Overview of Aedes aegypti biologyand interactions with dengue

and Zika viruses

Louis Lambrechts

Insect-Virus Interactions, Institut Pasteur-CNRS UMR 2000, Paris, France

22 June 2018 – Les Pensières Center for Global Health

Aedes aegypti, a major arbovirus vector

DENV-1, -2, -3, -4ZIKVYFVCHIKV

Worldwide distribution of Aedes aegypti

Powell Science 2016; Photo: Lindy McBride

AaaAaf

What does makeAedes aegyptisuch a goodarbovirus vector?

Vector-borne pathogen transmission

R0 (basic reproduction number) = total number of infectious vector bites thatarise from 1 infected person introduced into a susceptible human population

ma2pnbR0 =

– ln(p)

c

r

Vector-borne pathogen transmission

R0 (basic reproduction number) = total number of infectious vector bites thatarise from 1 infected person introduced into a susceptible human population

ma2pnbR0 =

– ln(p)

c = human host competencec

rr = daily recovery rate

of infected humansHUMAN

Vector-borne pathogen transmission

R0 (basic reproduction number) = total number of infectious vector bites thatarise from 1 infected person introduced into a susceptible human population

ma2pnbR0 =

– ln(p)

m = vector densityper person

a = daily probabilityof human biting

p = daily probabilityof vector survival

b = vector competence

n = duration in days ofextrinsic incubation period

c = human host competencec

rr = daily recovery rate

of infected humansVECTOR HUMAN

Vector-borne pathogen transmission

R0 (basic reproduction number) = total number of infectious vector bites thatarise from 1 infected person introduced into a susceptible human population

ma2pnbR0 =

– ln(p)

m = vector densityper person

a = daily probabilityof human biting

p = daily probabilityof vector survival

b = vector competence

n = duration in days ofextrinsic incubation period

c = human host competencec

rr = daily recovery rate

of infected humansVECTOR HUMAN

Vector-borne pathogen transmission

R0 (basic reproduction number) = total number of infectious vector bites thatarise from 1 infected person introduced into a susceptible human population

ma2pnbR0 =

– ln(p)

m = vector densityper person

a = daily probabilityof human biting

p = daily probabilityof vector survival

b = vector competence

n = duration in days ofextrinsic incubation period

c = human host competencec

rr = daily recovery rate

of infected humansVECTOR HUMAN

Aedes aegypti abundance and DENV infection risk

Cromwell et al. PLoS Negl Trop Dis 2017

Household-level indicators of Ae. aegypti abundance are associated with DENV seroconversion when they are calculated from longitudinal entomological data

Impact of mosquito blood feeding behavioron vector-borne pathogen transmission

Aedes aegypti

• >90% blood meals taken on humans

• Multiple blood feeding

• 0.63 to 0.76 blood meals per day

• No sugar feeding when human blood available

Reviewed in Scott & Takken Trends Parasitol 2012

Most adult female anautogenous mosquitoes

• One vertebrate blood meal per egg-laying cycle

• Consumption of plant carbohydrates

Vector-borne pathogen transmission

R0 (basic reproduction number) = total number of infectious vector bites thatarise from 1 infected person introduced into a susceptible human population

ma2pnbR0 =

– ln(p)

m = vector densityper person

a = daily probabilityof human biting

p = daily probabilityof vector survival

b = vector competence

n = duration in days ofextrinsic incubation period

c = human host competencec

rr = daily recovery rate

of infected humansVECTOR HUMAN

Vector-borne pathogen transmission

R0 (basic reproduction number) = total number of infectious vector bites thatarise from 1 infected person introduced into a susceptible human population

ma2pnbR0 =

– ln(p)

