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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.

Surviving Extinct

Antigenic sites 33 31

Non-antigenic sites 10 35

Hemagglutinin (HA): cell entry

Neuroaminidase (NA): cell exit

Evolution of antigenic sites
Evolution of antigenic sites influenza

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 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 influenza

  • 1918 Spanish flu (40m deaths) H1N1

  • 1957 Asian (1m deaths) H2N2

  • 1968 Hong Kong H3N2

  • 1977 Russian H1N1

  • 1997 Avian (22 deaths) H5N1

Where do pandemics come from
Where do pandemics come from? influenza

Phylogeny of nucleoprotein gene of influenza A.

A role for pigs
A role for pigs? influenza

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 influenza

Phylogeny of flu A hemagglutinin genes

High virulence influenza

= 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

increased chance of transmission at each influenza


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

Evolution of Virulence: Australia’s plague of rabbits influenza

13 wild introduced in 1858. 9 years later, 50 km spread. 1870s: 150 km / yr

Myxoma virus
Myxoma virus influenza

Virulence of field strains
Virulence of field strains influenza

Tests carried out on domestic rabbits

What is the optimal level of virulence? influenza

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? influenza

Water-borne diseases

What is the optimal level of virulence? influenza

Vector-borne diseases

I d evolution of antibiotic resistance
I-D. Evolution of antibiotic resistance influenza

  • 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? influenza

Time to resistance?

Drug Introduction Resistance

Penicillin 1943 1946

Streptomycin 1945 1959

Tetracycline 1948 1953

Vancomycin 1956 1988

Methicillin 1960 1961

Cefataxime 1985 1988

Modes of resistance
Modes of resistance influenza

Drug action resistance

Tetracycline: blocks translation ribosome mutation

cellular pumps upregulated

Penicillin blocks cell walls beta-lactamase digests


cipro DNA packing mutation to enzymes

(fluoroquinolones) (inhibits


Efflux pumps
Efflux pumps influenza

Initial competition without antibiotics
Initial competition without antibiotics influenza

Time (generations)

An evolutionary mystery vancomycin resistance
An evolutionary mystery: vancomycin resistance influenza

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

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%.

Hypotheses to explain human disorders
Hypotheses to explain human disorders sequences

Always deleterious:

Sometimes deleterious:

Only seem deleterious, actually a defense

G x E: Myopia (near-sightedness) sequences

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” sequences

  • “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?

Proportion with NVP sequences

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

Diseases are really defenses: “Morning sickness” sequences

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 sequences

  • 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 sequences

  • 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 sequences

  • 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 sequences

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 57:139-154.

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.

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.