Chapter 14 Evolution and human health

1. Chapter 14 Evolution and human health • The germ theory of disease was one of the most important breakthroughs in medicine. • Louis Pasteur in 1858 proposed that diseases were caused by microorganisms. • Within a few years the bacteria responsible for diseases such as anthrax, gonorrhea, typhoid fever and tuberculosis had been identified.

2. Anti-bacterial developments • Infection-fighting developments followed soon thereafter. • Antiseptic surgery was developed by Joseph Lister, improved housing and sanitation reduced infection rates, and the discovery of antibiotics allowed infections to be treated.

3. Anti-bacterial developments • As a result of these developments, death rates from infection declined rapidly. • By 1997 the TB death rate was < 0.4 per 100,000, less than 0.2% of the 1900 death rate. • By the end of the 1960’s the medical community considered that infectious disease had been conquered.

4. Fig 13.2

5. Evolving pathogens: antibiotic resistance • Unfortunately, pathogens have evolved in response to the selection pressures imposed by medicine. • Antibiotics are chemicals that kill bacteria and the first antibiotic was penicillin isolated from the mold Penicillum by Alexander Fleming.

6. Evolving pathogens: antibiotic resistance • Penicillin saved thousands of lives in World War II and subsequently. • Today, however, penicillin is ineffective against bacteria that previously were highly vulnerable and many bacteria have evolved resistance to multiple antibiotics. • As a result, infectious diseases have reemerged as a significant threat.

7. Evolving pathogens: antibiotic resistance • There is clear evidence that use of antibiotics selects for resistance in bacteria. • Studies have documented the evolution of antibiotic resistance in bacterial populations within individual patients and also in larger-scale studies of human and bacterial populations.

8. Evolving pathogens: antibiotic resistance • For example, researchers have found that the incidence of antibiotic-resistant bacteria is higher among patients who have been previously treated with that antibiotic. • For example the incidence of isoniazid-resistant bacteria is 21% in relapsed cases of TB, but only 8% in new cases.

9. Evolving pathogens: antibiotic resistance • On a larger scale, antibiotic resistance has been shown to track society-wide antibiotic use. • In the late 1980’s and early 1990’s penicillin resistance levels among Pneumococus bacteria in Iceland rose sharply.

10. Evolving pathogens: antibiotic resistance • When health authorities campaigned to reduce use of the antibiotic, rates of use of penicillin fell 13% and rates of bacterial resistance declined.

11. Fig 13.7

12. Costs of resistance to bacteria • The fact that resistance rates fell in Iceland when Penicillin use dropped suggests resistance imposes a cost on bacteria. • If the cost is high, non-resistant bacteria should have an advantage in a penicillin-free environment.

13. Costs of resistance to bacteria • Costs of resistance suggest that suspending use of an antibiotic might allow populations to evolve to a non-resistant state again.

14. Costs of resistance to bacteria • Unfortunately, resistant bacteria may also evolve ways to reduce or eliminate the costs of resistance and so not be outcompeted by non-resistant strains. • A study by Schrag et al. (1997) documented this.

15. Schrag et al. (1997) • They studied streptomycin-sensitive E. coli and screened for resistant mutants. • Streptomycin interferes with protein synthesis by binding to a ribosomal protein. • Point mutations in gene rpsL coding for that ribosomal protein can confer resistance.

16. Schrag et al. (1997) • Researchers competed resistant and sensitive strains against each other. Found that, initially, resistant strains were at a disadvantage and sensitive strains grew better.

17. Schrag et al. (1997) • Next, resistant strains that were allowed to evolve for many generations in the lab and then competed against sensitive strains. • Resistant strains had evolved and mutations that compensated for costs of streptomycin resistance had been selected for. • As a result, resistant strains outcompeted sensitive strains.

18. Schrag et al. (1997) • Schrag et al.’s results suggest that there is no guarantee that bacterial populations can be restored to vulnerability by withdrawing an antibiotic from use. • Thus, steps to avoid bacteria developing resistance need to be taken.

19. Steps to avoid evolution of resistance • Reduce infection rate (avoid e.g. undercooked eggs and meat; wash hands to slow disease spread). • Limit use of antibacterial soaps and cleaners. • Doctors should avoid prescribing antibiotics for viral infections. • Drugs that target as few bacteria as possible should be used. • Antibiotic use in animal feed should be eliminated.

20. Evolving pathogens: Evading host immune response • The human immune system mounts a formidable defense against microbes. • Pathogens naturally evolve responses. • Large population sizes, short generation times and high rates of mutation make pathogens a formidable opponent.

