transition écologique du paludisme et implications thérapeutiques
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Vascular Immunology UnitVascular Immunology Unit
Transition écologique du paludisme et implication thérapeutique
Transition écologique du paludisme et implication thérapeutique
Ronan Jambou MD, PhD
VascularImmunology
Unit
1. Who is ill Rural Malaria / Urban Malaria
2. « BBB alteration » hypothesis • Histamine and BBB • Effector role of platelets• Microparticules• Direct effect of Infected red blood cells
PLAN
1. Who is ill Rural Malaria / Urban Malaria
2. « BBB alteration » hypothesis • Effector role of platelets• Histamine and BBB• Microparticules
PLAN
Severe Malaria
NewbornfeverdehydrationconvulsionMetabolic disorders= impaired consciousness
ChildSevere anaemia +++High parasitaemia +++Cerebral pathology
AdultRespiratory distresscerebral malarialow parasiteamia= delay in treatment
29
15 17
53
6154 55
85 82
42
76
3737
47
74
Monde Afrique Asie Amériquelatine/Caraïbes
Régions plusavancées
1950 2000 2030 (projections)
Source : Nations Unies, Perspectives de la population dans le monde, Edition 2003 (scénario moyen), 2004.
From rural to urban: trends of the population From rural to urban: trends of the population
15°
14°
13°
16°N
Dakar
17°W 16° 15° 14° 13° 12°
SENEGAL
Area of Dakar
Seasonal transmission
4 M inhabitants = 1/3 Senegal
3.5% surface
What’s a seasonal transmission
Gouly coulyIncidence of Malaria in a small village Gouye Kouly 08/2004-08/2006
0
50
100
150
200
250
8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8
2004 2005 2006mois et années
nom
bre
é
piso
des épisodes non febriles
épisodes fébrilesaccés
In West Africa
Prevalence and risk of Malaria are highly variable
They summarize all the parameters of the transmission
risk is not the same everywhere and for everyone
Adaptation of strategies
WHO Africa report 2006WHO Africa report 2006
ITN implementationITN implementationChange in drug strategyChange in drug strategy
Expected decrease of Rural Malaria transmissionExpected decrease of Rural Malaria transmission
Swaziland WHO Report 2006Swaziland WHO Report 2006Kilifi _ Kenya Malaria J 2007Kilifi _ Kenya Malaria J 2007
Kilifi _ East Africa Mwangi et al JID 2005Kilifi _ East Africa Mwangi et al JID 2005
Changes in transmission modulate Malaria profil Changes in transmission modulate Malaria profil
53%32Saharevo, Madagascar: ≤1 b.i.a./human/year
50%25Pikine, Sénégal: ≤1 b.i.a./human/year
41%62Ndiop, Sénégal: 10-30 b.i.a./human/year
23%43Dielmo, Sénégal: 100-300 b.i.a./human/year
10%25Danané, Côte d'Ivoire: ≥ 300 b.i.a./human/year
% withinadluts
Total Nb of attacks 60 years old
53%32Saharevo, Madagascar: ≤1 b.i.a./human/year
50%25Pikine, Sénégal: ≤1 b.i.a./human/year
41%62Ndiop, Sénégal: 10-30 b.i.a./human/year
23%43Dielmo, Sénégal: 100-300 b.i.a./human/year
10%25Danané, Côte d'Ivoire: ≥ 300 b.i.a./human/year
% withinadluts
Total Nb of attacks 60 years old
Annu
al N
bof
mal
aria
atta
cks
0
1
2
3
4
5
6
0 5 10 15 20 25 30 35 40 45 50
Age (years)
60
Annu
al N
bof
mal
aria
atta
cks
0
1
2
3
4
5
6
0 5 10 15 20 25 30 35 40 45 50
Age (years)
60
West Africa / Madagascar (meta-analysis)West Africa / Madagascar (meta-analysis)
Major challenge for the next 10 years
Changes of risks Changes in control strategies
Prevalence of malaria in consultations
0
0,05
0,1
0,15
0,2
0,25
0,3
septembre octobre novembre decembre
00,10,20,30,40,50,6
septembre octobre novembre decembre
00,050,1
0,150,2
0,250,3
0,350,4
sept oct nov dec
part of class of age in the malaria cases
prevalence of severe malaria.
