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The Evolution of Virulence

The Evolution of Virulence. Lecture Outline Introduction to virulence theory Transmission mode experiment Transmission timing experiment Metapopulation experiment Summary. A Model Host-Pathogen System. T4. reproduction. dilution. dilution. infection. dilution.

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The Evolution of Virulence

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  1. The Evolution of Virulence • Lecture Outline • Introduction to virulence theory • Transmission mode experiment • Transmission timing experiment • Metapopulation experiment • Summary

  2. A Model Host-Pathogen System T4 reproduction dilution dilution infection dilution • We used Escherichia coli (host) and phage T4 (pathogen) to study the dynamics of a large host-pathogen metapopulation. • Bacteria and virus are grown in microtiter plates, which impose a metapopulation structure. E. coli • Bacteria and phage do not coexist in a well. There are three types of wells: empty, bacteria-filled, and phage-filled, exhibiting “rock-paper-scissors” • The transitions in the state of any well (due to dilution or immigration) can be gauged empirically and organized into a transition matrix.

  3. Stochastic Cellular Automata phage density (107/mL) bacteria Restricted F time phage density (107/mL) Unrestricted F bacteria time Migration Pattern Ecological Dynamics Spatial Dynamics Predictions: Under restricted migration, (1) metapopulation dynamics are more stable (2) phage mean density is lower and bacterial mean density is higher

  4. True Cellular Automata m Restricted Unrestricted metapopulations m sterile shell Ecological Dynamics Spatial Dynamics Migration Pattern arm Predictions: Under restricted migration, (1) metapopulation dynamics are more stable (2) phage mean density is lower and bacterial mean density is higher

  5. Evolved Phage Properties • For each evolved isolate, we measured: • productivity: the average number of progeny phage per parent • competitive ability: how well the evolved isolate does in head-to-head competition with a marked mutant • In both cases, we controlled for the initial ratio of phage to bacteria (called the “multiplicity of infection”) • Restricted phage were significantly more productive • Unrestricted phage were significantly more competitive • After pooling the data, we found (for 2 of 3 MOI levels) a significant negative correlation between productivity and competitive ability.

  6. A Microbial ‘Tragedy’ rapacious competitive ability prudent productivity dilution dilution dilution dilution reproduction & competition dilution • Different migration treatments have evolutionarily favored different strategies: • “Rapacious” phage in the Unrestricted treatment • “Prudent” phage in the Restricted treatment. • We have a tragedy of the commons: phage evolve in the Unrestricted treatment phage persist in the Restricted treatment • Rapacious phage outcompete prudent phage in a mixed population • Pure wells of prudent phage have higher progeny outputs than pure wells of rapacious phage. • Why are rapacious phage found in the Unrestricted treatment? • As rapacious mutants are generated, they take over, lowering productivity • Less productive phage are less persistent. • The probability of migration to hosts is lower in the Restricted treatment • This limited host access in the Restricted treatment makes rapacious phage extinction-prone reproduction reproduction

  7. Averting the Tragedy of the Commons Unrestricted: Tragedy Realized prudent phage density (107/mL) rapacious phage rapacious phage bacteria time Restricted: Tragedy Averted density (107/mL) bacteria prudent phage rapacious phage rapacious phage time Rapacious phage fare better in the Unrestricted treatment for two reasons: 1) Mixing of phage types is more likely (leading to more tragedies) 2) Persistence is less important (any well’s tragedy is less severe) Restricted Migration with Evolution Take 3 minutes to talk to your neighbor about the following: So far the description of rapacious and prudent phage has been at the population level. What would you want to know about the phage itself in terms of its evolution? What would you want to know phenotypically? Genetically?

  8. The Evolution of Phage Life History Lytic phage life cycle • The life cycle of lytic phage: • Adsorption to host and injection of phage genome • Production of progeny particles in the host • Lysis of the host and progeny release • Phage evolved under Unrestricted Migration are more infective, virulent, and tend to be shorter-lived outside their host. phage (pathogen) adsoption & injection bacteria (host) progeny production host lysis

  9. From Demes to Genes rIA mutant rIB mutant wild type OUTSIDE HOST CELL outer membrane periplasmic space T T T T T RI RI inner membrane INSIDE HOST CELL •••TAAAAAT••• E E E E E E E E E wild-type •••TAAAAT••• rI mutant • Current working model (Tran et al. 2005): • At a specific time, holins disrupt the inner membrane allowing endolysin to pass. • Cell wall is degraded and the cell lyses. • Progeny phage are released. • Gene t is an attractive candidate locus: • Non-synonymous mutations in holins produce different latent periods. • Null mutants overproduce progeny without lytic release (‘t’ from Tithonus) • We found no mutations in gene t. • Gene rI codes for an antiholin that forms a complex with the holin; mutations in rI can hasten lysis (shorten latent period). • We found two unique deletions in rI: • More rI mutants were found in the Unrestricted treatment. • The rI mutations are sufficient to have visible effects on the host population.

  10. A Genetic Basis for the Tragedy of the Commons phage (pathogen) adsoption & injection bacteria (host) progeny production host lysis • Relative to wild type, the engineered rI mutants have: • A shorter latent period • A smaller burst size • Relative to wild type, the engineered rI mutants are: • More competitive for hosts • Less productive when alone • Mutations at rI are sufficient to generate a tradeoff between competitive ability and productivity. • Thus, we have rapacious and prudent alleles at the rI locus: a genetic basis of the tragedy of the commons.

  11. Acknowledgements Roxy Vouk Christal Eshelman Jodi Stewart Josh Nahum Jake Cooper Sterling Sawaya Brandon Rogers Spencer Smith Chris Shyue Stacy Schneider Mily Gualu Kelsea Laegreid Yen Nhan Dang Kelsey Hobbs Sara Drescher Shawn Decew Beth Halsne

  12. The Evolution of Virulence • Lecture Outline • Introduction to virulence theory • Transmission mode experiment • Transmission timing experiment • Metapopulation experiment • Summary

  13. Summary • Virulence is the damage to a host caused by an inhabiting pathogen (increased mortality, decreased reproduction, etc.) • Virulence varies between and within pathogen species (both naturally and in the laboratory). • The conventional wisdom is that virulence should decrease evolutionarily, but it is sometimes predicted to increase if it trades off with transmission or within host competition. • Many factors (host density, superinfection frequency, environmental reservoirs) will affect the predicted level of virulence and some of these factors have been experimentally tested: • - Bull et al. found higher virulence in a phage pathogen under horizontal transmission. • - Cooper et al. found higher virulence in an insect pathogen under early transmission. • - The pattern of migration in a metapopulation can affect the evolution of virulence

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