21. Evolution of influenza virus • Influenza A causes annual flu epidemics and occasional global pandemics including the infamous 1918 Spanish flu. • In a normal flu season flu kills about 20,000 Americans. The 1918 flu infected about 20% of the world’s population and killed 50-100 million people.

22. Evolution of influenza virus • Influenza A has a genome of 8 RNA strands that code for a total of 10 proteins. • These include polymerases, structural proteins and coat proteins.

23. 13.3

24. Evolution of influenza virus • Main viral coat protein is hemagglutinin. This binds to sialic acid on host cell’s surface to gain entry. • Hemagglutinin is also the primary protein recognized and attacked by the immune system.

25. Evolution of influenza virus • Survival for a viral strain means it must constantly find new hosts that do not recognize its hemagglutinin protein. • The immune system recognizes certain stretches of the hemagglutinin protein, which are called antigenic sites. • Viruses that have novel antigenic sites should have a selective advantage.

26. Evolution of influenza virus • Fitch et al. (1991) tested this hypothesis by examining frozen flu virus strains dating from 1968 to 1987. • Flu virus evolves about 1 million time faster than humans so 20 years is equivalent to 20 million years of human evolution.

27. Evolution of influenza virus • Flu strains evolved at a steady rate (about 6.7 X 10–3 mutations per nucleotide per year.

28. 13.4

29. Evolution of influenza virus • Most flu samples examined represented side branches of one main evolutionary tree of multiple closely related strains. • Instead of a wide variety of lineages derived from different 1968 era flu viruses there was one main lineage, the other viruses from 1968 having gone extinct.

31. Evolution of influenza virus • Fitch et al. suspected that the successful strain would have had more mutations in its antigenic sites than the extinct strains. • In surviving lineage they identified 33 amino acid replacements in antigenic sites and 10 in non antigenic sites. In extinct lineages found 31 replacements in antigenic sites and 35 in non antigenic sites.

32. Evolution of influenza virus • Surviving strain had more than 75% of replacements in antigenic sites versus less than 50% for extinct strains. • Statistically significant difference, which suggests increased variability in antigenic sites gave the surviving strain an advantage.

33. Evolution of influenza virus • Further evidence that flu is under strong selection from human immune systems comes from examining the rate of silent versus replacement nucleotide substitutions in strains of flu virus. • Silent mutations don’t result in a change in the amino acid coded for.

34. Evolution of influenza virus • Rates of replacement substitutions are statistically much higher than rates of silent mutations, which infers selection is strongly favoring replacements.

35. Origins of pandemic flu strains • Flu strains with novel hemagglutinin genes have a selective advantage. • Hence, any strain with a hemagglutinin sufficiently different from any that human immune systems had previously been exposed to, could spread uncontrollably.

36. Origins of pandemic flu strains • The influenza virus contains 8 different RNA strands and different strains of flu can infect a host. • If a host becomes infected with two different flu strains these strains could swap RNA strands • As a result of this gene exchange a novel, very different, flu strain might result.

37. Origins of pandemic flu strains • There is strong evidence that flu strains do swap genes. • Phylogenetic analysis of flu strains by Gorman et al. (1991) shows this.

38. Origins of pandemic flu strains • Gorman et al. (1991) determined the nucleotide sequences of influenza nucleoprotein genes. • Nucleoprotein gene apparently most important gene for determining host specificity (enables strain to infect a certain host) and tends to limit it to that species. • Thus, phylogeny of this gene should give good strain history.

39. Origins of pandemic flu strains • There are distinct clades of strains that infect mainly humans, mainly pigs, mainly birds, etc.

45. Origins of pandemic flu strains • Branch tips give date of strain and a viral subtype (e.g. H3N2). • Viral subtype specifies hemagglutinin-3 and neuraminidase-2). Neuraminidase, like hemagglutinin, is a coat protein. • The number specifies a group of proteins that provoke the same antibody response.

46. Origins of pandemic flu strains • Each hemagglutinin group constitutes a clade. H1s are more closely related to each other than H2s, etc. • Same logic applies to the neuraminidases.

47. Origins of pandemic flu strains • Examining two strains of flu from Australia in 1968 Victoria (H2N2) and Northern Territory (H3N2) shown in bold on next slide we see that they have nucleoproteins and neuraminidases that are closely related, but hemagglutinins that are distantly related.

49. Origins of pandemic flu strains • How is this possible? • Simplest explanation is that flu strains swap genes. • Before 1968 pandemic human flu strains had never carried H3. Where did H3 come from?

50. Origins of pandemic flu strains • A phylogeny of H3 strains by Bean et al. (1992) shows that human H3 branches from within the bird H3 tree.