Virulence and disease

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Virulence and disease

• What can evolution tell us about disease and
  medicine?

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Outline virulence and disease

• Pathogen evolution
• Origins of novel pathogens
• Causes of virulence (esp. trade-off)
• Evolution of antibiotic resistance
• Evolution and human health
• Disorders due to changes in environment
• Diseases as defenses
• Disorders due to sexual conflict

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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
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Evolution of antigenic sites
What kind of substitution in hemagglutinin? 18
codons with excess replacement (dN gt dS)
Figure 13.4
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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)

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Flu pandemics

• 1918 Spanish flu (40m deaths) H1N1
• 1957 Asian (1m deaths) H2N2
• 1968 Hong Kong H3N2
• 1977 Russian H1N1
• 1997 Avian (22 deaths) H5N1

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Where do pandemics come from?
Phylogeny of nucleoprotein gene of influenza A.
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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.
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H3 1968 from birds
Phylogeny of flu A hemagglutinin genes
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IC. What causes virulence?
Virulence tendency to reduce survival or
reproductive capacity of host
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Why doesnt HIV evolve to become more virulent?
With high virulence you get
many virions/ml blood
rapid illness and death of host
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Evolution of Virulence Australias plague of
rabbits
13 wild introduced in 1858. 9 years later, 50 km
spread. 1870s 150 km / yr
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Myxoma virus
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Effect of myxoma virus on rabbits 1951-1953
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Virulence of field strains
Class Survival time Fatality rate Year I lt13 99 II 13-16 95-99 III 17-28 70-95 IV 29-50 50-70 V - lt50
1950-1 99
1951-2 33 50 17 0 0
1952-3 4 13 74 9 0
1953-4 16 25 50 9 0
1954-5 16 16 42 26 0
Tests carried out on domestic rabbits
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Trade-off hypothesis of virulence
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Rabbit resistance evolves
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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 dont some pathogens seem to become
less virulent?
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What is the optimal level of virulence?
Water-borne diseases
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What is the optimal level of virulence?
Vector-borne diseases
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Second virulence hypothesis short-sighted
evolution
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Third virulence hypothesis coincidental
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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

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Acquisition of anti-biotic resistance?

• Time to resistance?
• Drug Introduction Resistance
• Penicillin 1943 1946
• Streptomycin 1945 1959
• Tetracycline 1948 1953
• Vancomycin 1956 1988
• Methicillin 1960 1961
• Cefataxime 1985 1988

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Modes of resistance

• Drug action resistance
• Tetracycline blocks translation ribosome
  mutation
• cellular pumps upregulated
• Penicillin blocks cell walls beta-lactamase
  digests
• drug
• cipro DNA packing mutation to enzymes
• (fluoroquinolones) (inhibits
• topoisomerase)

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Efflux pumps
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Experimental test of cost of resistance Schrag
(1997)
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Initial competition without antibiotics
Time (generations)
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After many generations in the lab?
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After many generations in the lab?
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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

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Mechanism of resistance
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Vancomycin resistance
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Origins of vancomycin resistance comparison of
amino acid sequences
Numbers above sequence similarity to VanA from
E. foecium. Below GC.
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Source of resistance
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Antibiotic resistance summary
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Hypotheses to explain human disorders

• Always deleterious
• Sometimes deleterious
• Only seem deleterious, actually a defense

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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
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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?

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Diseases are really defenses Morning sickness
Prediction 1 NVP most severe when need for
protection greatest
Sherman and Flaxman 2002
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Diseases are really defenses Morning sickness
Prediction 2 NVP should be associated with
positive pregnancy outcomes
Sherman and Flaxman 2002
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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 arent there more to start
  with?)
• adaptive??

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Study questions

1. 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?
2. 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.
3. Explain why virulence rapidly declined for
   myxomatosis in Australian rabbits using the
   requirements of natural selection.
4. 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.

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Study questions

• 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.

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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
  494227-4233.
• Hay, A. J. et al. 2001. The evolution of human
  influenza viruses. Philosophical transactions of
  the Royal Society Series B 3561861-1870.
• 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 501054-1062.
• Lewis, D. 2006. Avian flu to human influenza.
  Annual review of medicine 57139-154.
• 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
  S190-S197.
• Stearns, S. and Ebert, D. 2001. Evolution in
  health and disease a work in progress.
  Quarterly review of biology 76417-432.
• Walsh, C. T. et al. 1996. Bacterial resistance
  to vancomycin five genes and one missing
  hydrogen bond tell the story. Current biology
  321-28.
• White, D. G. et al., eds. 2005. Frontiers in
  Antimicrobial Resitance. American Society for
  Microbiology.