DETERMINANTS OF DENGUE VIRUSPHYLODYNAMICS
JOSÉ LOURENÇOUNIVERSITY OF OXFORDZOOLOGY DEPARTMENT
2ND YEAR PHD STUDENTPROGRAMA DE DOUTORAMENTO EM BIOLOGIA COMPUTACIONALINSTITUTO GULBENKIAN DE CIÊNCIA
THE CASE OF SPORADIC POSITIVE SELECTION
JOSÉ LOURENÇO (PHD STUDENT) | EUROPEAN CONFERENCE ON MATHEMATICAL AND THEORETICAL BIOLOGY 2011, KRAKÓW, POLANDJOSÉ LOURENÇO (PHD STUDENT) | EUROPEAN CONFERENCE ON MATHEMATICAL AND THEORETICAL BIOLOGY 2011, KRAKÓW, POLAND 1 / 20
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DENGUE: DISEASE AND VIRUS DENGUE: DISEASE AND VIRUS
DENGUE DISEASE:
➔ Most cases are selflimited or clinically silent➔ Occasionally result in a febrile illness Dengue Fever (DF)➔ Rarely progresses to severe lifethreatening illnesses: Dengue Haemorrhagic Fever (DHF), Dengue Sock Syndrome (DSS)
DENGUE VIRUS:
➔ Dengue virus (DENV) is a RNA virus transmitted mainly in urban and periurban settings by the A. aegypti and A. albopictus mosquitoes ➔ 4 closely related serotypes – DENV1, DENV2, DENV3 and DENV4
ANTIBODY DEPENDENT ENHANCEMENT:
➔ Whereby subneutralizing antibodies from primary infection can mediate viral entry into host cells leading to increased replication and disease manifestations
IMMUNITY: ➔ Homotypic: recovery provides lifelong protection to the infecting serotype➔ Heterologous: recovery provides shortterm immunity to all serotypes
MOTIVATION, PHD PROJECTMOTIVATION, PHD PROJECT
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mechanismsat the
individual andpopulation
levels
phylogeneticpatterns
epidemiologicalpatterns
RECKER et al. Proc. R. Soc. B 2009
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EPIDEMIOLOGYEPIDEMIOLOGY
DETERMINANTS:
➔ Competition for susceptibles➔ Immune interactions➔ ADE➔ Vector population dynamics
PHYLOGENETICSPHYLOGENETICS
GRENFELL et al. Science 2004
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Genotypes
TRANSMISSION BOTTLENECKS
SPORADIC ADAPTIVE MUTATIONS
(...)
purifying selection
positive selection
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SELECTIVE PHYLOGENETIC DETERMINANTSSELECTIVE PHYLOGENETIC DETERMINANTS
HOST POPULATION BOTTLENECKS
season x season x+1 season x+n
severepopulation
bottleneck(...)
severepopulation
bottleneck
HOST POPULATION STRUCTURE
geneticdrift
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NONSELECTIVE PHYLOGENETIC DETERMINANTSNONSELECTIVE PHYLOGENETIC DETERMINANTS
spatial andtemporalclustering
INTRIGUING ASPECTS:
➔ Time to detection: phylogenetics suggest Asian1 was introduced in the late 90's but first detected in 2003
➔ Relative fitness: replacement was fast enough to suggest significant fitness advantage but no visible epidemiological change was found in data
➔ Hypothesis: Increased viraemia levels in patients infected with Asian1
➔ Observation: Replacement of DENV2 resident genotype (Asian/American) by a new genotype (Asian1) in SouthEast Asia
HANG et al. PLoS NTD 2010
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STUDY CASE: POSITIVE SELECTIONSTUDY CASE: POSITIVE SELECTION
OBJECTIVE OF THE STUDYOBJECTIVE OF THE STUDY
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To address whether classical epidemiological models can helps us understand events at the (phylo)genetic level, and viceversa
STRATEGY: ➔ Using a 4 serotype epidemiological model based on the main classical biological assumptions➔ Analyzing the dynamics of invasion and fixation of new emerging genotypes➔ Focusing on a specific case study as a starting point
HUMAN POPULATION:
VECTOR POPULATION:
➔ extended SIR with 4 serotypes
➔ lifelong homotypic immunity
➔ temporary heterologous immunity
➔ 2 infections – complete immunity
➔ ADE in heterologous infections
➔ no exposed/latent periods
➔ seasonality in biting rate
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THE MODEL FRAMEWORKTHE MODEL FRAMEWORK
MODEL OUTPUT, FITNESS ASSUMPTIONMODEL OUTPUT, FITNESS ASSUMPTION
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Fitness advantage due to increased humantovector transmission
RESULTS: INVASION & FITNESSRESULTS: INVASION & FITNESS
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LOURENÇO & RECKER PLoS NTD 2010
Low advantage (4.5%)
➔ Fixation within the time scale of field observations➔ Cyclical serotype behaviour remains invariant➔ No signature is present in incidence series
➔ A period of low frequency circulation is also observable in accordance with what phylogenetic data proposed
High advantage
● Fixation in a few seasons ● Incidence and serotype patterns are disrupted● Future persistence is hampered after a major outbreak
Phase I: period of low frequency 'emergence phase'
Phase II: rapid shift in dominance'replacement phase'
'replacement phase' is independent of the time point of introduction
Implying that...
