Download Topic 19: Virulence and disease

Virulence and disease
What can evolution tell us
about disease and
medicine?
Outline: virulence and disease
I.
Pathogen evolution
A.
B.
C.
II.
Origins of novel pathogens
Causes of virulence (esp. trade-off)
Evolution of antibiotic resistance
Evolution and human health
A.
B.
C.
Disorders due to changes in environment
Diseases as defenses
Disorders due to sexual conflict
I. Pathogen evolution: eluding the
immune system - influenza
Do amino acid substitutions occur
at antigenic sites?
Sample flu lineages from 1968 to
1987.
Surviving
Extinct
Antigenic sites
33
31
Non-antigenic sites
10
35
Hemagglutinin (HA): cell entry
Neuroaminidase (NA): cell exit
Evolution of antigenic sites
What kind of substitution
in hemagglutinin?
18 codons with excess
replacement (dN > dS):
Figure 13.4
IB: Origins of novel pathogens influenza
• Three types of influenza viruses:
– A and B have 8 RNA strands, C has 7
– type A and B encode HA and NA, C does not
– A and B can be severe, C generally mild
• Hosts:
– type A: humans, swine, horses, waterfowl, gulls
– type B: humans and seals
– type C: humans and swine
• Flu A viruses are classified by HA type (1-15)
and NA type (1-9)
– only H1, H2, H3 and N1, N2 in humans (until recently)
Flu pandemics
•
•
•
•
•
1918
1957
1968
1977
1997
Spanish flu (40m deaths)
Asian (1m deaths)
Hong Kong
Russian
Avian (22 deaths)
H1N1
H2N2
H3N2
H1N1
H5N1
Where do pandemics come from?
Phylogeny of
nucleoprotein gene
of influenza A.
A role for pigs?
Sialic acid – galactose on epithelial cell surface key to infection
– binding site for hemagglutinin (HA)
Can bind two different ways. Avian 2-3. Human 2-6.
H3 1968 from birds
Phylogeny of flu A
hemagglutinin genes
IC. What causes virulence?
Virulence: : tendency to reduce survival or reproductive capacity of host
High virulence
= rapid growth
rate of virus
leads to severe host
illness and/or death
Low virulence
= slow growth
rate of virus
leads to slow
development of illness or
little effect on host
Why doesn’t HIV evolve to become more virulent?
With high virulence you get:
many virions/ml blood
rapid illness and death of host
decreased # copulations
before death of host
Cost to virus
increased chance of
transmission at each
copulation
Benefit to virus
Evolution of Virulence: Australia’s plague of
rabbits
13 wild introduced in 1858. 9 years later, 50 km spread. 1870s: 150 km / yr
Myxoma virus
Effect of myxoma virus on rabbits
– 1951-1953
Virulence of field strains
Class
Survival
time
Fatality
rate
Year
I
<13
1950-1
99
1951-2
33
1952-3
II
13-16
III
IV
17-28 29-50
V
-
7095%
5070%
<50
50
17
0
0
4
13
74
9
0
1953-4
16
25
50
9
0
1954-5
16
16
42
26
0
99% 9599%
Tests carried out on domestic rabbits
Trade-off hypothesis of virulence
Rabbit resistance evolves
What is the optimal level of virulence?
But why is there a different balance in different pathogens--why are
some more virulent than others?
Why don’t some pathogens seem to become less virulent?
What is the optimal level of virulence?
Water-borne diseases
What is the optimal level of virulence?
Vector-borne diseases
Second virulence hypothesis:
short-sighted evolution
Third virulence hypothesis:
coincidental
I-D. Evolution of antibiotic
resistance
• 70% of bacterial infections requiring
hospitalization are resistant to some
antibiotic
• Sepsis (infected blood / tissue) rates
tripled in US from 1979 to 2000
Acquisition of anti-biotic
resistance?
Time to resistance?
Drug
Introduction
Penicillin
1943
Streptomycin 1945
Tetracycline 1948
Vancomycin 1956
Methicillin
1960
Cefataxime
1985
Resistance
1946
1959
1953
1988
1961
1988
Modes of resistance
Drug
action
resistance
Tetracycline:
blocks translation
ribosome mutation
cellular pumps upregulated
Penicillin
blocks cell walls
beta-lactamase digests
drug
cipro
(fluoroquinolones)
DNA packing
(inhibits
topoisomerase)
mutation to enzymes
Efflux pumps
Experimental test of cost of
resistance: Schrag (1997)
Initial competition without
antibiotics
Time (generations)
After many generations in the lab?
After many generations in the lab?
An evolutionary mystery:
vancomycin resistance
Vancomycin: 32 years before resistance seen.
500K staph infections per year in hospitals. By 1990s, commonly
resistant to other antibiotics.
Until recently, the last-resort antibiotic when other resistant.
Mechanism: blocks cell-wall biosynthesis by forming complex
with peptidoglycans
Cross-linker: D-alanine D-alanine di-peptide
Gram-positive bacteria
Mechanism of resistance
Vancomycin resistance
Origins of vancomycin resistance:
comparison of amino acid sequences
Numbers above: sequence similarity to VanA
from E. foecium. Below: GC%.