0
200
400
600
800
1000
1200
1400
M F M F M F M F M F0-1 an 1- 4ans 5-14 ans 15- 49 ans 50ans &+
consultations by age
0-1 y1- 4 y5-14 y
15- 49 y> 50 y
From children to adults From children to adults
« most of the cases occur among children under 5 years » : still true ?
« most of the cases occur among children under 5 years » : still true ?
Nb countries
Cases= or > 5y
Cases < 5y
ratio CountriesDeaths ratio >1
(>= 5y / <5) total 25 19.5 13.4 1.4
West Africa 13 9.5 4.9 1.88 9/4
Central Africa 6 3.7 3.2 1.12 3/0
East – southern 9 6.2 5.3 1.2 5/3
WHO African report 2006 : data 2005WHO African report 2006 : data 2005
57,8%31,7%35,3%patients consulting before 4 days after beginning of the symptoms
18,4 %38,5 %27,5 %patients treated before consultation
1043612762656Parasitemia (paras. / µL)
10,612,29,7Hemoglobin (mean g/L)
14 %12,5%14,7%Patients with temperature > 40°C (%)
0.81.51Sex ratio
13.7 (11)15.5 (13)14.5 (10.3)Mean age (SD)
1024234N° patients
Mild Mal. dispensary
Mild Mal Hospital
Cerebral malaria
CM is associated with delay in efficient treatment
Self treatment / DelaySelf treatment / Delay
+++triple+++++two
+-+oneNRImutant
SCNwild1085951codon
MM n= 28CM n= 16
MM n= 102CM n= 37
DHFR CRT exon 2
0%5%
10%15%20%25%30%35%40%45%
Wild 1 mutat. 2 mutat. 3 mutat.
0%
10%
20%30%
40%
50%
60%70%
80%
90%
CVIET CVIET/CVMNK CVMNK
CM
MM
CM is associated with drug resistance
0102030405060708090
100
Cerebral Malaria
Mild Mal (hosp)
Mild Mal. (dispens)
0
0,5
1
1,5
2
2,5
Percent of multi-infectionn° isolates / patients
0
5
10
15
20
25
Fann HPD Gued All0,660,680,70,720,740,760,780,80,82A
He
HPD n=59GUED n=129
-15 -5 5 15-15
-5
0
5
10
15
Axis 1
Axi
s 2
10
CM is associated to multi-infection and specific isolates
FstatFstat
PCAPCA
toxtox
pathogenpathogenpathogenhosthosthost
toxtox
Infectious pathologyInfectious pathology
ImmunopathologyImmunopathology
Which mechanisms ?
Adaptation of the treatmentHealthcare supply
Adaptation of the treatmentHealthcare supply
models models additive treatments additive treatments
toxtox
pathogenpathogenpathogenhosthosthost
toxtox
Infectious pathologyInfectious pathology
ImmunopathologyImmunopathology
Which mechanisms ?
Adaptation of the treatmentHealthcare supply
Adaptation of the treatmentHealthcare supply
additive treatments additive treatments
1. Who is ill Rural Malaria / Urban Malaria
2. « BBB alteration » hypothesis • Role of platelets and TNF• Histamine and BBB• Microparticules• Direct effect of IRBC
PLAN
sequestration
Schofield & Grau
5: 722-735, 2005
Hunt & Grau
24: 491-499, 2003
mechanisms?mechanisms?
Plasmodium?
NKT
inflammatory CTKs ↑ Mo
CD8
CD4
NKMφ
DC
?
