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Resitance is useful? Exploiting resistance evolution to generate sustainable tools for malaria control Penelope A Lynch pennymath@lynch-fm.demon.co.uk Vector Control for Malaria The primary public health vector control tools use insecticides

  1. Resitance is useful? Exploiting resistance evolution to generate sustainable tools for malaria control Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  2. Vector Control for Malaria The primary public health vector control tools use insecticides applied inside properties, targetting vector species which have evolved to feed indoors at night IRS ITNS Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  3. Resisting Insecticides Mortality generated by insecticides exerts strong selection for resistance, comprising.. • The ability to survive exposure to the insecticide by negating its toxicity ( metabolic, target site or penetration resistance ) or • Avoidance of contact with the insecticide through behavioural change • ( behavioural resistance ) Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  4. Behavioural Resistance There is currently active work to find effective spatial repellents to keep indoor-biting malaria vectors out of homes If we see the creation of indoor ‘safe spaces’ as an effective public health tool, then ‘ behavioural resistance’ becomes a potential public health tool Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  5. Fit for Purpose – Using a spatial repellent to keep vectors outdoors Anopheles vectors which have evolved to feed on sleeping humans indoors at night should have reduced fitness if they change their strategy. so Repellent Selection should favour phenotypes which ignore the repellent and enter to feed in the normal way Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  6. Fit for Purpose – Using a repellent and an insecticide Selection should favour phenotypes which are deflected and so avoid the insecticide Repellent IRS Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  7. Fit for Purpose – Using a repellent and an insecticide Perfect, cost-free insecticide resistance would mean that non-deflected resistant vectors would be as fit as susceptibles in the absence of insecticide, and hence Repellent fitter than deflected vectors IRS Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  8. Fit for Purpose – Using a repellent and an insecticide but Resistant phenotypes which were also deflected would not gain any fitness benefit from resistance ( only any costs ). Repellent IRS Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  9. Fit for Purpose – Using a repellent and an insecticide Non-deflected resistants would be mating in a population with many susceptible and deflected genotypes, not primarily other resistants. Repellent IRS Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  10. Fit for Purpose – Using a repellent and an insecticide The fitness threshold for resistance mutations is higher – they must generate phenotypes fitter than deflected rather than susceptible vectors Repellent IRS Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  11. Evolved Spatial Repellence? Could we use evolution to turn a mediocre spatial repellent into a good one, and at the same time protect IRS insecticides from the spread of resistance? “Using evolution to generate sustainable malaria control with spatial repellents” Penelope A Lynch, Mike Boots eLife 2016, 5:e15416, DOI 10.7554/eLife.15416 Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  12. Fitness assumptions? No insecticide use - susceptible, non-deflected vectors fitness - deflected vectors With insecticide use - resistant non-deflected vectors fitness - deflected vectors (susceptible & resistant) - susceptible, non-deflected vectors Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  13. Fitness equations The average fitness of offspring into which deflection alleles are inherited is      )    − + − Dr R DR Dr r ( ( ) = + − + − F F F F F F     − − D S RD S D S D D The average fitness of offspring into which non-deflection alleles are inherited is   )           dr dr Dr dR Dr    ( ( )   ( ) = + + − + − + + −     F F dR 1 F F F F DR F F          − − − d S R S D S RD S  d  d  d  Deflection alleles will spread when                −  2 dr dr dR R     1    ( )  ( ) ( )   −  + − + − + − −         F F F F dR 1 F F DR 1 Dr F F                 − − − − − D d D S R D RD D d  d   D   d D    Resistance alleles will spread when             − RD d Rd rD rd rD   ( )   (  ) ( ) ( )   − + − + + − −  −   F F rd F F rD F F rD F F F F         − − − R r R S R D RD R D S  R r  r Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  14. Fitness equations tell us that ‘establishment’ of an ESR is supported by.. • low initial levels of resistance allele • high initial levels of deflection allele • maximum positive difference between fitness of deflected and non-deflected susceptibles • Minimum fitness benefit for resistant vs deflected phenotypes Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  15. Fitness equations tell us that ‘establishment’ of an ESR is supported by.. • low initial levels of resistance allele • high initial levels of deflection allele • maximum positive difference between fitness of deflected and non-deflected susceptibles • Minimum fitness benefit for resistant vs deflected phenotypes Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  16. Influencing fitness Y 1 Y 2 Y 3 Y 4 Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  17. Possible population changes Two-locus bi-allelic vector popgen model, tracking proportion of deflected & resistant phenotypes & population-level infectious bite rate Essentially three kinds of outcome “Using evolution to generate sustainable malaria control with spatial repellents” Penelope A Lynch, Mike Boots eLife 2016, 5:e15416, DOI 10.7554/eLife.15416 Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  18. ESR Establishment 10% initial prevalence of deflection alleles Baseline assumptions Susceptibles 20% survival/cycle 0.5% Initial prevalence of resistance alleles 2% initial prevalence of resistance alleles 25% initial prevalence of deflection alleles resistant+deflected phenotypes same fitness as deflected 60% per cycle susceptible survival Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  19. ESR ~The dark side Prevalence of deflected phenotypes after 300 cycles per cycle survival probability of deflected phenotypes Evolution undermines efficacy of 90% repellent unless deflected phenotypes are fitter than non- deflection 80% phenotype deflected phenotypes maintained 70% 60% 50% What happens if deflection phenotype you use a highly 40% diminishing effective spatial 30% repellent on its own? 20% deflection phenotype lost 10% 10% 20% 30% 40% 50% 60% 70% 80% 90% per cycle survival probability of non deflected phenotypes Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  20. Features • ESR could be cheap & easily deployed • Reversible if repellence no longer wanted • May ‘cue’ repulsion instead of insecticides • Partner insecticide can be changed ▪ allows establishment if some resistance already present, & maintenance over longer term ▪ allows switch to cheaper insecticide once ESR established • Established ESR can also protect LLIN insecticides • May have synergies rather than conflict with agricultural insecticide use Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  21. Evolved spatial repellence Summary.. Penelope A Lynch pennymath@lynch-fm.demon.co.uk

  22. if You may think it's great to spray your repellent every day & to cover every homestead with its pong. But if, when it is smelled there's a cost to things repelled, then selection for indifference will be strong But add insecticide, to kill things which come inside, and you may have a sustainable solution. For the ones which are selected will be those which are deflected and your program will be saved by evolution! Anoph Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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