: Parasite factors

: Host factors

Assoc. Prof. Dr. Kesinee Chotivanich

Department of Clinical Tropical Medicine
Faculty of Tropical Medicine
Mahidol University.
 Malaria

host
parasite
 Disease

What factors?
Multiplication capacity of the parasites
Multiplication capacity of the parasites
Figure. Parasitized erythrocyte multiplication rate (PEMR) of
20
P. falciparum in uncomplicated and severe malaria

15

10

0
UNCOMPLICATED SEVERE
 The Selectivity index (SI)
SI = Observed number of multiply invaded RBC
Expected number from a Poisson distribution
Fig 2. The selectivity index (geometric mean (95%CI)) ofP. falciparum in uncomplicated ( )
and severe malaria ( )
9

4
_
3

2 _ _
1 _
0
UNCOMPLICATED SEVERE
Chotivanich et al, 2000
Adhesion properties of
malaria parasites
 Sequestration
= the adhesion of red cells containing mature
form of parasites to vascular endothelial
cells and thus disappear from the blood
circulation.
 P. falciparum
Schizont

Trophozoite

Sequestration
Ring
Sequestration in placenta
Parasite adhesion in placental malaria

There is intense sequestration of P.

falciparum infected red cells in placenta.

Placental insufficiency
Fetal growth retardation
Low birth weight
(reduction average : 170 g)

Fried M, et al. 2001

THE PATHOPHYSIOLOGY OF MALARIA

Brain: ICAM1

Placenta: CS-A, HA??

Elsewhere: CD 36
Cellular adhesion of P. falciparum
P. falciparum
Pathophysiology

Cytoadherence
Rosetting
Agglutination
Chotivanich et al. Ann Trop Med Parasitol. 1998 Jan;92(1):45-56.
Chotivanich et al . Am J Trop Med Hyg. 1998 Jul;59(1):73-6.
Chotivanich et al. Ann Trop Med Parasitol. 2000 Apr;94(3):219-26.
Chotivanich et al. J Infect Dis. 2004 Mar 15;189(6):1052-5
Cytoadherence
 P.f P.v
Rosette formation

P.m P.o
P.f. Cytoadherence P.v.
Rosette formation
Platelet induced agglutination

Chotivanich et al, JID. 2003

Auto-agglutination

Chotivanich et al,2003
Number of IRBCs/1000 IRBCs

100

80

60

A
40 A

A
20
R
R R
0
Uncomplicated Severe Cerebral malaria
Chotivanich et al, 2003
 Adhesion properties of
malaria parasites
Sequestration

Cytoadherence Rosette formation Agglutination

Only P.falciparum cytoadheres, agglutinatesbut all species rosette

Artemisinin derivatives prevent cytoadherence
Fever accelerates cytoadherence
Udomsangpetch et al. J Infect Dis. 1996 Mar;173(3):691-8.
Udomsangpetch et al. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11825-9.
Plasmodium vivax

Benign
malaria
and/ or
severe/fatal
-Unusual manifestation
-Co-infection
- Multiple drug resistance
 Birthweight reduction

P.falciparum: 170g
P.vivax: 110g

How does P.vivax reduce birthweight?

Nosten et al. Lancet. 1999 Aug 14;354(9178):546-9.

Does P. vivax infected red cell sequester?

Rosette formation

Agglutination

? Cytoadhesion
Pv IRBC bound /mm2
 Glycosaminoglycans (GAGs)

Hyarulonic acid

Chondroitin sulfate
Which stage of parasites cytoadhere?
Chotivanich et al, 2000
120 Relative adhesion (%)

100

80
CSA
60
HA
40
37OC
20

0
6 12 18 24 30 36 42
Age (hours)

140 Relative adhesion (%)

120

100

80 CSA
60 HA
39OC
40

20

0
6 12 18 24 30 36 42
Age (hours)
Adhesion on placenta
 Chotivanich et al

P. vivax infected red cells adhered to the placental surface

 Chotivanich et al

P. vivax infected red cells adhered to the placental surface

 Chotivanich et al

P. vivax infected red cells adhered to the placental surface

Conclusions
 CSA HA
Adhesion receptors of P. vivax
None of the P. vivax-IRBCs adhered to immobilized CD36,
ICAM-1, the major receptors for P. falciparum adhesion. All
parasite isolates adhered to immobilized CSA and HA.
 How does P.vivax reduce birthweight?

Chondroitin sulfate A Hyaluronic acid

Adhesion receptors of P. vivax
 Cytoadherence of P. vivax
to CSA and HA in placenta
Avoid splenic clearance
and immune clearance
Trigger local inflammatory process

-Interfere fetal-maternal exchange

Intrauterine growth retardation

CSA and HA may synergize the effects like co-expression

CD36, ICAM-1 in endothelial cells.
 Genetic differences in
red cells susceptibility to
falciparum malaria
World distribution of the red cell polymorphism

HbE

G6PD Def
HbS

Thalassemia
 Haemoglobinopathies

Quantity abnormal Quality abnormal

Alpha-thal; HbH disease HbH

Beta-thal; Beta-thal/HbE HbE

Alpha-thal/Beta-thal Hb Constant Spring

RBCS

ring schizont

Malaria protection by
genetic variant RBCs

IgG

P. vivax
THAL NORM
RBC RBC

1% SCHIZONT-IRBC
 Thal RBC

parasite

Normal RBC
 Susceptbility of abnormal hemoglobinopathy red cells to
P. falciparum malaria
susceptibility ratio (SR)
1.6

1.4


1.2



_


1




_*


0.8




_







0.6











_
_ _
0.4








*





_ _











_

_
0.2




_






_


0
AA AE BE EE H HCS
red cells hemoglobin
The mechanisms of parasite
clearance
Acute P. falciparum infected patients with intact spleen
from peripheral blood Spleen imprinted blood

RESA-PRBC
RESA-positive red cells
with intracellular parasites

RESA-RBC
RESA-positive parasite
negative red cells

Angus et al 1998, Chotivanich et al, 2000

 number/ul
350000
* Serial mean (SE) of PRBC and RESA-RBC
300000
densities in the blood of severe falciparum
250000 malaria patients treated with artesunate

200000

150000

100000

50000 RESA-RBC
PRBC
0
0 12 24 36 48 60 72 84 96 108 120
time (hours)
Chotivanich et al , 2000
 PRBC RESA-RBC
spleen

PITTING In patients blood

Splenic imprinted blood spleen

* RESA-RBC PITTING
Courtesy of Prof. Pongponratn E.
 Log parasite count (/mL)
7
6
5
4
3
2
1
0
0 7 14 21 28 35 42 49 56 63
Days

Parasite clearance in splenectomized patients after

artemisinin derivatives treatment
Thick and thin blood films from
spenectomized P. falciparum-
infected patients following
artemisinin derivative treatment
Host factors
Immunity
Genetic polymorphism
- CD36
- TNF receptor
Multiplication potential
Selectivity in red cell invasion
Adhesion properties

Red cell susceptibility

Splenic function