Virulence and disease
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Virulence and disease. What can evolution tell us about disease and medicine?. Outline: virulence and disease. Pathogen evolution Origins of novel pathogens Causes of virulence (esp. trade-off) Evolution of antibiotic resistance Evolution and human health

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Virulence and disease

Virulence and disease

What can evolution tell us about disease and medicine?

Outline virulence and disease

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

I pathogen evolution eluding the immune system influenza

I. Pathogen evolution: eluding the immune system - influenza

Do amino acid substitutions occur at antigenic sites?

Sample flu lineages from 1968 to 1987.


Antigenic sites3331

Non-antigenic sites1035

Hemagglutinin (HA): cell entry

Neuroaminidase (NA): cell exit

Evolution of antigenic sites

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

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

Flu pandemics

  • 1918Spanish flu (40m deaths)H1N1

  • 1957Asian (1m deaths)H2N2

  • 1968Hong KongH3N2

  • 1977RussianH1N1

  • 1997Avian (22 deaths)H5N1

Where do pandemics come from

Where do pandemics come from?

Phylogeny of nucleoprotein gene of influenza A.

A role for pigs

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

H3 1968 from birds

Phylogeny of flu A hemagglutinin genes

Virulence and disease

High virulence

= rapid growth

rate of virus

Low virulence

= slow growth

rate of virus

leads to severe host

illness and/or death

leads to slow

development of illness or

little effect on host

IC. What causes virulence?

Virulence: : tendency to reduce survival or reproductive capacity of host

Virulence and disease

increased chance of transmission at each


decreased # copulations before death of host

Cost to virus

Benefit to virus

Why doesn’t HIV evolve to become more virulent?

With high virulence you get:

many virions/ml blood

rapid illness and death of host

Virulence and disease

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

Myxoma virus

Virulence and disease

Effect of myxoma virus on rabbits – 1951-1953

Virulence of field strains

Virulence of field strains

Tests carried out on domestic rabbits

Trade off hypothesis of virulence

Trade-off hypothesis of virulence

Rabbit resistance evolves

Rabbit resistance evolves

Virulence and disease

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?

Virulence and disease

What is the optimal level of virulence?

Water-borne diseases

Virulence and disease

What is the optimal level of virulence?

Vector-borne diseases

Second virulence hypothesis short sighted evolution

Second virulence hypothesis: short-sighted evolution

Third virulence hypothesis coincidental

Third virulence hypothesis: coincidental

I d evolution of antibiotic resistance

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

Acquisition of anti-biotic resistance?

Time to resistance?








Modes of resistance

Modes of resistance


Tetracycline: blocks translationribosome mutation

cellular pumps upregulated

Penicillinblocks cell wallsbeta-lactamase digests


cipro DNA packingmutation to enzymes



Efflux pumps

Efflux pumps

Experimental test of cost of resistance schrag 1997

Experimental test of cost of resistance: Schrag (1997)

Initial competition without antibiotics

Initial competition without antibiotics

Time (generations)

After many generations in the lab

After many generations in the lab?

After many generations in the lab1

After many generations in the lab?

An evolutionary mystery vancomycin resistance

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

Mechanism of resistance

Vancomycin resistance

Vancomycin resistance

Origins of vancomycin resistance comparison of amino acid sequences

Origins of vancomycin resistance: comparison of amino acid sequences

Numbers above: sequence similarity to VanA from E. foecium. Below: GC%.

Source of resistance

Source of resistance

Antibiotic resistance summary

Antibiotic resistance summary

Hypotheses to explain human disorders

Hypotheses to explain human disorders

Always deleterious:

Sometimes deleterious:

Only seem deleterious, actually a defense

Virulence and disease

G x E: Myopia (near-sightedness)

Hypothesis: myopia is environment dependent

Test: Barrow, Alaska

Test in 1970 (35 years later)

Age:MyopicNot myopic%


35+ 8152 5

Virulence and disease

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?

Virulence and disease

Proportion with NVP

Post-menstrual week of pregnancy

Sensitive Fetal organ

Post-menstrual week of pregnancy

Diseases are really defenses: “Morning sickness”

Prediction 1: NVP most severe when need for protection greatest

Sherman and Flaxman 2002

Virulence and disease

Diseases are really defenses: “Morning sickness”

Percentage of pregnancies with miscarriage


**Prediction 2: NVP should be associated with positive pregnancy outcomes

Sherman and Flaxman 2002

Evolution of menopause

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

Study questions

  • 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 questions1

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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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 57:139-154.

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 76:417-432.

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