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ECOL/MCB/CPH/VSC 409/509 Evolution of Infectious Disease Dr. Michael Worobey BSW 324 [email protected] 626-3456 Goals of the course •Learn some fundamental evolutionary theory as it relates to infectious disease •Learn about some of the evolutionary tools that are used to understand infectious disease, such as molecular phylogenetics •Acquire cutting-edge knowledge about some of the most important human infectious diseases, like HIV •Learn how to read and critique the primary scientific literature, and interpret stories in the popular media The transmissible agent causing canine transmissible venereal tumor (CTVT) is thought to be the tumor cell itself. To test this hypothesis, we analyzed genetic markers including major histocompatibility (MHC) genes, microsatellites, and mitochondrial DNA (mtDNA) in naturally occurring tumors and matched blood samples. In each case, the tumor is genetically distinct from its host. Moreover, tumors collected from 40 dogs in 5 continents are derived from a single neoplastic clone that has diverged into two subclades. Phylogenetic analyses indicate that CTVT most likely originated from a wolf or an East Asian breed of dog between 200 and 2500 years ago. Although CTVT is highly aneuploid, it has a remarkably stable genotype. During progressive growth, CTVT downmodulates MHC antigen expression. Our findings have implications for understanding genome instability in cancer, natural transplantation of allografts, and the capacity of a somatic cell to evolve into a transmissible parasite. Questions raised? SOME REASONS FOR STUDYING THE EVOLUTION OF INFECTIOUS DISEASE 1. We all have a vested interest since we’re susceptible and infectious disease touches everyone’s life - HIV, flu, colds, antibiotics, immune system SOME REASONS FOR STUDYING THE EVOLUTION OF INFECTIOUS DISEASE 2. It’s where the data are. - There is a huge amount of sequence data from medically important microbes - Viruses and bacteria were the first sequenced genomes, beguilingly simple SOME REASONS FOR STUDYING THE EVOLUTION OF INFECTIOUS DISEASE 3. “infectious disease” covers a sizable fraction of the diversity of life on Earth "So, the naturalists observe, the flea, Hath smaller fleas that on him prey; And these have smaller still to bite 'em; And so proceed, ad infinitum" --Jonathan Swift SOME REASONS FOR STUDYING THE EVOLUTION OF INFECTIOUS DISEASE 4. You can often see evolution’s fingerprint more clearly in pathogens… -microbes evolve in “real time”, fast-paced -vertebrate immune system as an evolutionary response -positive selection, amino acid by amino acid SOME REASONS FOR STUDYING THE EVOLUTION OF INFECTIOUS DISEASE 5. Infectious disease may help explain some “evolutionary scandals” such as the ubiquity of sex “Parasite Red Queen” SOME REASONS FOR STUDYING THE EVOLUTION OF INFECTIOUS DISEASE 6. We’re all shaped to a great extent by our long arms race with infectious disease agents -examples? SOME REASONS FOR STUDYING THE EVOLUTION OF INFECTIOUS DISEASE 7. Gives us a sort of crystal ball to try to predict the future. -Will HIV evolve toward low virulence? -What will next year’s flu strain look like? -How long will current malaria drugs work? Topics covered: EVOLUTION: • Brief history of evolutionary theory • The concept of natural selection • Some evolutionary themes that are relevant across many different perspectives, including those involving infectious disease: 1. 2. 3. 4. Adaptation Conflicts Trade-offs Constraints What’s the role of parasites in the biological big picture? •Sex is costly, not to mention complicated and dangerous •Searching for mates takes time and energy, and has risks (?) •Potential mates may demand additional exertion or investment before mating •After all that, mating might prove to be infertile •Why go to all the trouble? In a population conforming to JMS’s assumptions, asexual females produce twice as many grandchildren as sexuals Case study I: Parasites and the advantage of sex Which reproductive mode is better: sexual or asexual? Null model: (what a null model?) 1. A female’s reproductive mode does not affect the number of offspring she can make 2. A female’s reproductive mode does not affect the probability that her offspring will survive (John Maynard Smith, 1978) QuickTime™ and a TIF F (Uncompressed) decompressor are needed to see this picture. The central role of parasites in evolution How do humans and other animals protect themselves against pathogens? Brief history of immunology • • • Relatively new science; origin usually attributed to Edward Jenner, but has deep roots in folk medicine Jenner discovered in 1796 that cowpox (vaccinia) induced protection against smallpox Jenner called his procedure “vaccination” Brief history of immunology • • It took almost two centuries for smallpox vaccination to become universal Vaccination enabled the WHO to announce in 1979 that smallpox had been eradicated, arguably the greatest triumph in modern medicine. Figure 1-15 How does the immune system work? How do diseases evolve in response to it? What are the consequences? MHC class I molecule presenting an epitope Figure 3-23 When and how did our immune defenses come to be? Evolution of the immune system • • • The most ancient immune defenses lie within the innate immune system Drosophila spp. Have well developed innate immune system The first defense molecules in evolutionary terms were probably antimicrobial peptides, produced by plants and animals What sorts of organisms make us sick? The three domains of life BACTERIA ARCHEA * 0.1 CHANGES/SITE EUCARYA Major killers: malaria • Forty-one percent of the world's population live in areas where malaria is transmitted (e.g., parts of Africa, Asia, the Middle East, Central and South America, Hispaniola, and Oceania). • * An estimated 700,000-2.7 million persons die of malaria each year, 75% of them African children. • * In areas of Africa with high malaria transmission, an estimated 990,000 people died of malaria in 1995 – over 2700 deaths per day, or 2 deaths per