VIRUS INFLUENZA E O ORGANISMO HUMANO Influenza virus and ...
Influenza virus evolution…getting personal...% Outpatient visits for influenza like illness...
Transcript of Influenza virus evolution…getting personal...% Outpatient visits for influenza like illness...
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Adam LauringDepartment of Medicine, Infectious DiseasesDepartment of Microbiology and ImmunologyUniversity of Michigan
Influenza virus evolution…getting personal
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Why influenza evolution?
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Engines of genetic diversity
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Influenza A virus, what you need to know
Medina and Garcia-Sastre, Nat Rev Micro 2011
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A review of some population genetics
Mutation
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Mutation Selection
A review of some population genetics
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Mutation Selection
Genetic Drift
A review of some population genetics
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Mutation Selection
Genetic Drift Migration
A review of some population genetics
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Antigenic drift and seasonal influenza
Smith et al. Science 2004
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Global evolution of seasonal influenza viruses
Rambaut et al. Nature 2008
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Understanding evolution across scales
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What is the influenza virus mutation rate?
• Sequencing assays- Bias- Lack of power
• Genetic markers- Only measure some classes
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What is the influenza virus mutation rate?
Pauly et al. eLife 2017
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Influenza mutation rate…2-3 per replicated genome
1.8 x 10-4 2.5 x 10-4
Pauly et al. eLife 2017
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Are mutations generally good or bad?
Visher et al. PLoS Pathogens 2016
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The distribution of fitness effects in influenza A
Visher et al. PLoS Pathogens 2016
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Understanding evolution across scales
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How does influenza evolve in people?
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Within host selection?
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Do vaccine-induced antibodies select for escape variants?
• FLUVACS study, 2004-2008
• Last placebo controlled RCT
• 60-70% efficacy
• 5119 person years of observation
• 166 samples analyzed
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Pre-season serostatus of sampled individuals
Debbink et al, PLoS Pathogens 2017
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Pre-existing antibodies do not impact within host diversity
Debbink et al, PLoS Pathogens 2017
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No evidence for positive selection of antigenic variants
Debbink et al, PLoS Pathogens 2017
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Evolutionary forces
Mutation Selection
Genetic Drift Migration
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How does influenza virus evolve in people?
?• Household influenza vaccine effectiveness
- Prospective household cohort- Families ≥ 4, 2 children- > 6000 person years of observation- 249 samples, 200 individuals
• Transmission pairs within households
• Next generation sequencing- Infer transmission and bottleneck- Define within host dynamics
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Study design
Cross-sectional study Longitudinal study
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Within host genetic diversity is low
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Little evidence for positive selection
Season Subtype Frequency Mutation Site10/11 H3N2 0.07 E62G E10/11 H3N2 0.09 L86I E11/12 H3N2 0.07 V297A C12/13 H3N2 0.07 I214T D13/14 H1N1 0.02 R208K Ca14/15 H3N2 0.18 F193S B14/15 H3N2 0.11 T128A B14/15 H3N2 0.41 I260V E14/15 H3N2 0.03 S262N E14/15 H3N2 0.36 G208R D14/15 H3N2 0.03 A163T B14/15 H3N2 0.12 I307R C14/15 H3N2 0.04 K189N B14/15 H3N2 0.03 D53E C14/15 H3N2 0.02 S312G C14/15 H3N2 0.03 I242T D14/15 H3N2 0.16 I242L D14/15 H3N2 0.16 I307R C
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Study design
Cross-sectional study Longitudinal study
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Within host dynamics, 2014-2015 season
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Within host dynamics, 2014-2015 season
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Within host dynamics, 2014-2015 season
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Selection vs. Drift….depends on population size
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Describing within host processes – effective population size
999,999 Hens ; 1 Cock
Census Population : 1,000,000
Effective Population: 4
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Describing within host processes – effective population size
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Diffusion models to estimate effective population size
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Genetic drift is a dominant force in small populations
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What happens between hosts?
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Sequence based inference of 41 transmission pairs
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Bottleneck size – presence/absence model
Mean Bottleneck = 1.68Probability of >5 is 0.0017
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Bottleneck size – beta binomial model
Sobel et al. JVI 2017
Mean Bottleneck 1.7
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Evolution within and between hosts
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Evolution across scales
Very high mutation ratesStrong purifying selection
Very high mutation ratesStrong purifying selectionLots of genetic driftMigration?
Lots of genetic driftRandom fixation of deleterious allelesWeak selection?
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Influenza viruses are like compulsive gamblers
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Acknowledgements
@lauringlab
Will FitzsimmonsDanny LyonsJT McCroneKayla Peck
FormerKari DebbinkMatt PaulyElisa VisherShawn Whitefield
UM School of Public HealthArnold MontoEmily MartinJosh Petrie
Doris Duke Charitable FoundationIDSA/Pfizer Young Investigator AwardNIAID R01 AI11886Burroughs Wellcome Fund, PATH
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High quality variant calling is critical in deep sequencing
McCrone and Lauring, JVI 2016
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Evolution within and between hosts
Mutation rate and effective population size (Ne)