Annual Report 2008 - 2009 - Liverpool School of Tropical Medicine

MOLECULAR & BIOCHEMICAL PARASITOLOGY GROUP
MALARIA PATHOGENESIS GROUP
Infected red blood cells binding to platelets
Platelets binding to ultra-large von Willebrand Factor ‘string’
Cytoadherence in P. falciparum malaria is thought to play a major
role in the pathophysiology of severe disease. Research in Professor
Craig’s laboratory into this important feature of malaria uses static and
dynamic ex vivo models of parasite binding, functional genomics
and cell biology. His group uses this information to identify possible
therapies for severe malaria, for example small molecules capable
of reversing or blocking cytoadhesion. They also look at the host
response to parasite sequestration and its potential impact on
disease outcome as well as novel mechanisms of cytoadherence.
PROF A CRAIG, DR Y WU, DR J
MONTGOMERY, DR S WASSMER AND
DR D BRIDGES
Research overseas is a critical component of
Professor Craig’s group. Projects are mainly
based in Malawi and Kenya, looking at variant
adhesive parasite types in patient populations,
as well as an analysis of the tissue distribution of
parasite populations during sequestration and
variation in the host response to infection.
Some of their recent work has identified a new
method by which malaria parasites within
infected red blood cells can attach to host cells
lining the blood vessels. This novel pathway
does not rely on long-term activation of the
host, but uses quick-acting chemicals to release
long strings of a sticky protein (ultra-large von
Willebrand Factor (ulVWF)) into the lumen
of the vessel to which platelets can bind,
acting as a bridge for adhesion of parasitized
erythrocytes.
Dr B Urban and Dr E Gitau
Clinical immunity to malaria is dependent
on repeated exposure to Plasmodium
falciparum-infected erythrocytes, which
adhere to endothelial cells and sequester in
capillaries. Our group, currently based at the
KEMRI-Wellcome Trust research programme
in Kilifi, Kenya, is researching whether and
how the cytoadhesive properties of infected
erythrocytes shape the immune response to
a given isolate. We have developed a system
to identify and express a small region of the
variant cytoadhesion protein identified in
parasite isolates from children admitted to the
local hospital. We use the recombinant proteins
for the activation of antigen-specific T cells
from the same child and measure the type
and duration of cytokine responses. Together
with the cytoadhesion profile of the infecting
parasite isolate, we are now able to establish
whether there is a relationship between
cytoadhesion and immune responses to a
particular parasite variant.
We are also investigating B cell responses in
children with acute malaria. We have shown
that children with acute malaria maintain B cell
memory cells after the acute attack, indicating
that they are induced although a considerable
number are IgM positive. We are now
investigating the role of IgM memory B cells in
acute malaria.
26 LSTM ANNUAL REPORT