Schofield & Grau
5: 722-735, 2005
Mo?
endotheliumendothelium
Which effectors
Which interaction between blood cells?
1. Who is ill Rural Malaria / Urban Malaria
2. « BBB alteration » hypothesis • Role of platelets and TNF• Histamine and BBB• Microparticules• Infected red blood cells
PLAN
TNF: a central mediator in immunopathology
adhesionmolecules
microvessel(brain, lung, ...)
TISSUE LESIONS :graft-versus-host
pulmonary fibrosis granuloma
arthritisDTH
TNF
anti-TNF antibody VASCULAR LESIONS :
septic shock (*)cerebral malaria
(*) Beutler & Cerami, 1985
Grau et al., Immunol Rev; 112: 49-70 (1989)Int Rev Exp Pathol 34: 159-171 (1993)
Cytokines and pathology: approaches
+S ?cytokinecytokine
mini-pumps
Δ pathology?S
Pathogen
R
S + ?antibodies,inhibitors
observationobservation
inductioninduction
inhibitioninhibition
brain endothelial cells
TNF plays a major role in sequestrationTNF plays a major role in sequestration
Lucas et al., Eur J Immunol 27: 1719, 1997Lou, Lucas & Grau Clin Microbiol Rev 14: 810, 2001
Stoelcker et al., Infect Immun 70: 5857, 2002
monocyte bindingICAM-1 upregulation
platelet binding
memTNF
TNFR2TNFR2
sol or
memLT
PRBC binding
Functional consequence of TNFR2 upregulation (Functional consequence of TNFR2 upregulation (mouse modelmouse model, PbA infection), PbA infection)
TNF-dependent pathology is also platelet-dependent
Pulmonary fibrosisPulmonary fibrosis
Cerebral malariaCerebral malaria
Shwartzmann reactionShwartzmann reaction
DTHDTH J Exp Med. 1991 Mar 1;173(3):673-9 J Exp Med. 1991 Mar 1;173(3):673-9
Nature. 1990 Mar 15;344(6263):245-7.Nature. 1990 Mar 15;344(6263):245-7.
Science. 1987 Sep 4;237(4819):1210-2.Science. 1987 Sep 4;237(4819):1210-2.
J Leukoc Biol. 1993 Jun;53(6):636-9.J Leukoc Biol. 1993 Jun;53(6):636-9.
Accumulation of platelets in a TNF-mediated pathology (LPS shock)
Platelets: the conventional viewPlatelets: the conventional view
PreventionPrevention of LPSof LPS--induced mortalityinduced mortalityby antiby anti--platelet antibodiesplatelet antibodies
LPSLPS survivors/total (%)survivors/total (%)
--++++++++++
10/10 (100)10/10 (100)4/41 (10)4/41 (10)
0/6 (0)0/6 (0)0/6 (0)0/6 (0)
10/12 (83%)10/12 (83%)7/9 (77%)7/9 (77%)
nonenonenonenonenormal mouse IgGnormal mouse IgGnormal rabbit IgGnormal rabbit IgGmouse antimouse anti--platelet mAbplatelet mAbrabbit antirabbit anti--platelet IgGplatelet IgG
pretreatmentpretreatment
Prevention of hemorrhagic necrosis by anti-platelet or anti-CAM mAbs
Prevention of hemorrhagic necrosis Prevention of hemorrhagic necrosis by antiby anti--platelet or antiplatelet or anti--CAM mAbsCAM mAbs
0 25 50 75 100 125
*
*
*
-- 24 h (id)24 h (id) -- 2 h (ip)2 h (ip) 0 h (id)0 h (id)
PBSPBS
LPSLPS
LPSLPS
LPSLPS
LPSLPS
LPSLPS
nonenone
nonenone
normal IgGnormal IgG
antianti--CD11aCD11a
antianti--CD54CD54
antianti--plateletplatelet
TNFTNF
PBSPBS
TNFTNF
TNFTNF
TNFTNF
TNFTNF
5151CrCr--erythrocytes (% cpm)erythrocytes (% cpm)
Platelet-EC interactions
microvessel
stroke
metastasis
