Do FcgammaRIIb polymorphisms improve resistance to malarial infection at a cost of increased sepsis in severe infection?

Lead Research Organisation: University of Cambridge
Department Name: Cambridge Institute for Medical Research

Abstract

Malaria is a major cause of illness and death in the developing world. Fc RIIb is a molecule that inhibits inflammatory responses, acting as a brake on the immune system. Our laboratory has shown that Fc RIIb mutations which reduce its function cause immune brake failure, with a hyperactive immune system which can attack the body leading to autoimmune disease such as lupus (SLE). Mice without Fc RIIb have enhanced inflammation, clear bacterial infections quickly, but may die from excessive inflammation (septic shock). Mutations in Fc RIIb have also been found in humans, where they are also associated with SLE. These mutations are more common in populations from malarial areas, leading us to question whether the mutations may be protective against infection with malaria. We will study the effect of various levels of Fc RIIb on malarial infection in mice and in human cells. We will then study mutations in Fc RIIb in an African population to see how responses to malaria are affected by defects in Fc RIIb (immune brake failure). We will test the hypothesis that the mutation protects people from developing malaria, but at the cost of higher death rates in severe disease. If Fc RIIb is involved in malaria, it would make an attractive target for new therapies for this important disease.

Technical Summary

Malaria affects 40% of the world‘s population and claims the lives of more children worldwide than any other infectious disease. We predict that Fc RIIB profoundly influences the pathogenesis of malaria. We aim to study polymorphisms of Fc RIIB on the immune response to, and clinical features of, malarial infection in vitro and in vivo.
Fc RIIB is an inhibitory immunoglobulin receptor that acts to down-regulate the immune system. Fc RIIb deficiency in knockout mice results in a propensity to autoimmunity, and we have shown that naturally occurring polymorphisms can also reduce its expression and function in mice prone to polygenic SLE. Fc RIIb deficient mice demonstrate improved bacterial clearance, but at a cost of increased septic shock. We have since shown that a human Fc RIIB polymorphism linked to SLE defunctions the receptor by excluding it from lipid rafts. This polymorphism, where isoleucine is replaced by threonine at position 232 in the transmembrane domain, is more frequent in populations historically exposed to malaria, leading us to the hypothesis that polymorphisms that reduce Fc RIIB function improve resistance to mild P. falciparum infection, but at the cost of increased cytokine-mediated problems in severe infection. We will test this hypothesis:
(i) in vitro using malarial parasites and macrophages from mice deficient in Fc RIIb, those over-expressing Fc RIIb transgenes, or those with either the mouse or human polymorphisms knocked in. We will also use P. falciparum with monocyte-derived macrophages and dendritic cells from patients with I/I, I/T or T/T at position 232 (in collaboration with Dr Britta Urban at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford)
(ii) in vivo in the aforementioned mouse models using P. chabaudi.
(iii) genetically, using well defined malarial cohorts established by Dr Tom Williams at the Kenya Medical Research Institute/Wellcome Trust Programme in Kilifi, Kenya. We will develop an automated strategy to genotype the Fc RII and RIII region on chromosome 1. This should allow us to assess the effect of the polymorphisms on the inflammatory and cytokine-mediated features of disease.

We hope to determine if Fc RIIb controls the response to malarial infection, and if defective Fc RIIb leads to exaggerated inflammation. This may identify a system which could be manipulated to reduce the mortality of malaria.

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