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Stephanie Blandin – IBMC Strasbourg – INSERM U963

Mosquito resistance to malaria parasites:Genetic intelligence against disease transmission

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Malaria transmission cycle

malaria 250.000.000 cases / year860.000 deaths / year

Anopheles gambiae

Plasmodium

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Anopheles gambiae

Plasmodium

Some mosquitoes are resistant tomalaria parasites…

Why? Potential applications

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Mosquito genetic factors control susceptibility

Resistant

Susceptible

Midgut Salivary Glands

Laboratory model:A. gambiae / Plasmodium berghei

Midguts infected with GFP parasites

Susceptible (S) strain

Resistant (R) strain

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Fig. 1

LO

D s

core

s

A

B

F2: 4Arr x L3-5F2: L3-5 x 4Arr

0 1 5 10 25 25001

5

50

250400

0 1 10 25 50 25001

5

25

100

400

10

25

100

50 100

250

50

10

1005

F1: 4Arr x L3-5F1: L3-5 x 4ArrF0: 4ArrF0: L3-5

0

20

40

60

80

100melanisingresistant

Nu

mb

er

of

live

pa

rasi

tes

/ m

idg

ut

Number of melanised parasites / midgut

Pe

rce

nta

ge

of

mo

squ

itoes

C

10 cM

3R 3L

C

3E37B

3E36D

CLIPB15

3E34B2

3E33D

3H119

3H776

3E38C1

3H127

3A2-29

TEP4

3E40A1

CTL2

3L09-C1

3H544EG

3A19-32

19C20-B1

3A5-25

0

5

1 0

1 5

2 0

2 5

3 0

Pfmel1Pcen3R

Pen2Pcen3L

Pfea2Pbmel2

Pbres1

TEP1

2R 2L

Pfin2Pen1 Pen3

Pcen2R

Pfea1Pfin1,4,5Pfmel2

Pbmel1

C

2H46

2H135

2E141

GNBPB3

CLIPB7

SCRASP3

2EF2

2H175

2EG15

2H796

3B20-B1

CLIPB5

2H125

2H770

2H147

2H603

2H802

LRIM1

APL1

0

5

1 0

1 5

0

3

CX

Pfin3

r e s i s t a n tm e l a n i s i n g

XH503

XH36

XH53

XH711w

4Arr

x L

3-5

(131

)

L3-5

x 4

Arr

(271

)

4Arr

x L

3-5

(39)

L3-5

x 4

Arr

(72)

4Arr

(43

)

L3-5

(35

)

F0 F1 F2

Candidate gene within locus:

TEP1

(ThioEster containing Protein 1)

ResistanceClearance

Quantitative Traits:

Blandin, Science 2009

1000 genes

Resistance to parasites is linked to a major locus

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TEP1 has antiparasitic activity

- Complement-like protein

- Labels bacteria for phagocytosis

Control TEP1-depleted

Resistant mosquitoes, 8 days post infectionBlandin, Cell 2004

- Labels malaria parasites and promotes their killing

- Circulates in hemolymph as a complex with LRR proteins

- Polymorphic

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TEP1 polymorphisms confer resistance to parasites

Reciprocal allele-specific RNA interference

Blandin, Science 2009

*S3/S3

R

*R1/S3

∆R ∆S

S*R1/R1

F1

TEP1 TEP1

RxS cross infected with P. berghei

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Perspectives in mosquito control for global malaria eradication

8

Understand resistance:• Mosquito genetics

• Parasite virulence

• Environment

Collaborators in Africa• IRD-OCEAC Cameroon• ICIPE Kenya• MRTC Mali

Laboratory

Diagnostics of mosquito resistance to parasites

Kill malaria susceptible mosquitoes, not resistant ones

Applications