angiogenesis
THROMBOSIS
INFLAMMATION
Mol. Pathol. 50: 175-185 (1997)
PRBC
Wassmer et al., J Infect Dis 189: 180-9, 2004
PLT
PLTPLT
PLT
ECEC
PRBC
In vitroIn vitro evidence for a role of platelets in evidence for a role of platelets in PRBCPRBC--EC bridgingEC bridging
Wassmer et al., J Immunol 176: 1180-1184, 2006
Other roles of platelets in malaria: clumpingOther roles of platelets in malaria: clumping
Pain et al., Proc Natl Acad Sci USA 98: 1805-10, 2001
clump
•• aggregation of PRBCaggregation of PRBC
•• formation of giant clumps formation of giant clumps
•• role in sequestration and in role in sequestration and in ““sludgingsludging””
1. Who is illRural Malaria / Urban Malaria
2. « BBB alteration » hypothesis• Effector role of platelets• Histamine and BBB• Microparticules• IRBC
PLAN
Major role in: Major Major rolerole in: in: ECECEC
Vascular permeability
DiabetesDengue feverAge degenerescenceARDSMyocardial infarctionTumour angiogenesisBrain injury
DiabetesDengue feverAge degenerescenceARDSMyocardial infarctionTumour angiogenesisBrain injury
VVO Junctionremodelling
pinocytosis
pathogenspathogenspathogens stimulistimulistimuli
Histamine induces vascular congestionGuido Majno (1961)
vein
arteriole
Histamine induces opening of intercellular junctionsJ cell Biol (1969)
Histamine induces opening of intercellular junctionsJ cell Biol (1969)
Histamine
HRF/TCTPbasophyls
cytokine network (IL4, IL2..) eicosanoid pathway
endothelial cells responseto inflammation
platelets / neutrophils
DC response to TH2 typeproduction of IgE
vascular permeability
Cerebral malaria ??Histamine Increases
during malaria
( HR1, HR2, HR3, HR4, HR5 )
IgE AntigenAllergy / helminths
Histamine can modulate endothelial and immune cells functions
15°
14°
13°
16°N
Dakar
17°W 16° 15° 14° 13° 12°
SENEGAL
Area of Dakar
Seasonal transmission
4 M inhabitants = 1/3 Senegal
3.5% territory
An arabiensis
Gouly Couly
Longitudinal study: Gouly couly Longitudinal study: Gouly couly
Nov. 04Baso, IgE
Follow up
EnrolmentJun 04
Jun 05Baso, IgE
july 04IgE
EndJun 06
Rainy season Rainy seasondry season dry seasondry season
Drug resistance study
Low
high
medium
0
20
40
60
80
100
9-19 20-39 40-80
0
2
4
6
8
10
Total IgE ug/L
9-19 20-39 40-80
0
0,5
1
1,5
july 04 Nov 04 July 05
IgE
ug/m
L
0
0,5
1
1,5
2
2,5
IgE
ug/m
L
05
1015202530
1 2 3
IgE
ug/m
L
% of subjects with > 0.4µg/l
0
5
10
15
20
25
30
35
40
45
9-19 20-39 40-80
% Ig
E_Pf
pos
itive
nov_04Jun_05
% of subjects with IgE-Pf
No difference according to age for
high IgE level
Stability of IgE level
Higher percent of Pf-IgE during dry
season
IgE responses : Gouly couly IgE responses : Gouly couly
IgE Deposition in brain microvessels and on parasitized erythrocytes from cerebral malaria patientsYoshimasa maeno, AJTMH 2000,
Immunoglobulin E (IgE) containing complexes induce IL-4 production in human basophils: effect on Th1/Th2 balance in malariaM.A. Nyakeriga, Acta Tropica 2002
IgE+anti-E
IgG+anti-G
IgG+anti-E
Pathology ? TH2 response ?
