Evolution and Human Health

1. Evolution and Human Health Chapter 13

2. Evolving Pathogens: Evasion of the host’s immune response Influenza A virus

3. 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

4. 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

5. Influenza A virus (Fig. 13.3)

6. 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 non-antigenic sites • In extinct lineages, the ratio of antigenic to non-antigenic site replacements was 31 to 35

7. 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

8. Evolution of hemagglutinin genes in influenza A (Fitch et al. 1991) (Fig. 13.4)

9. 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

10. 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

11. 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

12. 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

13. Phylogeny of influenza A viruses based on the hemagglu-tinin 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

14. 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

15. Penicillin resistance among Pneumococcus bacteria in Icelandic children (Austin et al. 1999) (Fig. 13.7)

16. 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

17. 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)

18. Cost of resistance to streptomycin in E. coli (Schrag et al. 1997) (Fig. 13.8) – 1

19. 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

20. 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?

21. 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

22. 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

23. 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

24. 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

25. Evolution of virulence in bacteriophage F1 in cultures of E. coli (Messenger et al. 1999) (Fig. 13.9) 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 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

26. 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

27. The virulence of vector-borne versus directly transmitted diseases (Ewald 1994)

28. 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

29. The virulence of intestinal bacteria as a function of the tendency toward waterborne transmission (Ewald 1991)(Fig. 13.11)

30. 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

31. 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

32. 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

33. 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

34. 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