Snail / schistosome compatibility Réunion Scientifique mardi 3 Avril 2007 André THERON UMR 5244...
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Transcript of Snail / schistosome compatibility Réunion Scientifique mardi 3 Avril 2007 André THERON UMR 5244...
Snail / schistosome compatibility
Réunion Scientifique mardi 3 Avril 2007
Université de Perpignan Via Domitia
E
HP
E
CENTRE NATIONAL
de la RECHERCHE
SCIENTIFIQUE
ECOLE PRATIQUE
des HAUTES
ETUDES
WHO
COLLABORATING
CENTER
André THERON
UMR 5244 BIOLOGIE ET ECOLOGIE TROPICALE ET MEDITERRANEENNEUniversity of Perpignan - 66860 Perpignan - France
from populations to mechanisms
Mollusc / Trematode models
Trematodelife cycles
Schistosoma mansoni
Biomphalaria glabrata
Mollusc / Trematode models
Adults
Egg
Miracidium
Cercariae
Schistosomelife cycle
Schistosoma mansoni
Biomphalariaglabrata
rainy season rainy season
Snail infection in Field populations
dry season
The typically low Infection rates
Most of the field surveys on natural populations
of Biomphalaria snails report :
(1-5%)
variations of population size high mortality rates
genetic bottleneck (extinction /
recolonisation, founder effect)
Ecologie moléculaire de la transmission : recrutement et diversité génétique
Théron et al., 2004. Parasitology.
Génotypage intra-hôte :- parasites adultes HD (microsatellites)- Parasite larvaires HI (microsatellites)
1%
100%
?
1 2
Limitedcontact
RESISTANT/SUSCEPTIBLE
SUSCEPTIBLEHOST
RESISTANTHOST
Resistance / Susceptibility
Polymorphism of hostsusceptibility/resistance
Laboratory strainsExperimental infections
50 - 60 %
2
0 %
50 %
100 %
504030201012 nMi
selected «SUSCEPTIBLE»
strain
Selected«RESISTANT»
strain
… Evolutionary inferences
(Co-evolution, Life history and Red Queen theories, …)
Fitness Cost associated
with resistance(Webster & Woolhouse, 2001 ).
Mating behaviour associated with resistance
(Webster et al., 2003 ).
Molecular markers associated with resistance
(Spada et al., 2002 ).
EVOLUTIONARY IMPLICATIONS >>
Maintenance ofresistance/susceptibility
polymorphism
Resistance is heritable and
dominant(Richards et al., 1992 ).
Routinely used to investigate :
-host defence mechanisms-Genetics of resistance-Genes of resistance
2 Selected “Resistant“strains:
selected «RESISTANT» strain
trade-offs between the FITNESS COST associated with
RESISTANCE (reduced fertility) and the fitness costs
resulting from parasitism (increased mortality).
(Webster & Davis, Parasitology , 123, 2001)
Laboratory selected “resistant“strains: use and limitation.
However, despite extensive efforts and use of various complementary biomolecular approaches, no linkage group, no genetic or functional marker has been assigned to any locus controlling resistance.
Théron & Coustau (J. Helminthol., 2005) raised the question :
Are Biomphalaria snails RESISTANT to Schistosoma mansoni ?
based on some arguments …
B. glabrata resistance : a relative concept
Developed sporocystSUSCEPTIBLE HOST
Encapsulated sporocysts
SUCCESSFUL INFECTION
FAILURE of INFECTION
RESISTANT HOST
Compatibility is tested independently for each entering miracidium.
We conclude that …
The phenotype (resistant vs susceptible) of the host is expressed as a function of the parasite genotype it harbors.
The phenotype (un-infective vs infective) of the parasite is expressed as a function of the host genotype it enters.
This means that the CONCEPT of RESISTANCE (and its evolutionary implication) appears un-adapted to the B. glabrata / S. mansoni system
… Evolutionary inferences
(co-evolution, life history and Red Queen theories, …)
Molecular markers associated with resistance
Fitness Cost associated
with resistance
Mating behaviour associated with resistance
“Resistant“selected
(Webster & Woolhouse, 2001 ).
(Webster et al., 2003 ).
(Spada et al., 2002 ).
EVOLUTIONARY IMPLICATIONS >>
Resistance is heritable and
dominant(Richards et al., 1992 ).
2 Selected “Resistant“strains:
Apparent R
esista
nce
Warn
ing
“Resistance“ / Infectivity in Field populations
Going back to the field ……,
2
RESISTANT/SUSCEPTIBLE
Genotype-by-genotypeInteraction
3
GENETICDIVERSITY
Compatible Un-Compatible
Polymorphism of
compatibility
Genotype-by-Genotype interactionMatching genotype
Parasitegenotypic diversity
- - - +
+ - - +
+ + + +
Snailgenotypic diversity
Compatibility polymorphism andB. glabrata « resistance » in the field ?