IgE increase in CM and can induce IL4 productionIgE increase in CM and can induce IL4 production
Basophiles responses : Gouly couly Basophiles responses : Gouly couly
standard antigens
flmpD farinaeD pteronyssinus
0102030405060708090
9-19y 20-39y 40-80y
Perc
ent r
espo
nder
s nov jun
Percent of responders maximum during rainy
season
Pf can induce response for 10% of villagers during rainy season
High response for salivary glandsHemozoin
Pf ghostSalivary glands
0
1020
30
40
5060
70
80
9-19y 20-39y 40-80y
nov jun nov jun nov jun
Perc
ent r
espo
nder
s
Mosquitoes can trigger basophiles
activation
Pf antigens
Mosquitos bites induce mast cells activationJI Demeure (2005)
Mosquitos bites induce mast cells activationJI Demeure (2005)
ECIS™: Electric Cell-substrate Impedance Sensing
Monitoring of cells monolayer impedance to measure junction permMonitoring of cells monolayer impedance to measure junction permeabilityeability
HBEC-D3
HBEC1.5 h
washingHistamine, TNF
Spreading: 5 days
TEER
24 h
IRBC, NRBC
Attachment and spreading of the cells
0
5000
10000
15000
20000
0 20 40 60 80 100
Time (hours)
Res
ista
nce
(ohm
s)
Histamine or platelet supernatant induce opening of junctions
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
29 29.5 30 30.5 31 31.5 32
stimulationHistamine
Control medium
hours
Resistanceohm
LPS
PLT SN
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
23 28 33 38 43
stimulationMedium change
Histamine
Control medium
hours
Resistanceohm
LPS
PLT SN
ratio
at T
0
-0,35
-0,3
-0,25
-0,2
-0,15
-0,1
-0,05
0
0,05
0,1
1 2 3 4 5 6 7 8 10 11 12 13 14 16 17 18 19 20 21 22 23 24 25
his100-anti_H1histamine100TNFhist100-antiH2control
H1 receptor mediates histamine effect on HBECs
Histamine 100 µM
Histamine induce calcium mobilization thru HR1Histamine induce calcium mobilization thru HR1
Histamine 1 µM
-1000
100200300400500
0 5 10 15 20 25Time (min)
Ca
(nM
)
Histamine 10 µM
Histamine
Time (min)
0.6
1.6
2.6
3.6
0 20 40 60Time (min)
Nor
mal
ised
Rat
io
Diphenylhydramine (20µM)
Histamine
Cimetidine (40µM)
0.6
1.6
2.6
3.6
4.6
0 20 40 60 80
Nor
mal
ised
Rat
io
Histamine
(Pre-incubation 40 min)
H1
H2
Histamine increases VCAM but not ICAM expression
0
2
4
6
8
10
12
14
16
18
control Histamine100 Histamine100
+ antiH1H2
Histamine_10 Histamine_1
Per
cent
of p
ositi
ve c
ells
Histamine 100µM, 10µM, 1µMCimetidine 20µM, diphenylhydramine 20µM,
39.128.4237.246.
5.
DPHCiticoline ControlDay post-PbA infection
ControlCiticholinediphenyhydramine
0 7 140
25
50
75
100
Day post-PbA infection
Perc
ent s
urvi
val
Anti_H1 increases survival of P berghei infected mice
Beghdadi et al 2008
Histamine release and HRFsHistamine release and HRFs
Human TCTP (IgE-dependent HRF)-Gene locus 13q12-q14
- induces histamine release by basophiles of atopic patients
- in vitro : increase reactivity of basophiles to other stimulus (IgE, ..etc)
- induce proliferation of B cells and activation of eosinophiles
TCTP- found in all eukaryotes , with two conserved motifs (microtubules binding domain)
- control cells proliferation, division, and apoptose => overexpression in cancer
Induction of idiopathic allergy ?