Source of resistance
Antibiotic resistance summary
Hypotheses to explain human
disorders
Always deleterious:
Sometimes deleterious:
Only seem deleterious, actually a defense
G x E: Myopia (near-sightedness)
Hypothesis: myopia is environment dependent
Test: Barrow, Alaska
Test in 1970 (35 years later)
Age:
Myopic Not myopic
%
6-35
146
202
42
35+
8
152
5
II. Diseases are really defenses: “Morning sickness”
•“nausea and vomiting of pregnancy”, or NVP
•About 2/3 of all pregnant women worldwide affected
•All hours (not just morning)
•Affects healthy mothers, who have healthy babies
seems negative:
reduced food intake, reduced activity level
why persistent and common?
Diseases are really defenses: “Morning sickness”
Proportion with NVP
Prediction 1: NVP most severe when need for protection greatest
Sherman and Flaxman 2002
0.6
0.4
0.2
0
Sensitive Fetal organ
0
5
10
CNS
H
UL
Ey
LL
T
P
EG
E
15
20
25
30
35
40
Post-menstrual week of
pregnancy
0
5
10
15
20
25
30
35
Post-menstrual week of pregnancy
40
Diseases are really defenses: “Morning sickness”
**Prediction 2: NVP should be associated with positive pregnancy
outcomes
MISCARRIAGES
25
NVP
No NVP
20
15
10
5
0
1
2
3
4
5
6
7
Study
Sherman and Flaxman 2002
Evolution of menopause
• 7 million oogonia at fifth fetal month
• 2 million oocytes at birth: meiotic prophase
• 400,000 at puberty
– 400 lost to ovulation
– remainder degenerate (atresia)– why?
– when few remain, menopause
• Hypotheses:
– proximate: mitochondrial damage leads to apoptosis
(but why aren’t there more to start with?)
– adaptive??
Study questions
1.
2.
3.
4.
If you compare the pattern of mutations in a virus over time,
what would indicate neutral evolution? What would indicate
that selection was at work?
The hypothesis is that the 1918 flu virus incorporated many
avian flu elements. Two hypotheses could be formulated:
the 1918 flu involved recombination between human and
avian flu strains, or the 1918 flu involved an avian strain
shifting to humans. Imagine that you had access to flu
sequences from 1900, 1905, 1910, and 1918 for ducks and
humans and that you built two phylogenies, one for
nucleoprotein and one for hemagglutinin. Sketch what the
phylogenies would need to look like to support each
hypothesis.
Explain why virulence rapidly declined for myxomatosis in
Australian rabbits using the requirements of natural
selection.
The 1918-1920 flu epidemic killed 40 million people.
Formulate three hypotheses for why this virus did not
continue killing humans at such high rates.
Study questions
5.
6.
7.
Why do some pathogens evolve to become less virulent but
not others? Explain why some of the key variables include
mode of transmission and primary hosts.
Consider two diseases. In one case, hosts are infected by a
single strain at a time. In the other case, hosts are infected
by multiple strains at one time. How would you predict this
difference to affect the evolution of virulence?
You are investigating the hypothesis that antibiotic
resistance in a bacterial infection originated via horizontal
gene transfer. Explain how you would use phylogenies to
assess this.
References
Frank, Steven A. 2002. Immunology and evolution of infectious disease.
Princeton University Press.
Guardabassi, L. et al. 2005. Glycopeptide VanA Operons in Paenobacillus strains
isolated from soil. Antimicrobrial agents and chemotherapy 49:4227-4233.
Hay, A. J. et al. 2001. The evolution of human influenza viruses. Philosophical
transactions of the Royal Society Series B 356:1861-1870.
Hurtado, A. M. et al. 1999. The evolution ecology of childhood asthma. In
Trevathan, W. R. et al., eds. Evolutionary medicine. Oxford University Press.
Launay, A. et al. 2006. Transfer of vancomycin resistance transposon Tn1549 from
Clostridium symbiosum to Enterococcus spp. in the gut in gnotobiotic mice.
Antimicrobial agents and chemotherapy 50:1054-1062.
Lewis, D. 2006. Avian flu to human influenza. Annual review of medicine 57:139154.
Nesse, R. M. and Williams, G. C. 1996. Why we get sick: the new science of
Darwinian medicine. Random House, New York.
Sherman and Flaxman. 2002. Nausea and vomiting of pregnancy in an
evolutionary perspective. American Jr of Ostetrics and Gynecology 186: S190S197.
Stearns, S. and Ebert, D. 2001. Evolution in health and disease: a work in
progress. Quarterly review of biology 76:417-432.
Walsh, C. T. et al. 1996. Bacterial resistance to vancomycin: five genes and one
missing hydrogen bond tell the story. Current biology 3:21-28.
White, D. G. et al., eds. 2005. Frontiers in Antimicrobial Resitance. American
Society for Microbiology.