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Laboratory for Infectious & Tropical Diseases

Research

LITD Research

We are interested in the cellular and molecular biology, and immunology of malaria parasites. Most of our work is focused on the transmission stages of P. falciparum parasites, gametocytes. The majority of malaria episodes in sub-Saharan African are caused by P. falciparum, which is more virulent than other species and causes severe forms of malaria. Gametocytes are responsible for transmission of parasites between humans via mosquito bites. Together, childhood malaria and malaria in pregnancy are important causes of mortality in sub-Saharan Africa. We use a range of modern molecular, cell biological, transcriptomic, genomic and immunological approaches to understand fundamental parasite biology and use this knowledge to identify and develop targets for disease intervention. At the moment, we are focusing on the following specific research areas:

Bone marrow malaria– understanding and preventing gametocyte sequestration and retention

Gametocytes of P. falciparum go through several forms of development in different sites of the human body. The earliest forms of gametocytes develop in tissues of the bone marrow, emerge into circulation when mature and ready to be transmitted to mosquitoes. We have limited understanding how gametocytes arrive in the human bone marrow, which specific parts of the bone marrow tissues they are in, what processes maintains them there, and how they are released back into circulation. In addition, changes in the bone marrow driven by infection-induced inflammation may exert their effects far beyond the acute phase of the malaria infection, such as disrupting immune memory. We are using molecular, immunohistochemical, immunological tools and single cell transcriptomics to perform in-depth investigations in human bone morrow obtained from living and malaria semi-immune individuals. These would allow us to understand the dynamics of gametocyte sequestration in these tissues more fully and comprehensively characterize parasite-induced changes in human bone marrow. We are working in close collaboration with Drs. Joseph Korpisah and Ali Ayamba at UHAS School of Medicine, Dr. William Gyau Dwamena at St Anthony’s Hospital, Dzodze, and Dr. Daniel Yao Dodzie Agbeley at Ho Teaching Hospital, Ho, all in the Volta Region of Ghana. Our international collaborators include Dr. Pietro Alano at ISS, Rome, Italy, Dr. Britta Urban at LSTM, Liverpool, UK and Prof. Oliver Billker, MIMS, Umea, Sweden.

Antibody and cellular immune responses to gametocytes

The current drug of choice for acute malaria is Artemisinin-based combination therapies (ACTs). ACTs reduce but do not eliminate gametocyte carriage, allowing some transmission to occur after treatment. Antibody responses directed at the sexual stages in the mosquito have been shown to reduce malaria transmission whereas little is known about antibody responses directed against gametocytes in the human host. We have described distinct antibody responses recognising gametocytes which are associated with reduced gametocyte carriage, but the target antigens are unknown. We are using molecular and immunological approaches, transcriptomics to identify and characterize gametocyte-specific antigens in order to illuminate on gametocyte immunity and to develop transmission blocking interventions. We work in close collaboration with Dr. Britta Urban at LSTM, Liverpool, UK, Prof. Colin Sutherland at the LSHTM, London, UK, Prof. Gordon Awandare, WACCBIP, Legon, Accra and Prof. Fred Binka at UHAS.

Gametocyte sex ratio determination and variant antigen expression— regulated epigenetically?

Malaria parasites have to sense their environment to regulate gene expression, for instance in order to evade immunity or to produce gametocytes at the optimal sex ratio. The underlying molecular mechanisms are largely unknown, but available evidence suggests a strong element of epigenetic regulation. We have established several malaria parasite lines isolated from symptomatic patients and we are using sequencing techniques (RNA-seq and ChIP-seq) to understand the mechanisms of regulation of sex ratio determination and associated variant antigen expression in gametocytes derived from these recent clinical isolates. We work closely with Prof. Oliver Billker, MIMS, Umea, Sweden, at this questions.

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