host-parasite interactions patrick duffy 206 256 7311 pduffy@sbri.org
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Host-Parasite Interactions
Patrick Duffy
206 256 7311
pduffy@sbri.org
Outline of class
•Antigenic variation–Background–Primary literature
•Parasite modulation of immune response–T cell epitopes and immunomodulation–Parasite modulation of DC function–Primary literature
•Parasite co-opting the immune response
•Host resistance versus host immunity
Richie & Saul 2002
Malaria life cycle
ANTIGENIC VARIATION
SULFA
Antigenic variants within strainsPlasmodium knowlesi
Brown & Brown 1965Nuri strain in Rhesus
VARIANTSPECIFICIMMUNITY
VARIANTTRANSCENDINGIMMUNITY
Brown 1973Nuri strain in RhesusAntibody-induced variation
NO VACCINE VACCINATED (variant A + IFA)
Variant-specific immunity in monkeysP. knowlesi
Par
asit
emia
Hommel 1985Saimiri monkeys
Strain AInoculum(Indo-1)
Strain BInoculum(UgPA)
Strain-specific immunity in monkeysP. falciparum
Par
asite
mia
Yount & Coggeshall 1949Joilet, IL prison studies
QUININE
Strain Ainoculum
Strain Binoculum
Strain-specific immunity in humansP. vivax
Variant antigens on the IE surfaceP. falciparum
Leech/Barnwell/Howard 1984 (P. knowlesi)
MC extract SL extract
IP with sera: SLSL MCMC
200 kD-- 1. Large MW2. Tx100 insoluble/SDS soluble3. Surface iodinatable (I125)4. Strain-specific IP
(similar to cytoadherence)
5. Trypsin-sensitive(similar to cytoadherence)
Variant surface antigen:
Serum antibodies from monkeys infected withMalayan Camp (MC) or Santa Lucia (SL) parasites
Exon-1 (Extracellular domain)
Acidic Terminal SegmentExon-2
(Cytoplasmicdomain)
Semi-conservedhead structure
Tandemassociation
TM
Tandemassociation
DBL1 CIDR1 DBL2 C2 CIDR2 ATSDBL4
DBL1 CIDR1 CIDR2 ATSDBL2
DBL5DBL3
Rosetting CD36 ICAM-1 PECAMCSA
NT
SN
TS
Exon-1
Exon-2
CR1HS
Blood group AHeparin
CD31IgMCSA
CSA/CIgG
Cell 1995Su & Wellems Smith & MillerBaruch & Howard
Many years later… PfEMP1
CD36 Binding and Non-binding PfEMP1 GroupsC
D36
bin
ding
Non
-CD
36 b
indi
ng
Joe Smith
~60 copies per haploid genomeMajority are subtelomeric
Switching inT. brucei
PRIMARY LITERATURE
Bull et al., J Infect Dis 182:252
SICK
RECOVERED
ISOLATE
SICK
RECOVERED
ISOLATE
AGGLUTINATION SCORE 0 1 2 3 4
3 MONTH OLD CHILD
26 MONTH OLD CHILD
Bull & Marsh 1999
Serum agglutination of field isolates:Evidence for variant specific immunity
FIELD ISOLATES
SE
RU
M S
AM
PL
ES
Serum agglutination of field isolates:Rare Variants and Prevalent Variants
Bull & Marsh 1999
IMMUNE MODULATION
HLA Class I molecules may be involved in liver stage immunity
Hoffman, S. L and Doolan, D. L. ( 2000) Nature Medicine
HLA Class Iantigenassociated with resistance to severe malaria
Hill et al., Nature, 1991
Expected at Parasite Rate of
CSP variant Observed 100% 50% 10%
cp26 36 58 138* 195*
cp27 405 257* 329* 378*
cp28 15 10 30 48*
cp29 16 33 89* 134*
cp26 & cp29 124 22* 22* 6*
cp27 & cp29 4 99* 53* 11
cp26 & cp27 71 171* 82 16*
cp26 & cp28 2 7 7 2 *P<.05
Frequency of CSP variants in parasites collected from 795 Gambians with malaria.