m = vector densityper person

a = daily probabilityof human biting

p = daily probabilityof vector survival

b = vector competence

n = duration in days ofextrinsic incubation period

c = human host competencec

rr = daily recovery rate

of infected humansVECTOR HUMAN

Talk outline

Genetic determinants of vector-virus interactions

• G x G interactions

• Ae. aegypti vs. Ae. albopictus

Non-genetic determinants of vector-virus interactions

• Temperature

• Larval microbiota

• Vertebrate host factors

Talk outline

Genetic determinants of vector-virus interactions

• G x G interactions

• Ae. aegypti vs. Ae. albopictus

Non-genetic determinants of vector-virus interactions

• Temperature

• Larval microbiota

• Vertebrate host factors

Vector competence

LumenHemocoel

Midgutepithelium

2. Dissemination 1. Infection

3. Transmission

Release in saliva

Intrinsic ability to become infected and subsequently transmit a pathogen

Genotype-by-genotype (G x G) interactions

DENV-1 isolates

Ae. aegyptigenotypes

Lambrechts et al. BMC Evol Biol 2009; Lambrechts Trends Parasitol 2011

HIGHLOW Vectorcompetence

Ratchaburi, Thailand

Genetic mapping of G x G interactionsbetween Ae. aegypti and DENV

InfectionDisseminationG x G interaction

Fansiri et al. PLoS Genet 2013

Worldwide survey of Ae. aegypti susceptibilityto diverse strains of ZIKV

Aubry et al. (bioRxiv 2018)

Cambodia2010

Philippines2012

F. Polynesia2013

Thailand2014

Puerto Rico2015

Senegal2015

• 8 field-derived Ae. aegypti colonies

• 6 low-passage ZIKV strains:

2010_Cambodia 2012_Philippines 2013_French_Polynesia

2014_Thailand 2015_Puerto_Rico 2015_Senegal

0.00

0.25

0.50

0.75

1.00

0.00

0.25

0.50

0.75

1.00

5.0 5.5 6.0 6.5 7.0 5.5 6.0 6.5 7.0 5.0 5.5 6.0 6.5 7.0

5.0 5.5 6.0 6.5 6.0 6.5 7.0 7.5 8.0 6.0 6.5 7.0

Blood meal titer (log FFU/ml)

Pro

po

rtio

n in

fecte

d

Sample_size5101520

PopulationThailand

Aedes aegypti susceptibility to ZIKV

Aubry et al. (bioRxiv 2018)

2010_Cambodia 2012_Philippines 2013_French_Polynesia

2014_Thailand 2015_Puerto_Rico 2015_Senegal

0.00

0.25

0.50

0.75

1.00

0.00

0.25

0.50

0.75

1.00

5.0 5.5 6.0 6.5 7.0 5.5 6.0 6.5 7.0 5.0 5.5 6.0 6.5 7.0

5.0 5.5 6.0 6.5 6.0 6.5 7.0 7.5 8.0 6.0 6.5 7.0

Blood meal titer (log FFU/ml)

Pro

po

rtio

n in

fecte

d

Sample_size5101520

PopulationThailand

Aedes aegypti susceptibility to ZIKV

Aubry et al. (bioRxiv 2018)

2010_Cambodia 2012_Philippines 2013_French_Polynesia

2014_Thailand 2015_Puerto_Rico 2015_Senegal

0.00

0.25

0.50

0.75

1.00

0.00

0.25

0.50

0.75

1.00

5.0 5.5 6.0 6.5 7.0 5.5 6.0 6.5 7.0 5.0 5.5 6.0 6.5 7.0

5.0 5.5 6.0 6.5 6.0 6.5 7.0 7.5 8.0 6.0 6.5 7.0

Blood meal titer (log FFU/ml)

Pro

po

rtio

n in

fecte

d

Sample_size5101520

PopulationThailand

Aedes aegypti susceptibility to ZIKV

Aubry et al. (bioRxiv 2018)

OID50= 5

OID50= 6

2010_Cambodia 2012_Philippines 2013_French_Polynesia

2014_Thailand 2015_Puerto_Rico 2015_Senegal

0.00

0.25

0.50

0.75

1.00

0.00

0.25

0.50

0.75

1.00

5.0 5.5 6.0 6.5 7.0 5.5 6.0 6.5 7.0 5.0 5.5 6.0 6.5 7.0

5.0 5.5 6.0 6.5 6.0 6.5 7.0 7.5 8.0 6.0 6.5 7.0

Blood meal titer (log FFU/ml)

