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|Title: ||Rosetting and the innate immune response to plasmodium falciparum|
|Authors: ||Corrigan, Ruth Alexandra|
|Supervisor(s): ||Rowe, Alex|
|Issue Date: ||2009|
|Publisher: ||The University of Edinburgh|
|Abstract: ||Rosetting is an adhesion property of malaria parasites whereby infected erythrocytes
bind to two or more uninfected erythrocytes, forming a so-called rosette. Rosetting of
Plasmodium falciparum is associated with disease severity and high parasitaemia in
sub-Saharan Africa, although currently the function of rosetting remains unknown.
An early IFNg response elicited from the innate immune system is associated with
resolution of malaria infection in mice. Published data suggests that optimal IFNg
production may require contact between peripheral blood mononuclear cells and P.
falciparum infected erythrocytes. The first part of this thesis investigates the
hypothesis that rosetting is an immune evasion strategy to hide infected erythrocytes
from detection by innate immune cells. Across five laboratory strains of P.
falciparum rosetting was not associated with differential IFNg production when
parasites were grown in group O blood. Reappraisal of the data with respect to blood
group for one strain found that rosetting significantly reduced the IFNg response to
parasites grown in group A blood (P=0.022, Wilcoxon signed-rank test), where it is
known that rosettes are bigger and stronger. This is consistent with the hypothesis
that rosetting is an immune evasion strategy and the first study to find evidence for a
function of rosetting. Further work is needed in order to generalise this finding.
The cytokine response to P. falciparum varies between people and this variation may
be indicative of disease progression. In mice infected with malaria it is also apparent
that parasite strain can determine the cytokine response of the host. It is unclear
whether P. falciparum strains vary in their ability to induce cytokines. The second
part of this thesis investigates variation in cytokine induction between P. falciparum
strains. Across four laboratory strains of P. falciparum, IFNg production was
significantly dependent on parasite strain (F3,178= 48.49, P<0.001). Production of
GM-CSF, IL-1b, IL-6, IL-10 and TNFa significantly correlated with production of
IFNg (P<0.001, Pearson correlation) and followed the same strain-dependent pattern.
The ratio of pro-inflammatory cytokines to IL-10 was also dependent on parasite
strain. These data provide strong evidence for P. falciparum strain-dependent
cytokine responses which may be an important determinant of disease outcome.
Phagocytosis by splenic macrophages is proposed to be the principle mechanism of
parasitaemia control in malaria infection. CD36 mediated phagocytosis may by an
important mechanism of non-opsonic parasite clearance. The final part of this thesis
investigates the hypothesis that rosetting is an immune evasion strategy of P.
falciparum in order to evade phagocytic clearance, in particular that mediated by
CD36. Overall the data obtained were inconsistent. Phagocytosis was significantly
reduced in rosetting versus non-rosetting parasites in some strains (e.g. R29;
P=0.048, paired T test), whereas others showed no effect (e.g. Muz12; P=0.228,
paired T test) or increased versus non-rosetting parasites (e.g. HB3, P=0.004, paired
T test). The relationship between CD36 binding and phagocytosis was also unclear,
and anti-CD36 antibody did not effectively block phagocytosis, suggesting the
involvement of alternative mechanisms. Further experiments are needed to clarify
Data presented in this thesis are suggestive that rosetting in non-group O blood may
be an immune evasion strategy with regard to IFNg production by innate immune
cells, mechanistically linking rosetting with enhanced parasitaemia and disease
severity. Furthermore, parasite strain significantly affects cytokine production and
may be a determinant of disease outcome. This thesis demonstrates the importance of
continued research into the effect of parasite virulence on the immune response, with
particular emphasis on rosetting.|
|Appears in Collections:||Biological Sciences thesis and dissertation collection|
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