Plasmodium can induce histamine release : TCTP/HRF protein
Plasmodium can induce histamine release : TCTP/HRF protein
PfTCTP is expressed by late trophozoitesPF
TCTP
Tr
ansc
ript R
Q
2 8 14 20 3226 38 44 50 hours0,5
11,5
22,5
33,5
44,5
05
10152025303540
P0 P6 P12 P18 P30P24 P36 P42 P48
- synchronisation + sampling every 6h over 54h = « sampling time »
- use of thin smear and timing genes (P David) to define the « parasite time » (gene 8h= MAL8P1.4, gene 12h=PFI1735c- normalisation of mRNA on average of (N1= PFC0255c and N2=PFA0570), then at time with less mRNA (T44 = 1 for PfTCTP)
Parasite cycle time
Sampling time
gene T8hgene T12h
Tim
ing
gene
s
Pf TCTP- 38% identity, 53% similarity with hTCTP
- mimics hTCTP in vitro on histamine release
- 0.1 to 1µg/ml in serum from patients with malaria
- totally conserved in 350 P falciparum field isolates => target human cells ??
PfTCTPhTCTP
10 µg/ml
His
tam
ine
histamine release by basophils induced by rTCTP is IgE dependant(MacDonald et al 2001)
Plasmodium can induce histamine release Plasmodium can induce histamine release
100 µg/ml
Conclusion 2 Conclusion 2
20% of population with high IgE level = stable
Seasonal variation of basophiles activation
Impact of mosquitoes bites on histamine release
Histamine modulates endothelial cells thru H1R
Histamine induces rapid opening of intercellular junction responsive for edema
PfTCTP poorly active on HBEC ( ongoing .. Hypoxia) => HRF
Anti-histamine = new way to improve the treatment of CM ?
1. Who is ill Rural Malaria / Urban Malaria
2. « Parasite » hypothesis3. « BBB alteration » hypothesis
• Effector role of platelets• Histamine and BBB• Microparticules• IRBC
PLAN
Membrane vesiculationMembrane vesiculationMembrane vesiculation
From Zwaal et al.From Zwaal et al.
Phosphatidyl-serinePhosphatidyl-serine
Phosphatidyl-ethanolaminePhosphatidyl-ethanolamine
resting
HUVEC
EMP
250
0
50
100
150
200
3EM
P / 1
0ce
lls
0 10 100 1000TNF (ng/ml)
Release in culture
Combes et al., J. Clin. Invest. 104: 93, 1999
Electron microscopy+ TNF
TNF enhances MP production by endotheliumTNF enhances MP production by endothelium
Combes et al, JAMA 291: 2542-4, 2004
acute phasefollow up
025
50
75
100
125
150
175
EMP
/ µl p
lasm
a
60N 138 80 37 35 27 1348
p = 0.01p = 0.005
p < 0.0001
Malaria - + + + + + + +CM - - + + - - + +SMA - - - - + + + +
Dramatic increase of plasma endothelial microparticles in Malawian children with CM
Dramatic Dramatic increase increase of pof plasma endothelial lasma endothelial microparticlesmicroparticles in Malawian children with in Malawian children with CMCM
Citicoline can protect against CMCiticoline can protect against CM
Protection of mice injected with PBA
Injection 1g/kg day 4 to end
First trial in human (Dakar HPD 2007)
Qunine + CTC 1.5g/day
no significant improvement of mortality at this dose
0 7 14 210
25
50
75
100 Control
Citicoline
Artesiminin
Day post-PbA infection
%su
rviv
al CTC + Artesiminin
1. Who is ill Rural Malaria / Urban Malaria
2. « BBB alteration » hypothesis • Effector role of platelets• Histamine and BBB• Microparticules• IRBC
PLAN
NKT
TregMo
CD8
host cells
P. falciparum-infected red cells
brainendothelialcellmembranes
What happens during IRBC/endothelial cells contactsWhat happens during IRBC/endothelial cells contacts
AutoMACS® - purified PRBC
CoCo--cultures of parasitised red blood cells (PRBC) and cultures of parasitised red blood cells (PRBC) and human brain endothelial cells (HBEC) human brain endothelial cells (HBEC)
HBEC 1 h 30MicroscopyTEERQ PCRFlow cytometry
unbound cellremoval
0 / 1 h / 2 h / 4h
TNF
O/N
INCUBATION
washing
PRBC-PKH26 Calcein AM
HBEC D3 + IRBC (3Ci)HBEC D3 + IRBC (3Ci)1 h incubation1 h incubation
HBEC
PRBC
hemozoin
merozoite
knobs
HBEC D3 + IRBC (3Ci)HBEC D3 + IRBC (3Ci)Engulfing ?Engulfing ?
