Immunology and immunopathogenesis of malaria infections

Lead Research Organisation: The Francis Crick Institute

Abstract

Malaria, caused by infection with the protozoan parasite Plasmodium, is one of the most prevalent transmissible human diseases with approximately 200 million infections and 300,000 deaths annually. Despite the magnitude of this global health problem, we still do not understand the mechanisms underlying severe disease and mortality, or protective immunity. There is an urgent need to develop new intervention therapies. This project is aimed at understanding the immune response to the parasite, so that we will be able to design effective vaccine strategies and possibly immuno-therapy for treating the disease. We study the immune response of children, as well as an experimental model infection in mice in order to determine the various ways the immune system can recognise and attack the parasite, which resides in red blood cells.
In addition, we are identifying the molecules of the parasite that are important for stimulating an effective immune response. When this is known, these molecules can be incorporated into a vaccine. Different ways of administering vaccines are being tested in the mouse model. It is hoped that these studies can be directly applied to the human infection

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

Malaria is one of the most prevalent transmissible human diseases with approximately 200 million infections and 300,000 deaths annually. Despite the magnitude of this global health problem, we still do not understand the mechanisms underlying severe disease and mortality, or protective immunity. My laboratory studies immune responses in a relevant mouse model and in children with malaria.
Children in endemic areas acquire immunity to malaria after several clinical episodes, but a significant minority experience many episodes before developing immunity. We are investigating whether we can identify immune responses that characterize those children who will suffer frequent clinical malaria episodes. In a cross-sectional study, children have been identified who; a) have already experienced many episodes, b) experienced a "normal" number of episodes, with similar exposure; and c) live in a similar area but with very low malaria transmission. Immune responses using transcriptomics, flow/mass cytometry, and plasma cytokines/chemokines are being analysed to determine immune profiles that define these children. In a longitudinal study, we will determine whether these or other immune markers identify/predict children at risk from many episodes of clinical malaria. Using human in vitro studies and animal models, the functional relevance of these profiles will be investigated.
Plasmodium chabaudi infection in mice demonstrates many features of human malaria: chronicity, antigenic variation and cytoadhesion. Mechanisms of immunity are well described and, as for human malaria, antibodies are important for protective immunity. There is similarly evidence of impaired immunity, and immune-mediated pathology. We investigate the requirements for effective T follicular helper cell (Tfh) responses, their interaction with B cells and the development of B-cell responses, and whether chronic and virulent malaria and the pro-inflammatory Th1 response, impair Tfh cells. We will use a variety of inducible and conditional knockout/transgenic mice, including a CD4 T-cell receptor transgenic mouse and a B-cell receptor H-chain knock-in mouse we developed, recognizing P. chabaudi MSP1. This will allow us to investigate Plasmodium-specific atypical/exhausted Tfh and B cells and their relevance in development of protective immunity and/or virulence.
Parasite components, particularly those encoded by subtelomeric multigene families contribute to virulence and chronicity of blood-stage malaria. My laboratory focuses on the pir family, which is present in the genomes of all Plasmodium species so far sequenced, including the important human pathogens P. falciparum (rif/stevor genes) and P. vivax. Our studies suggest a causal link between pir expression and virulence, and the ability of the host to establish chronic infections. We aim to elucidate these relationships, and the mechanisms by which virulence is altered. Understanding the role of this Plasmodium-wide gene family is critical to the understanding of the basic biology of these infections and in engendering new research directions that could inform new interventions to combat malaria.
The combined approaches of mouse and human studies will increase our understanding of human immune responses in malaria, and improve mouse models so that they can better elucidate underlying mechanisms and thus development of more effective immunotherapies and vaccines.

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