Reciprocal CTL antagonism in PBMC cultures by two naturally occurring P. falciparum CS protein variants.
Gilbert et al., Science, 1998
CS protein and HLA B35:Evidence for Host-parasiteCo-evolution?
Taylor et al., 2000
Urban et al.Figure 2
MF Good commentaryNature 1999
PRIMARY LITERATURE
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 5
Fig. 6
CO-OPTING THE IMMUNE SYSTEM
S. mansoniexpresses host-likemolecules on its surface
Trottein, JI, 1997
Immune masking
Ig and associated complexes affinity-purified from S. mansoni with protein G
McManus, 2001
Adsorption of human Igon the surface of red cellsinfected with P. falciparum
IgG
IgM
Flick, 2001
Schistosomes develop poorly in RAG -/- mice
McKerrow 2001
S. mansoni development in mouse liver requires CD4+ T cells
McKerrow 2001
IS RESISTANCE IMMUNITY?
Resistance to malaria during childhood and adolescence
Parasitemia
Pregnancy malaria
Severe childhood malaria
Pre
vale
nc
e
Age (years)
Epidemiology and Immunity
1 10 20
0
10
20
30
40
50
60
70
80
2-5 6-10 11-15 16-25 26-40 >40
Age group (years)
migrants after 8 months exposure
migrants after 20 months exposure
Adults acquire resistance more rapidly than children
Baird 1995
Age and susceptibility
Weeks after treatment
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16
Age 12-14
Age 15-20
Age 21-35
P < 0.0001
n = 243
Volu
nte
ers
in
fecte
d (
%)
0
1
2
3
4
5
6
Tan
ner
Sta
ge
12-14 15-20 21-35
Age group (yrs)
Mea
n P
aras
item
ia
Age (yrs)
12-14 15-20 21-35
.1
1
10
100
0
P<0.01
P<0.05 P<0.01
P<0.05
DHEA-S level:lowmediumhigh
DHEA-S levels predict resistance to malaria
Culture of Plasmodium falciparum Effect of DHEAS in vitro
0
1
2
3
4
5
6
7
0 24 48 72 96 120 144
Serum+ DMSO Serum + DHEAS
Time (hours)
% P
ara
sit
em
ia
IS RESISTANCE IMMUNITY?
Resistance to pregnancy malaria
Parity-related Susceptibility to Placental Malaria(1500 deliveries in Kisumu, Kenya)
Rate (%) Mean parasite density (%IE)0
20
10
30
0
6
2
8
4
Primigravid
Secundigravid
Multigravid
Parasites infecting pregnant mothers are different than other parasites
Parasite adhesion to placenta ex vivo
Placental parasitesParasites from adult
males
Fried, Duffy 1996
Parasites of Pregnancy Malaria
Parasites of Pregnancy Malaria
BSA CSA CD36
Placenta 2 110 2
Placenta 1 103 3
Male 1 0 59
Male 4 9 143Pa
ras
ite
so
urc
e
Parasites bound*
Ex vivo assay:Placental parasites ( )bind to lining ofplacenta
*per 20 hpf
Villus
Birth weight (kg)
An
ti-a
dh
esio
n A
b L
evel
Primi Secundi Multi
-40
0
40
80
120
0
40
80
120
1.5 2.5 3.5 4.5
Antibodies and Pregnancy Outcomes
5/21
2/47LBW
LBW
Gravidity
Antibodies against Parasites of Pregnancy Malaria
Take Home Lessons
• Antigenic variation– multigene families, mechanisms differ between parasites
• Parasites modulate the immune response
• Parasites co-opt the immune system
• Resistance to parasites may or may not be immune-mediated
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