The molecular arms race

1. Microbial evolution and infectious disease The molecular arms race Dr Sham Nair Department of Biological Sciences Faculty of Science Macquarie University snair@bio.mq.edu.au

2. Definitions • Microbes: microorganisms • Pathogens: microbes that causes disease • Host: usually multicellular organisms that harbour microbes • Epidemics: localiseddisease outbreaks that affect a number of people in a population. • Pandemics: disease outbreaks that occurs over a very large area.

3. DNA – the thread of life • DNA – deoxyribonucleic acid • All cells contain DNA • Encodes all phenotypic traits • A language of 4 alphabets (A, T, C and G) http://www.myheritageimages.com/H/storage/blogs/genealogyblog/MH_DNA_redblue_jan09.jpg

4. Mutations: changes to the script of life • Mutations are changes to DNA sequences. • Most mutations have no impact. • Mutations result in natural genetic variations in populations. 5th edition 6th edition 7th edition 8th edition

5. Natural selection acts on genetic variations Natural selection acts on mutations (Gould and Keeton,Biological Sciences, Norton Publishing, 1996) Beneficial mutations propagate in a population as a result of sexual reproduction

6. Host-microbe interactions • The human body contains about 1013 human cells and also about 1014 microbial. • A place to call home: a human host is a nutrient-rich, warm (constant temperature) and moist environment. Hence, microbes love to colonize and survive in/on our bodies.

7. Good bugs • Many infecting microbes remain unnoticed. • Many bacteria play important roles in human physiology. • Intestinal bacteria help digest food and provide essential nutrients (Vit K) • They are also essential for proper development of the gastrointestinal tract in infants. • Normal skin flora help prevent infections. • Disease is NOT the inevitable outcome of a host-microbe interaction

8. Immunity to infections • Physical barriers prevent the entry of most microbes into the human body. • Invading pathogens are confronted with a vast array of anti-microbial weapons. • Anti-microbial peptides • Antibodies • Microbe-destroying cells (white blood cells)

9. Infectious diseases • Infectious diseases cause about one-third of all human deaths in the world (more than all forms of cancer combined). • Antibiotics and vaccinations were very successfully in controlling infectious diseases. • “It is time to close the book on infectious diseases.” U.S. Surgeon General (1965)

10. Pathogen evolution and virulence genes • Pathogens evolve rapidly, while multicellular organisms evolve slowly. • Whereas humans and chimpanzees have acquired a 2% difference in genome sequences over about 8 million years of divergent evolution, poliovirus manages a 2% change in its genome in 5 days, about the time it takes the virus to pass from the human mouth to the gut! • Different strains of E. coli may differ by as much as 25% in their genomes. • Genes that contribute to the ability of an organism to cause disease are called virulence genes.

11. Pathogen evolution I Acquiring new virulence genes - bacteriophages

12. Cholera epidemics http://www.mansfield.ohio-state.edu/~sabedon/images/phage_attack_t_001_001.jpg http://dhiez.files.wordpress.com/2008/05/cholera.jpg http://images.clipartof.com/small/5725-Sick-Man-Sitting-In-A-Chair-Clipart-Illustration.jpg

13. Evolution of pathogenic Vibrio (1961) (1817-1923) (1991)

14. Pathogen evolution II Errors during viral replication

15. Errors during viral replication – Human Immunodeficiency Virus • HIV infects human white blood cells and causes the immune system to collapse (AIDS – Acquired Immune Deficiency Syndrome). • HIV is an RNA retrovirus and acquires on average one point mutation every replication cycle • Resistance to anti-viral drugs rapidly appears in patients undergoing chemotherapy. • The most virulent type of HIV, HIV-1, may have jumped from chimpanzees to humans as recently as 1930.

16. Evolution of drug resistance in HIV In a just a few weeks, 3TC resistant HIV made up 100% of the virus population in each case.

17. Evolution of the HIV

18. Pathogen evolution III Horizontal Gene Transfer

19. Horizontal Gene Transfer • Horizontal gene transfer often causes rapid evolution in bacteria. • Once a bacterium acquires a new set of virulence-related genes, it may quickly cause human epidemics. • Yersinia pestis, for example, is a bacterium endemic to rats and other rodents; it first appeared in human history in 542 A.D. 25 million people died of the plague. http://www.bio.hbnu.edu.cn/wdwsw/newindex/tuku/MYPER/zxj/zxjimage/97241a.jpg

20. Antibiotic resistance • Antibiotics, which kill bacteria, comprise the most successful class of interventions that cure rather than treat infections. • The rapid evolution of pathogens, however, enables bacteria to develop resistance to antibiotics very quickly. • It takes only a couple of years before resistance to newly developed antibiotics is observed. • It took 15 years for vancomycin resistance to develop – development of the superbug (MRSA).

