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Host-Parasite Interactions
Patrick Duffy
206 256 7311
[email protected]
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
Malaria life
cycle
Richie & Saul 2002
ANTIGENIC VARIATION
Antigenic variants within strains
Plasmodium knowlesi
VARIANT
SPECIFIC
IMMUNITY
VARIANT
TRANSCENDING
IMMUNITY
SULFA
Brown & Brown 1965
Nuri strain in Rhesus
Variant-specific immunity in monkeys
P. knowlesi
NO VACCINE
VACCINATED (variant A + IFA)
Brown 1973
Nuri strain in Rhesus
Antibody-induced variation
Parasitemia
Strain-specific immunity in monkeys
P. falciparum
Strain A
Inoculum
(Indo-1)
Strain B
Inoculum
(UgPA)
Hommel 1985
Saimiri monkeys
Strain-specific immunity in humans
P. vivax
Parasitemia
QUININE
Strain A
inoculum
Strain B
inoculum
Yount & Coggeshall 1949
Joilet, IL prison studies
Variant antigens on the IE surface
P. falciparum
MC extract
SL extract
Variant surface antigen:
1.
2.
3.
4.
200 kD--
5.
IP with sera: aMC
aSL
Large MW
Tx100 insoluble/SDS soluble
Surface iodinatable (I125)
Strain-specific IP
(similar to cytoadherence)
Trypsin-sensitive
(similar to cytoadherence)
aMC aSL
Serum antibodies from monkeys infected with
Malayan Camp (MC) or Santa Lucia (SL) parasites
Leech/Barnwell/Howard 1984 (P. knowlesi)
Many years later… PfEMP1
Semi-conserved
head structure
Tandem
association
Tandem
association
NTS
TM
DBL1a
CIDR1a
Rosetting
CR1
HS
Blood group A
Heparin
CD36
CD31
IgM
CSA
DBL2b
C2
ICAM-1
IgG
DBL3g
DBL4e
CSA
CSA/C
NTS
CIDR1a
DBL2d
CIDR2b
ATS
PECAM
Acidic Terminal
Segment
Exon-2
(Cytoplasmic
domain)
Exon-1
(Extracellular domain)
DBL1a
DBL5d
CIDR2b
ATS
Exon-2
Exon-1
Cell 1995
Su & Wellems
Smith & Miller
Baruch & Howard
CD36 Binding and Non-binding PfEMP1 Groups
Non-CD36 binding
CD36 binding
~60 copies per haploid genome
Majority are subtelomeric
Joe Smith
Switching in
T. brucei
PRIMARY LITERATURE
Bull et al., J Infect Dis 182:252
Serum agglutination of field isolates:
Evidence for variant specific immunity
AGGLUTINATION SCORE
0
1
2
3
4
ISOLATE
3 MONTH OLD CHILD
SICK
RECOVERED
ISOLATE
26 MONTH OLD CHILD
SICK
RECOVERED
Bull & Marsh 1999
SERUM SAMPLES
Serum agglutination of field isolates:
Rare Variants and Prevalent Variants
FIELD ISOLATES
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 I
antigen
associated with
resistance to
severe malaria
Hill et al., Nature, 1991
Reciprocal CTL antagonism
in PBMC cultures by two
naturally occurring P. falciparum
CS protein variants.
CS protein and
HLA B35:
Evidence for
Host-parasite
Co-evolution?
Gilbert et al., Science, 1998
Frequency of CSP variants in parasites collected
from 795 Gambians with malaria.
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
Taylor et al., 2000
Urban et al.
Figure 2
MF Good commentary
Nature 1999
PRIMARY LITERATURE
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 5
Fig. 6
CO-OPTING THE IMMUNE SYSTEM
S. mansoni
expresses host-like
molecules on
its surface
Trottein, JI, 1997
Immune masking
McManus, 2001
Ig and associated complexes affinity-purified from S. mansoni with protein G
IgG
Adsorption of human Ig
on the surface of red cells
infected with P. falciparum
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
Epidemiology and Immunity
Parasitemia
Severe childhood malaria
Prevalence
Pregnancy malaria
1
10
20
Age (years)
Adults acquire resistance more rapidly than children
80
migrants after 8 months exposure
70
60
50
40
30
20
migrants after 20 months exposure
10
0
2-5
6-10
11-15
16-25
26-40
Age group (years)
>40
Baird 1995
6
100
5
80
Age 12-14
Age 15-20
60
Age 21-35
40
P < 0.0001
n = 243
Tanner Stage
Volunteers infected (%)
Age and susceptibility
4
3
2
1
20
0
0
0
2
4
6
8
10
12
14 16
Weeks after treatment
12-14
15-20
21-35
Age group (yrs)
DHEA-S levels predict resistance to malaria
P<0.05
P<0.01
Mean Parasitemia
100
P<0.01
P<0.05
DHEA-S level:
low
medium
high
10
1
.1
0
12-14
15-20
Age (yrs)
21-35
Culture of Plasmodium falciparum
Effect of DHEAS in vitro
Serum+ DMSO
Serum + DHEAS
% Parasitemia
7
6
5
4
3
2
1
0
0
24
48
72
Time (hours)
96
120
144
IS RESISTANCE IMMUNITY?
Resistance to pregnancy malaria
Parity-related Susceptibility to Placental Malaria
(1500 deliveries in Kisumu, Kenya)
Primigravid
Secundigravid
Multigravid
30
8
6
20
4
10
2
0
0
Rate (%)
Mean parasite density (%IE)
Parasites of Pregnancy Malaria
Parasites infecting pregnant mothers are different than other
parasites
Parasite adhesion to placenta ex vivo
Placental parasites
Parasites from adult males
Fried, Duffy 1996
Parasites of Pregnancy Malaria
Ex vivo assay:
Placental parasites (
bind to lining of
placenta
)
Parasite source
Villus
Parasites bound*
BSA
CSA
CD36
Placenta
2
110
2
Placenta
1
103
3
Male
1
0
59
Male
4
9
143
*per 20 hpf
Anti-adhesion Ab Level
Antibodies
against Parasites
Antibodies
and Pregnancy
Outcomesof
Pregnancy Malaria
120
LBW
2/47
120
80
80
40
40
LBW
5/21
0
0
-40
Primi
Secundi
Gravidity
Multi
1.5
2.5
3.5
Birth weight (kg)
4.5
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