Pro

po

rtio

n in

fecte

d

Sample_size5101520

PopulationGabonCameroonUgandaThailandCambodiaColombiaGuadeloupeFrench_Guiana

Aedes aegypti susceptibility to ZIKV

Aubry et al. (bioRxiv 2018)

French_Guiana

Guadeloupe

Colombia

Cambodia

Thailand

Uganda

Cameroon

Gabon

2010_Cambodia

2012_Philippines

2013_French_Polynesia

2014_Thailand

2015_Puerto_Rico

2015_Senegal

ZIKV strain

Pop

ula

tion

5

6

7

8OID50

African Ae. aegypti are less susceptible to ZIKV

Aubry et al. (bioRxiv 2018)

African

populations

Non-African

populations

Talk outline

Genetic determinants of vector-virus interactions

• G x G interactions

• Ae. aegypti vs. Ae. albopictus

Non-genetic determinants of vector-virus interactions

• Temperature

• Larval microbiota

• Vertebrate host factors

Aedes aegypti vs. Aedes albopictus

Primary DENV/ZIKV vector:Aedes aegypti

Secondary DENV/ZIKV vector:Aedes albopictus

Feeding behavior of Ae. aegypti vs. Ae. albopictus

Aedes albopictus• Day biting• Opportunistic

Aedes aegypti aegypti• Day biting• Anthropophilic

However, multiple examples of Ae. albopictus preference for humans:– North Carolina (Richards et al. J Med Entomol 2006)

– La Réunion Island (Delatte et al. Vector Borne Zoonotic Dis 2010)

– Southern Thailand (Ponlawat & Harrington J Med Entomol 2005)

DENV competence of Ae. aegypti vs. Ae. albopictus

• Ae. albopictus 16% more susceptible to midgut infection

• Dissemination 26% less likely than in Ae. aegypti

Midgut infection Dissemination

Lambrechts et al. PLoS Negl Trop Dis 2010

Meta-analysis of 91 separate experiments from 14 studies (1971-2009)

Ae. aegypti> Ae. albopictus

Ae. albopictus> Ae. aegypti

Ae. aegypti> Ae. albopictus

Ae. albopictus> Ae. aegypti

ZIKV competence of Ae. aegypti vs. Ae. albopictus

Ae. albopictus is more susceptible but less competent than Ae. aegypti

Infection (body) Dissemination (legs) Transmission (saliva)

Ciota et al. Emerg Infect Dis 2017

• Data shown for 2016 ZIKV strain from Honduras

• Similar results for 2010 ZIKV strain from Cambodia

Talk outline

Genetic determinants of vector-virus interactions

• G x G interactions

• Ae. aegypti vs. Ae. albopictus

Non-genetic determinants of vector-virus interactions

• Temperature

• Larval microbiota

• Vertebrate host factors

Influence of ambient temperature onDENV extrinsic incubation period in Ae. aegypti

Tjaden et al. PLoS Negl Trop Dis 2013; Carrington et al. PLoS Negl Trop Dis 2013

26°C constant

20°C constant

20°C fluctuating

Talk outline

Genetic determinants of vector-virus interactions

• G x G interactions

• Ae. aegypti vs. Ae. albopictus

Non-genetic determinants of vector-virus interactions

• Temperature

• Larval microbiota

• Vertebrate host factors

The mosquito ‘holobiont’

Mosquito life cycle

Aquatic environment

Terrestrial environment

Carry-over effects of larval microbiota

Mosquito life cycle

Aquatic environment

Terrestrial environment

Carry-over effects

Carry-over effects of larval microbiota

Gnotobiotic mosquitoes

Water sampling from naturalbreeding sites in Gabon

Bacterial isolation

Surface sterilization

Axenic larva

Gnotobiotic larva

Exposure to known bacteria in otherwise

sterile conditions

Egg

Adult vector competence

Dickson et al. Sci Adv 2017

Exposure to different bacteria during larvaldevelopment affects adult DENV vector competence