21. Antibiotic abuse and resistance • Persistent and chronic misuse of antibiotics can eventually result in the evolution of antibiotic-resistant pathogens. • Antibiotic-resistant Shigellaflexneri originated in this way. • In Brazil, antibiotics are available without physician’s prescription. More than 80% of the strains of S. flexneri found in infected Brazilian patients are resistant to four or more antibiotics. • Antibiotics misuse in agriculture: an antibiotic closely related to vancomycin was used in cattle feed in Europe; the resulting resistance in the normal flora of these animals is widely believed to be one of the original sources for vancomycin-resistant bacteria that now threaten the lives of hospitalized patients.

22. Natural drug resistance • Bacteria commonly exchange genetic material across species boundaries. • Drug-resistance genes come from environmental reservoirs, where they play an important part in the competition between microorganisms. • Natural resistance to 7 or 8 antibiotics in clinical use already exist in unexposed soil bacteria. • Microbes can draw upon this world-wide and essentially inexhaustible source of genetic material to acquire resistance.

23. Pathogen evolution IV Genome recombinations in different hosts

24. Influenza epidmics – recombination betwwen flu viruses? http://www.drugdevelopment-technology.com/projects/fludase/images/1-influenza.jpg H: hemagglutinin N: neuraminidase Strains: e.g. H1N1

25. Most recent epidemic: swine flu • Bird and human flu viruses have been mixing in pigs (“triple-reassortant” viruses). • The immediate ancestors of swine flu virus have been present in pigs for about a decade. • The virus made the leap to humans around January 2009. http://chickenoreggblog.files.wordpress.com/2009/06/swinefluevolution1.jpg

26. Human evolution • Constant exposure to pathogens has strongly influenced human evolution. • 2 examples: • Malaria and sickle cell anemia • Resistance to HIV infections

27. Malaria • Malaria is a strong selective pressure on human populations, especially in areas of Africa. • It is caused by the parasite, Plasmodium falciparum. • Sickle-cell anemia is a genetic disease that causes red blood cells to deform and dysfunction. • The malarial parasites grow poorly in the deformed red blood cells from either sickle-cell patients or healthy carriers, and, as a result, malaria is seldom found among carriers of this mutation. • For this reason, malaria has served to maintain the otherwise deleterious sickle-cell mutation at high frequency in these regions of Africa.

28. Malaria and the selection for sickle cell anaemia allele http://www.bsw-uiuc.net/tutinf/sickle/introduction/image002.jpg

29. Resistance to HIV infections • Early in an infection, most of the viruses use CCR5 as a co-receptor, allowing them to infect macrophages. • As the infection progresses, mutant variants arise that now use CXCR4 as a co-receptor, enabling them to infect helper T cells. • Individuals fortunate enough to carry a defective Ccr5 gene are not susceptible to HIV infection.

30. Conclusion 1 • Host-pathogen interactions results in a constant arms race for survival – this contributes to both host and pathogen evolution: the Red queen hypothesis • Pathogen evolution is not directed at harming the host – sometimes, disease is the result of our immune responses to infection. • It is in the pathogens’ interest to keep the host alive. THEORY OF THE RED QUEEN (the Red Queen from Alice Through the Looking Glass was forced to constantly run against a howling gale. She made no headway, but had to run all the time simply to stop from being blown backwards) (http://www.1st-art-gallery.com/thumbnail/188618/1/Alice-And-The-Red-Queen,-Illustration-From-Through-The-Looking-Glass-By-Lewis-Carroll-1832-98-First-Published-1871.jpg)

31. Conclusion 2 • Natural selection is an editing process rather than a creative process. • E.g. a drug does not create resistant pathogens, but selects for resistant individuals already present in the population • Natural selection favours genetic variations in a population that provide an advantage in the current, local environment.

32. “There is grandeur in this view of life … [in which] endless forms most beautiful and most wonderful have been, and are being, evolved.” Charles Darwin The Origin of Species