ECOL/MCB/CPH/VSC 409/509ECOL/MCB/CPH/VSC 409/509

Evolution of Infectious DiseaseEvolution of Infectious Disease

Dr. Michael WorobeyDr. Michael WorobeyBSW 324BSW 324

worobey@email.arizona.eduworobey@email.arizona.edu626-3456626-3456

Goals of the courseGoals 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: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. Adaptation2. Conflicts3. Trade-offs4. Constraints

What’s the role of parasites in the biological big picture?

•Sex is costly, not to mention complicated and Sex is costly, not to mention complicated and dangerousdangerous

•Searching for mates takes time and energy, and has Searching for mates takes time and energy, and has risks (?)risks (?)

•Potential mates may demand additional exertion or Potential mates may demand additional exertion or investment before matinginvestment before mating

•After all that, mating might prove to be infertileAfter all that, mating might prove to be infertile

•Why go to all the trouble?Why go to all the trouble?

In a population conforming to JMS’s assumptions, In a population conforming to JMS’s assumptions, asexual females produce twice as many grandchildren asexual females produce twice as many grandchildren

as sexualsas sexuals

Which reproductive mode is better: sexual or asexual?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)

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Case study I: Parasites and the advantage of sexCase study I: Parasites and the advantage of sex

The central role of parasites in evolution

How do humans and other animals protect themselves against pathogens?

Brief history of Brief history of immunologyimmunology

• 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 Brief history of immunologyimmunology

• 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 1-15Figure 1-15

How does the immune system work?How do diseases evolve in response to it?What are the consequences?

Figure 3-23Figure 3-23MHC class I molecule presenting an MHC class I molecule presenting an

epitopeepitope

When and how did our immune defenses come to be?

Evolution of the immune Evolution of the immune systemsystem

• 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?

ARCHEA

BACTERIA

EUCARYA

0.1 CHANGES/SITE

*

The three domains of lifeThe three domains of life

Major killers: malariaMajor 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/AIDSGlobal impact of HIV/AIDS

Are parasites always “bad”?

evolutionary innovations evolutionary innovations through symbiosis: examplesthrough symbiosis: examples

• Eukaryotic cell (mitochondria)Eukaryotic cell (mitochondria)• Photosynthesis in eukaryotes (plastids)Photosynthesis in eukaryotes (plastids)• Colonization of land by plants Colonization of land by plants

(mycorrhizae)(mycorrhizae)• Nitrogen fixation by plants (rhizobia)Nitrogen fixation by plants (rhizobia)• Animal life at deep sea vents Animal life at deep sea vents

(chemoautotrophic life systems)(chemoautotrophic life systems)• Use of many nutrient-limited niches by Use of many nutrient-limited niches by

animal lineages animal lineages

Why do hosts and symbionts cooperate Why do hosts and symbionts cooperate so often? so often?

• Persistent association allows both to increase their persistence Persistent association allows both to increase their persistence and replication. and replication. – Coinheritance Coinheritance – Long-term infectionLong-term infection

• Intimate metabolic exchange generating immediate beneficial Intimate metabolic exchange generating immediate beneficial feedbackfeedback

maternal bacteriocytes containing symbionts

early embryos with symbionts visible

late embryos

J. Sandström

1 mm

colonizationof Asteraceae<20 Mya

ancestor ofextant aphids 100-200 Mya

Uroleucon & relatives

origin ofsymbiosis

host aphid gene phylogeny Buchnera gene phylogeny

AphididaePemphigus betae

Schlectendalia chinensis

Melaphis rhois

Chaitophorus viminalis

Mindarus kinseyi

Uroleucon sonchi

Acyrthosiphon pisum

Macrosiphum rosae

Myzus persicae

Rhopalosiphum padi

Schizaphis graminum

Rhopalosiphum maidis

Acyrthosiphon pisum

Macrosiphum rosae

Uroleucon erigeronense

Uroleucon caligatum

Uroleucon rurale

Uroleucon helianthicola

Uroleucon jaceicola

Uroleucon obscurum

Uroleucon rapunculoides

Uroleucon sonchi

Uroleucon solidaginis

Uroleucon jaceae

Uroleucon aeneum

Uroleucon rudbeckiae

Uroleucon astronomus

Uroleucon ambrosiae

->Strict vertical transmission since ancient infection of ancestral host->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?

Why are some species pathogenic to Why are some species pathogenic to humans while other (closely-related) humans while other (closely-related)

species are not?species are not?

The Evolution & Ecology of Infectious The Evolution & Ecology of Infectious DiseaseDisease

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 Inferrring lateral gene transfer (LGT) from sequence heterogeneity along the chromosomesequence heterogeneity along the chromosome

Neisseria meningitidis, 52% G+C

(from Tettelin et al. 2000. Science)

Yersinia pestis: Rapid evolution of an enteric Yersinia pestis: Rapid evolution of an enteric pathogenpathogen

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 The classis example: Myxoma virusvirus• 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 virus-

induced 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

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Trade-offs

How do our immune defenses shape the evolution of pathogens?

natural selectionnatural selection

How do pathogens circumvent our defenses?

•The surface of a trypanosome is covered with variant-specific glycoprotein (VSG)

•There are about 1000 different VSG genes

•Upon initial infection, antibodies are raised against the VSG initially expressed

Figure 11-4Figure 11-4• Initial infection by herpes simplex virus in the skin is cleared 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 3Figure 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 fundamentalsMolecular phylogenetics fundamentalsAll 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 therapyAntiretroviral 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 neurosyphilisCase 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(5) Predicting the future of influenza

Next class:

Evolutionary fundamentals….

1. Stearns handout

2. Darwin reading:http://www.literature.org/authors/darwin-charles/the-origin-of-species/