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
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)