minute. Global impact of HIV/AIDS Are parasites always “bad”? evolutionary innovations through symbiosis: examples • Eukaryotic cell (mitochondria) • Photosynthesis in eukaryotes (plastids) • Colonization of land by plants (mycorrhizae) • Nitrogen fixation by plants (rhizobia) • Animal life at deep sea vents (chemoautotrophic life systems) • Use of many nutrient-limited niches by animal lineages Why do hosts and symbionts cooperate so often? • Persistent association allows both to increase their persistence and replication. – Coinheritance – Long-term infection • Intimate metabolic exchange generating immediate beneficial feedback late embryos maternal bacteriocytes containing symbionts early embryos with symbionts visible 1 mm J. Sandström host aphid gene phylogeny Buchnera gene phylogeny Aphididae Uroleucon & relatives Pemphigus betae Ac yrthosi phon pi sum origin of symbiosis Sc hl ec tendalia c hinensi s Mac ros iphum ros ae Uroleuc on eri geronense Mel aphis rhois Uroleuc on caligatum Chaitophorus viminalis Uroleuc on rurale Uroleuc on helianthic ol a Mindarus ki ns eyi Uroleuc on jaceicola Uroleuc on sonc hi Uroleuc on ob sc urum Uroleuc on rapunculoides Ac yrthosi phon pi sum Uroleuc on sonc hi Mac ros iphum ros ae Myzus pers ic ae colonization of Asteraceae <20 Mya Uroleuc on solidaginis Uroleuc on jaceae Uroleuc on aeneum Rhopalosi phum padi ancestor of extant aphids 100-200 Mya Uroleuc on rudbeck iae Sc hi zaphis grami num Rhopalosi phum mai dis Uroleuc on as tronomus Uroleuc on ambrosi ae ->Strict vertical transmission since ancient infection of ancestral host Use of modified bacteria to manipulate natural communities to prevent disease states? Streptococcus mutans--recombinant does NOT make lactic acid (cavity-causing agent) makes toxin against competing (cavity inducing) strains persists for life and prevents cavities? Why are some parasites so virulent compared with others? The Evolution & Ecology of Infectious Disease Why are some species pathogenic to humans while other (closely-related) species are not? This question can approached from two directions: 1.From the point of view of the host. What specific defense mechanisms of the host allow it to suppress infection (entry, attachment, invasion, replication) by certain agents and not others? 2.From the point of view of the pathogen. What are the differences between the agents that cause disease and those that do not? Inferrring lateral gene transfer (LGT) from sequence heterogeneity along the chromosome Neisseria meningitidis, 52% G+C (from Tettelin et al. 2000. Science) Yersinia pestis: Rapid evolution of an enteric pathogen Three (of the 11) species of Yersinia are pathogenic to humans: Y. enterocolitica & Y. pseudotuberculosis cause gastroenteritis, whereas Y. pestis is the causative agent of the bubonic plague. Three known plague pandemics: Justinian, 541-767; Black Death, 1346-1800s; Modern 1894-present The classis example: Myxoma virus • • • • • • Pox virus introduced into Australia to control European rabbit populations Vectored by mosquitos and fleas, skin lesions Initially the virus was extremely virulent (99%) mortality A sharp drop in virulence was initially observed However, the circulating virus remained much more virulent than lab strains Positive coupling between transmission and virusinduced mortality 1. Think globally, act locally. 2. Given enough time a state of peaceful coexistence eventually becomes established between any host and parasite. -Rene Dubos Quic kT i me™ and a T IFF (Unc ompres s ed) dec ompres s or are needed t o s ee thi s pi c ture. Trade-offs How do our immune defenses shape the evolution of pathogens? natural selection How do pathogens circumvent our defenses? •The surface of a trypanosome is covered with variantspecific glycoprotein (VSG) •There are about 1000 different VSG genes •Upon initial infection, antibodies are raised against the VSG initially expressed • Initial infection by herpes simplex virus in the skin is cleared Figure 11-4 by an effective immune response •But residual infection persists in sensory neurons •When the virus is reactivated, the skin is re-infected. This can be repeated endlessly Figure 11-5 part 3 of 3 How have pathogens shaped human (and deeper) evolution? How has disease impacted human evolution? What techniques are used to test evolutionary hypotheses regarding infectious disease? Molecular phylogenetics fundamentals All of life is related by common ancestry. Recovering this pattern, the "Tree of Life", is one of the primary goals of evolutionary biology. Even at the population level, the phylogenetic tree is indispensable as a tool for estimating parameters of interest. Likewise at the among species level, it is indispensable for examining patterns of diversification over time. First, you need to be familiar with some tree terminology. How can evolutionary insights help control pathogens? Antiretroviral therapy • Currently, combination therapy involves some combination of reverse transcriptase inhibitors and protease inhibitors How does drug resistance evolve? How should it be avoided? Why do we get sick? or Why are humans not perfect (present company excepted)? • • Also pain, nausea, vomiting, diarrhea, anxiety, fatigue, sneezing, inflammation, anaemia, morning sickness Do we do a disservice by blocking these defenses? Case study: fever and neurosyphilis • Julius Wagner-Jauregg noted that some syphilis patients improved after getting malaria and that syphilis was rare in areas where malaria was common • intentionally infected thousands of syphilis patients with malaria • remission rates for syphilis increased from less than 1 percent to 30 percent • Won the 1927 Nobel Prize for medicine or physiology, but isn’t talked about much these days… Where did HIV/AIDS come from? When? How? Will avian flu jump into humans? Why do we have to keep developing new vaccines against flu? (5) Predicting the future of influenza Next class: Evolutionary fundamentals…. 1. Stearns handout 2. Darwin reading: http://www.literature.org/authors/darwin-charles/the-originof-species/