Resitance is useful? Exploiting resistance evolution to generate - - PowerPoint PPT Presentation

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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 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

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)

• r
• Avoidance of contact with the insecticide

through behavioural change

• (behavioural resistance)

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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

Fit for Purpose – Using a spatial repellent to keep vectors outdoors

Anopheles vectors which have evolved to feed

• n sleeping humans indoors at night should

have reduced fitness if they change their strategy. so Selection should favour phenotypes which ignore the repellent and enter to feed in the normal way

Repellent

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

Fit for Purpose – Using a repellent and an insecticide

Selection should favour phenotypes which are deflected and so avoid the insecticide

IRS Repellent

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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

• f insecticide, and hence

fitter than deflected vectors

IRS Repellent

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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).

IRS Repellent

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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

• ther resistants.

IRS Repellent

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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

IRS Repellent

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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

Fitness assumptions?

With insecticide use

• resistant non-deflected vectors
• deflected vectors (susceptible & resistant)
• susceptible, non-deflected vectors

No insecticide use

• susceptible, non-deflected vectors
• deflected vectors

fitness fitness

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

       ( )      ( )

D S RD S D S

Dr R DR Dr r F F F F F F D D − + − = + − + − − −       ( )      ( )        ( )

1

d S R S D S RD S

dr dr Dr dR Dr F F dR F F F F DR F F d d d     = + + − + − + + −         − − −    

   ( )       ( )               ( )

2

1 1 1

D d D S R D RD D

dr dr dR R F F F F dR F F DR Dr F F d d D d D         −   −  + − + − + − −                 − − − − −        

 ( )  ( )             ( )      ( )

R r R S R D RD R D S

RD d Rd rD rd rD F F rd F F rD F F rD F F F F R r r   −   − + − + + − −  −     − − −  

The average fitness of offspring into which deflection alleles are inherited is The average fitness of offspring into which non-deflection alleles are inherited is Deflection alleles will spread when Resistance alleles will spread when

Fitness equations

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

Fitness equations tell us that ‘establishment’

• f 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

Fitness equations tell us that ‘establishment’

• f 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

Influencing fitness

Y2 Y1 Y3 Y4

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

Possible population changes

“Using evolution to generate sustainable malaria control with spatial repellents” Penelope A Lynch, Mike Boots eLife 2016, 5:e15416, DOI 10.7554/eLife.15416

Two-locus bi-allelic vector popgen model, tracking proportion of deflected & resistant phenotypes & population-level infectious bite rate

Essentially three kinds

• f outcome

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

ESR Establishment

Baseline assumptions

Susceptibles 20% survival/cycle 0.5% Initial prevalence of resistance alleles 25% initial prevalence of deflection alleles resistant+deflected phenotypes same fitness as deflected 10% initial prevalence

• f deflection alleles

2% initial prevalence of resistance alleles 60% per cycle susceptible survival

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

ESR ~The dark side

10% 20% 30% 40% 50% 60% 70% 80% 90%

Prevalence of deflected phenotypes after 300 cycles per cycle survival probability of non deflected phenotypes per cycle survival probability of deflected phenotypes deflection phenotype lost deflection phenotype diminishing deflection phenotype maintained

Evolution undermines efficacy of repellent unless deflected phenotypes are fitter than non- deflected phenotypes

What happens if you use a highly effective spatial repellent on its

• wn?

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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

Evolved spatial repellence

Summary..

Penelope A Lynch pennymath@lynch-fm.demon.co.uk

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