Dickson et al. Sci Adv 2017

3

4

5

Non−axenic Rsp_ivi Esp_ivi Ssp_ivi

Gnotobiotic treatment

DE

NV

dis

sem

ina

tio

n titer

(log1

0 s

ca

le)

*

Non-axenic = controlRsp_ivi = Rhizobium isolateEsp_ivi = Enterobacteriaceae isolateSsp_ivi = Salmonella isolate

Talk outline

Genetic determinants of vector-virus interactions

• G x G interactions

• Ae. aegypti vs. Ae. albopictus

Non-genetic determinants of vector-virus interactions

• Temperature

• Larval microbiota

• Vertebrate host factors

Liu et al. Nature 2017

NS1 facilitates ZIKV infection of Aedes aegypti

Predictors of successful human-to-mosquitoDENV transmission in Cambodia

2.08

1

2.05

10.05

4.84

1

Male

Female

Viremia (+1 log copies/ml)

Asymptomatic

Presymptomatic

Symptomatic

1 2 10Odds Ratio (95% CI)

***

**

***

*

Ref.

Ref.

Duong, Lambrechts et al. PNAS 2015

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10Plasma viremia (log10 cDNA copies/ml)

%

mo

sq

uito

es in

fecte

d (

dire

ct

fee

din

g)

Disease categoryAsymptomaticPresymptomaticSymptomatic

Direct feeding

OID50 (95% CI)5.31 (4.81−5.80)5.68 (5.30−6.00)7.21 (7.05−7.36)

DENV dose response by disease category

Duong, Lambrechts et al. PNAS 2015

Take home

• Aedes aegypti is a major arbovirus vector owing to its widespread distribution, human biting behavior and vector competence

• Vector competence is governed by specific G x G interactionsbetween mosquito and arbovirus strains

• Arbovirus transmission by mosquitoes is modulated by manifold biotic and abiotic factors of the environment

• Understanding variation in vector-virus interactions provides insights into arbovirus epidemiology and supports development of innovative strategies to interrupt arbovirus transmission

AcknowledgementsIP ParisAlbin FontaineFabien AubryLaura DicksonIsabelle ConcloisSarah MerklingDaria MartynowArtem BaidaliukAnavaj SakuntabhaiRicchard PaulStevenn VolantAmine GhozlaneChristiane BouchierLaurence MaValérie CaroLaure Diancourt

UC DavisTom ScottIRD / CIRMF GabonChristophe PaupyDiego AyalaDavy JiolleCNRS LyonClaire Valiente MoroGuillaume MinardLouis Malardé TahitiMai Cao-LormeauAFRIMS BangkokThanyalak FansiriAlongkot PonlawatJason RichardsonRick Jarman

IP CambodiaPhilippe BuchyVeasna DuongIP DakarAmadou SallCheikh DiagneIP CayenneIsabelle DusfourIP GuadeloupeAnubis Vega-RuaUniNorte ColombiaClaudia Romero-VivasCVR GlasgowAlain KohlUVR EntebbeJulius Lutwama

Thank you for your attention

http://research.pasteur.fr/en/team/insect-virus-interactions

louis.lambrechts@pasteur.fr

Aedes aegypti subspecies

Gloria-Soria et al. Mol Ecol 2016

Blue = subspecies Ae. aegypti formosusRed = subspecies Ae. aegypti aegypti

ZIKV strains

Aubry et al. (bioRxiv 2018)

Distribution of Aedes aegypti and Aedes albopictus

Kraemer et al. eLife 2015

Ae. albopictus

Ae. aegyptiProbability of occurrence

Probability of occurrence

ZIKV competence of Ae. aegypti vs. Ae. albopictus

Ae. albopictus is more susceptible but less competent than Ae. aegypti

Ciota et al. Emerg Infect Dis 2017

HondurasZIKVstrain

CambodiaZIKVstrain

Infection (body) Dissemination (legs) Transmission (saliva)