Role of Immune Complex in Severe Malarial Anemia

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Severe anemia is one of the deadliest
complications in children infected with Plasmodium falciparum in sub- Saharan
Africa. This anemia cannot be accounted for solely on the basis of destruction
of parasitized RBCs. Therefore, the long-term objective of this application is
to identify the pathogenic mechanisms that lead to severe malarial anemia and
that involve destruction of uninfected RBCs. Children with severe malarial
anemia have acquired deficiencies of RBC complement regulatory proteins (CRPs)
(CRl and CD55) and the expression of these proteins is age-dependent, being
lowest among children with the highest risk of anemia. Other reported
abnormalities in children with severe malarial anemia are the excessive
production of immune complexes (ICs), pro-inflammatory cytokines and nitric
oxide (NO). Preliminary data indicate that ICs contribute to the inflammatory
response during malaria infection and that RBC CRl plays a crucial role in
modulating the production of pro-inflammatory cytokines and NO in response to
ICs. We postulate the following: 1) RBCs of children with severe malarial
anemia are more susceptible to complement-mediated lysis than those of
children with uncomplicated malaria due to deficiencies in RBC CR1 and CD55.
2) The level of pro-inflammatory cytokine and NO produced during malaria
infection is modulated by the capacity of RBCs to bind and remove immune
complexes from circulation. 3) There are no qualitative differences between
ICs formed in children with severe malarial anemia and those formed in
children with uncomplicated malaria. In the present application we propose to
test these hypotheses by carrying out case-control and cross-sectional studies
to determine if RBCs of children with severe malarial anemia have increased
susceptibility to complement-mediated lysis and decreased capacity to bind IC,
and whether these parameters change as CRP expression changes with age. The
studies proposed here will advance our understanding of the role of ICs and
CRPs in the pathogenesis of severe malarial anemia, and of the nature of the
ICs that form during malaria infection and their implications for the safety
of future experimental malaria vaccines in children.
StatusFinished
Effective start/end date8/15/026/30/03

Funding

  • National Heart, Lung, and Blood Institute: $276,485.00

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