'emergence phase' Is dependent on the time point of introduction
LOURENÇO & RECKER PLoS NTD 2010
Phase I
Phase II
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RESULTS: PHASES OF INVASIONRESULTS: PHASES OF INVASION
INITIAL ANALYSIS SUGGESTED:
➔ Small fitness differences are sufficient to explain the data
➔ Two phases of the invasion process: 'emergence and replacement phases'
➔ For fixed fitness levels, the epidemiological landscape at time of introduction strongly impacts the amount of time a new emerging genotype circulates in low relative frequencies in the population
BUT... IN FACT:
In a more realistic scenario, long periods of low frequency would correlate with high risk of stochastic extinction for newly arising genotypes
➔ these conclusions might not hold if extinction is considered in the simulations
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CONCLUSIONS I CONCLUSIONS I
Fitness advantage levels behave qualitatively equal to the ODE model (not shown)
LOURENÇO & RECKER PLoS NTD 2010
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STOCHASTIC SIMULATIONS STOCHASTIC SIMULATIONS
➔ Genotypes that reach fixation will suffer longer 'emergence times' if the serotype to which they belong is present at high prevalence levels
LOURENÇO & RECKER PLoS NTD 2010
Intraserotype competition induces long periods of low frequency circulation
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RESULTS: EMERGENCE PHASE/TIME RESULTS: EMERGENCE PHASE/TIME
It strongly varies depending on:
➔ Total number of infected at introduction
Highlighting strong interserotype competition
➔ Prevalence of the serotype to which it belongs
Highlighting strong intraserotype competition
Success Rate (SR)Probability of an invading genotype to reach fixation in N stochastic simulations
LOURENÇO & RECKER PLoS NTD 2010
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RESULTS: SUCCESS RATE OF INVASIONRESULTS: SUCCESS RATE OF INVASION
SMALL FITNESS DIFFERENCES:
Observed replacement events can be explained by competition between genotypes of relatively small fitness differences, which, although sufficient for intraserotype displacement, do not interfere with the overall interserotype dynamics
EPIDEMIOLOGICAL LANDSCAPE HAMPERS EMERGENCE:
Intra and interserotype interactions have a big influence on viral evolution by:
➔ reducing the success rate of new genotypes➔ forcing new genotypes to undergo 'emergence times' of several years prior reaching
sufficiently large population sizes to escape the risk of extinction
OUR RESULTS DEMONSTRATE THAT:
Even beneficial mutants are under sever threat of extinction.
This in turn suggests that apart from purifying selection reflected in data, viral competition and genetic drift beyond seasonal bottlenecks are equally important in shaping DENV evolution.
As a consequence, viral variants might be more common than previously accepted.
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CONCLUSIONS II CONCLUSIONS II
?spatial patterns
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CURRENT AND FUTURE WORK CURRENT AND FUTURE WORK
Impact of nonselective forces on dengue's epidemiology and evolutionary patterns
Host population structure
Individualbased metapopulation model
FUNDING:
➔ FCT (Fundação para a Ciência e Tecnologia, Portugal)➔ Siemens Portugal (PDBCIGC)
HOSTING:
➔ IGC (Instituto Gulbenkian de Ciência, Lisbon)➔ Zoology Department (University of Oxford, Oxford)
PEOPLE:
➔ Mario Recker (Supervisor, University of Oxford, Oxford)➔ Cameron Simmons (Oxford University Clinical Research Unit, Ho Chi Minh City)➔ Maíra Aguiar (Centro de Matemática e Aplicações Fundamentais, Lisbon)
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ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS