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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
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
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
CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
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
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