HBEC 1 h 30 confocal microscopy
PRBC-PKH26
washing
0 / 1 h / 2 h
TNF
ON
washing
HIS + anti human-IgG
AutoMACS® - purified PRBC
[HIS : pool of 10 hyper-immune sera from African adults with malaria]
30 min co30 min co--cultureculture 40 min co40 min co--cultureculturebefore washingbefore washing
Beginning of transferAdhesion
HBEC: D3 + IRBC-PKH26-calcein
Ration : 50 RBC/1 HBEC
HZ
PKH26
Mergecalcein
1 h 30 min1 h 30 min coco--culture culture (after washing)(after washing)
Diffusion of membrane compounds
HBEC: D3 + IRBC: 3Ci
HZ
4 h4 h coco--cultureculture
Diffusion of membraneand cytosoliccompounds
HBEC+ IRBCcalcein
PKH26
HBEC
HBEC + PRBC-PK26 HBEC + PRBC + HIS Merge
PRBC
5.5 h5.5 h coco--culture HBEC / parasitised RBCculture HBEC / parasitised RBC
Time (0.1 hour)
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1 6 11 16 21 26 31 36 41 46 51 56 61 66 71 76 81 86
resi
stan
ce ra
tion
(T/T
inje
ctio
n)
NRBC + IRBC (vol/vol)
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1 7 13 19 25 31 37 43 49 55 61 67 73 79 85 91 97 103
Time ( 0.1 hour)
resi
stan
ce (r
atio
T/T
0)
controlNRBCIRBCHistamine 100
IRBC but not NRBC induce opening of the junctions IRBC but not NRBC induce opening of the junctions
Stimulus Stimulus
Early endosomes
Cell activation
Phosphorylation +++Apoptosis ?Src activation ?
Opening of junctions
Recyclingpresentation Increase of VCAM
TLR , Coagulation
Modulation of genesexpression
T cellsantibodies
Ca ++
MP=0
Antigen presentation
Y YYIRBC
Adhesion of IRBC
Trogocytosis-like adhesion and transfer
start as soon as 30 min
Membrane transfer
HBEC
Conclusion 3 Conclusion 3
Structure of parasite/HBECInterface and
proteins (SNARE , Vamp)
Dakar
Cell activation (Src, Rac1)
Opening of junctions
Recyclingpresentation
T cellsantibodiesAntigen presentation
Y YY
Adhesion of IRBC
Structure of the interface proteins involved ?
Africa
Ongoing Ongoing
Field isolates
T and B cells
University SydneyV Combes
A Sanchez PerezF ElassaadMJ Jambou
GE. Grau
IMTSSA- Le PharoS PelleauD Parzy
Institut Pasteur de Dakar
D AldebertL Marrama
R PaulY Seck
ML VarelaF Diène-SarrIbrahima Dia
Hopitaux de DakarB Diop
JC Moreau
Institut Pasteur (PF5)F Nato
P Beguin
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