.g., H2N3 is hemagglutinin-2, neuraminidase-3
11
Phylogeny of influenza A viruses based on the
nucleoprotein gene (Fig. 13.5) – 3
Letter and numbers in parentheses indicate subtypes based on groups of hemagglutinin
and neuraminidase, e.g., H2N3 is hemagglutinin-2, neuraminidase-3
12
Phylogeny
of
influenza
A viruses
based on
the
hemagglutinin gene
(Fig. 13.6)
(part)
Letter and numbers in parentheses indicate subtypes based on groups of hemagglutinin
and neuraminidase, e.g., H2N3 is hemagglutinin-2, neuraminidase-3
13
Evolving Pathogens: antibiotic resistance
• Antibiotics exert strong selective pressure
on bacteria to evolve resistance
• Penicillin resistance by Pneumococcus
bacteria in children in Iceland
– Frequency of resistant bacteria increased 1998 93, and then decreased after penicillin use was
discouraged
14
Penicillin resistance among Pneumococcus bacteria
in Icelandic children (Austin et al. 1999) (Fig. 13.7)
15
Costs to bacteria of antibiotic resistance
• It is widely assumed that the evolution of
antibiotic resistance by bacteria incurs a
fitness cost in the absence of antibiotic
(remember HIV and AZT resistance)
• This is often, but not always, the case
• Compensatory mutations may reduce the
cost of resistance
16
Streptomycin resistance in E. coli
• Streptomycin interferes with protein synthesis by binding
to a ribosomal protein encoded by the rpsL gene
• Point mutations to the rpsL gene confer resistance to
streptomycin
• Schrag et al. (1997) evaluated the costs of streptomycin
resistance, and the ability of E. coli to evolve
compensatory mutations to offset the costs of resistance
• Given enough generations in the presence of streptomycin,
bacteria can overcompensate for the cost of resistance (at
least in the laboratory)
17
Cost of
resistance to
streptomycin
in E. coli
(Schrag et al.
1997) (Fig.
13.8) – 1
18
Cost of resistance
to streptomycin in
E. coli (Schrag et
al. 1997) (Fig.
13.8) – 2
(a) Short-term cost of
resistance
(b) Long-term “cost”
of resistance
19
Evolving pathogens: virulence
• Virulence refers to the harm that a pathogen
does to its host
• Pathogens vary greatly in virulence —
common cold to anthrax, small pox,
cholera, etc.
• What can evolutionary thinking tell us
about variation in virulence?
20
How virulence evolves – 1
1. Coincidental evolution hypothesis:
–
Virulence of many pathogens in humans is
not a target of selection — Claustridium
tetanae is a soil bacterium that can cause
tetanus and death in humans when it enters a
wound — but humans are not ordinarily
hosts for the bacterium and bacteria are not
transmitted from human to human
21
How virulence evolves – 2
2. The short-sighted evolution hypothesis:
•
•
•
Selection on pathogens occurs on two levels:
– Selection to reproduce rapidly within individual hosts
in order to avoid or overcome host defenses
– Selection for transmission between host individuals
Under this view, within-host selection is stronger and
virulence does not enhance transmission to new host
individuals
Poliovirus normally infects cells that line the digestive
tract, but may occasionally invade the nervous system,
where they may have a within-host selective advantage,
but from where they are unlikely ever to infect a new
host
22
How virulence evolves – 3
3. The trade-off hypothesis:
•
It used to be widely believed that pathogens would always evolve
toward lower virulence because to do so would increase the chance
of transmission between hosts
–
•
Long-term evolutionary interests of both host and pathogen are served
by lower pathogen virulence
The trade-off hypothesis asserts that evolution tries to find the best
balance between virulence (host survival) and transmission
A virulent strain may increase in frequency if, in the process of
killing its hosts, it sufficiently increases its chances of being
transmitted
•
–
–
Under some conditions, selection on pathogens may favor reduced
virulence
Under other conditions, selection on pathogens may favor increased
virulence
23
Evolution of virulence in bacteriophage F1 in
cultures of E. coli (Messenger et al. 1999)
• Phage can be transmitted horizontally (cell to cell) by
secretion of phage particles from infected cells
• Phage can be transmitted vertically when cells divide
because they are carried along with the cell contents
• Two experimental treatments:
 1-day vertical transmission + brief horizontal transmission phase
— should select for greater virulence because more phage particles
= greater fitness under horizontal transmission
 8-day vertical transmission + brief horizontal transmission phase