3
100 %
0 %
50 %
100 %
50403020101 2 nMi
- exposed snails directly collected in the site
- S. mansoni eggs obtained from a substantial number of naturally infected vertebrate hosts
- increasing miracidial dose exposures
Populational validation
Dans Fond
Dubelloy
Belle Plaine
100 % compatibility
Among Biomphalaria and S. mansoni associations, susceptibility of snails in the field is general if we take into account the total amount of genetic diversity present within the whole population of parasites within vertebrate hosts.
Snail genetic diversity Parasite genetic diversity
Field situation
100 % matching
We conclude that …
Meeting probability
1-5% infection rates
+Matching
probability
Snail genetic diversity Parasite genetic diversity
Field situation
100 % matching
Apparent resistance in Laboratory strains …
Laboratory Strains
0 à 60% matching
The functional point of view :
Schistosomes use molecular mimicry as infectivity strategy and are confronted to self/non-self recognition processes of the host (general immune defence)
success
MatchedMolecularVariants
failure
Un-MatchedMolecularVariant
A genetically determined mechanism theoretically
consistent with a matching genotype
model
Host Host
ParasiteParasite
CONCLUSION …
Matched vs Un-matched status of host-parasite combinations :
?
What phenotypic factors interact between host and parasite ?
What genomic mechanisms generate diversity ?
from populations to mechanisms (André THERON)
from mechanisms to populations (Guillaume MITTA)
Biomphalaria glabrata
Schistosoma mansoni
IncompatibleCompatible
Recherche des gènes acteurs de la compatibilité: Approches moléculaires comparatives entre
souches de S. mansoni
Sporocyste I installé chez le
mollusque
Sporocyste I en dégénérescence
Capsule hémocytaire
Approche protéomique comparative et identification de candidats prometteurs, les MSPPs
25015010075
50
37
25
20
15
Mw
pI (NL)3 10
25015010075
50
37
25
20
15
Mw
pI (NL)3 10
Parasites compatibles Parasites incompatibles
Mother Sporocyst Polymorphic Proteins
(MSPPs)répétitions de 9 aa en tandem 234 aaEtc..
analogies de structure pour des protéines immuno-
dominantes de Plasmodium et Coccidioides :
rôle «écran de fumée»
O-glycosylations
Les MSPPs et les variants au niveau cDNA
REPET B: GGTGACCTCGCATCAGACAAACCCACA B G D L A S D K P T
REPET BMOD: GGTGGCCTCGCATCAGACAAACCCACA B G G L A S D K P T
REPET G: GATGACTATGCATTGAGCGAACCAACA G D D Y A L S E P T
REPET GMOD: GATTACTATGCATTGAGCGAACCAACA G D Y Y A L S E P T
REPET M: GGTGACCTCGCATTAGACGAACCAACA M G D L A L D E P T
Compatible Incompatible
BBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBB
BBBBBB
BBBBBBBBBBB BBBBBBBBBBBBBBB
BBBBB
GGGGGGGGGGG
GGGGGGGGG
GGGG
GGG
GG
BBBBBB
BBBBBBBB BBBBBBBB
GGGGGGGGGGG
GGGGGGGG
GGGGG
GG
GG
GGMGG
GGBBBBBBBBBBB
GGBBGG
GGBBGG
GGBBG
GGBBBBG
0
0,05
0,1
0,15
0,2
0,25
eggs
miracidiasporocystscercariaemale worms
female worms
Ratio/28S
Les MSPPs: ume famille multigénique
MSPP1a 3 4 5 6 7 8 9 10 11 12 13 14 152
3 4 5 6 7 8 9 11 12 13 14 15MSPP2a 2 10
3 4 5 6 7 8 9 11 12 13 14 15MSPP3 2 10
3 432MSPP6
MSPP8 11 12 13 14 15
3 4 5 6 7 8 9MSPP1b 2 10
4 5 6 7 8 9 11 12 13*
14 15MSPP2b 10
11 12 13 14 155 6MSPP9
3 4 5 6 7 8 9MSPP4 2 10
3 7 8 9MSPP5 2 10
11 12 13 14MSPP7 9 10 15
3 gènes
8 pseudogènes
Retrotransposons (RT)
Gènes soumis à des insertions, remaniements fréquents médiés par ces RT
exons
- Protéines potentiellement impliquées dans le contournement du système de défense de B. glabrata
par S. mansoni
- Polymorphisme et organisation génomique génératrice de diversité
Le modèle B. glabrata/S. mansoni: les MSPPs des candidats de choix
Candidats de choix en tant que facteurs clefs de la compatibilité
Candidats pour une 1ère « approche populationnelle »
Comparaison des MSPPs:
Protéines « actrices » de la compatibilité en
populations naturelles?
Compatible Compatibles
Pop Nat LaboGuadeloupe Brésil
Isolats de S. mansoni
de Guadeloupe
4%
6%
Polymorphisme de compatibilité et MSPPs en populations naturelles