— should select for reduced virulence because faster host cell
division = greater phage fitness
24
Evolution of virulence in bacteriophage F1 in
cultures of E. coli (Messenger et al. 1999) (Fig. 13.9)
Vertical transmission
favors slower reproducing
phage and increased host
fitness (as measured by
host cell density after 24h
growth) —lower
virulence evolves because
it improves transmission
in this culture regime
even though it reduces
phage fitness within
individual host cells
Horizontal
transmission favors
faster reproducing
phage at the expense of
reducing host fitness
(as measured by host
cell density after 24h
growth) —greater
virulence evolves
because it improves
transmission in this
culture regime
25
Virulence in human pathogens – 1
• According to what we have just described with
bacteriophage in E. coli, virulence can be expected to be
evolve in response to the mode of transmission of a
pathogen
• Paul Ewald’s (1993, 1994) predictions concerning
virulence and mode of transmission of human pathogens:
– Pathogens that depend on direct contact between hosts should be
less virulent because transmission is enhanced if the host is not
seriously incapacitated by infection and has contact with as many
potential new hosts as possible
– Restraints on virulence are much lower for vector borne pathogens
(e.g. malaria) because direct contact is not necessary
26
The virulence of vector-borne versus directly
transmitted diseases (Ewald 1994)
27
Virulence in human pathogens – 2
• Ewald also predicted that among intestinal bacteria, those
with a stronger tendency to be transmitted by direct contact
would be less virulent than those that had a stronger
tendency to be spread by contaminated water
28
The virulence of intestinal bacteria as a function of the
tendency toward waterborne transmission (Ewald 1991)
(Fig. 13.11)
29
Tissues as evolving populations of cells
• A multicellular tissue or organism can be thought
of as a population of cells
• Cells can be genetically variable because of
somatic mutation
• This genetic variation is heritable
• If mutations increase cell division rate or cell
survival, then the tissue will evolve by natural
selection, just like a population of free-living cells
30
A case study of adenosine deaminase (ADA)
deficiency (Hirschorn et al. 1996) — 1
• ADA is a “housekeeping” enzyme normally made in all
cells of the body
• Function is to recycle purines — cells lacking ADA
accumulate two poisonous metabolites: deoxyadenosine
and deoxyadenosine triphosphate (dATP)
• Most sensitive cells are immune system B and T cells
• Individuals carrying loss-of-function mutations in both
copies of the ADA gene have no T cells and nonfunctional
(or no) B cells — without treatment usually die of
opportunistic infections at an early age
31
A case study of adenosine deaminase (ADA)
deficiency (Hirschorn et al. 1996) — 2
• In this case study, tissue evolution apparently saved the life of a boy
who inherited a loss-of-function allele from both of his heterozygous
parents
• Until 5 years old, the boy suffered bacterial and fungal infections
characteristic of severe combined immunodeficiency
• Between ages of 5 and 8, he spontaneously recovered.
• Genetic analysis of the boy and his parents revealed the following:
• Each parent carried a different mutant allele of ADA in heterozygous
state
• The boy had inherited both mutant alleles from his parents
• After recovery, the father’s mutation was still present in all cells
examined
• The mother’s mutation was still present in all the son’s white blood
cells but was absent in most of his B cells
32
A case study of adenosine deaminase (ADA)
deficiency (Hirschorn et al. 1996) — 3
• Conclusion:
– the ancestral cell to most of the boys existing B cells had sustained
a back mutation to a wild type ADA allele
– these reverted B cells became more abundant over time
– it is likely that the reverted B cells have a selective advantage over
non-reverted cells because they are making a crucial enzyme and
should, therefore, live longer
33
A case study of adenosine deaminase (ADA)
deficiency (Hirschorn et al. 1996) — 4
• Implications for enzyme replacement and gene therapy
– ADA is a candidate for gene therapy — remove lymphocytes
and/or bone marrow cells from patient, insert a functional copy of
the ADA gene, and return cells to patient
– However, as a precaution against the failure of gene therapy, it is
customary to also give patients enzyme replacement therapy
– But enzyme replacement may be counter-productive because it
reduces any selective advantage that the engineered cells would
have in the absence of enzyme replacement
34