UK:Brazil Joint Centre Partnership in leishmaniasis

Lead Research Organisation: University of York
Department Name: Biology

Abstract

Leishmaniasis is a neglected tropical disease of humans that primarily affects the poorest people in developing countries. There is currently no effective vaccine and treatment relies on chemotherapy with inadequate drugs as the first line approach for reducing the burden of disease. Visceral leishmaniasis (VL) is the most severe form of the disease and in Brazil it is caused by transmission of the protozoan parasite Leishmania infantum by sand flies; this leads to ~3,500 cases a year with ~10% deaths. Cutaneous leishmaniasis is also a significant public health concern, with Leishmania braziliensis being the most prevalent species. The UK:Brazil Joint Centre Partnership in leishmaniasis (JCPiL) will research the biology of the Leishmania parasite and its interaction with the mammalian host, primarily the human. Studies will be focused on understanding parasite genetic diversity in the context of variations in factors produced by Leishmania that evoke disease, mechanisms of immune evasion, diversity of host response and immunopathology. The Centre is built on a strong track record of current or recent joint projects with Brazil involving investigators from 3 UK Universities (York, Durham and Glasgow) and 3 Brazilian States (São Paulo, Rio de Janeiro and Piaui). Close collaborative working between Brazil and the UK investigators will facilitate the translation of fundamental research into new diagnostics and therapies. To this end the JCPiL will fund five inter-related projects and a workshop will take place to promote research at the interface of basic and clinical science, to extend existing collaborations between UK and Brazil and to develop new partnerships and interdisciplinary ways of working. Overall, we expect the outcome from this partnership to be a greatly improved understanding of how the parasite causes disease and how this knowledge can be exploited to develop novel therapies to treat leishmaniasis.

Technical Summary

Leishmaniasis is a devastating parasitic disease that targets the poorest of society and is the 9th largest global infectious disease burden (WHO). It is truly a Neglected Infectious Disease as the combined financial support of basic and clinical research equates to <2% of infectious disease R&D resources available. Consequently, there are no vaccines available currently and the limited available treatments are repurposed from other applications, have severe side effects; including anaphylaxis, growing drug resistances and are inappropriate for the primarily juvenile leishmaniasis patients. Disease pathologies range from tegumental (mucocutaneous and cutaneous leishmaniasis) to visceral and cases in Brazil alone range from 20,000 TL to 3,500 VL per annum.

The JCPiL will fund five inter-related projects and 3 workshops to promote research at the interface of basic and clinical science, to extend existing collaborations between UK and Brazil and to develop new partnerships and interdisciplinary ways of working. Travel will be used to cross train PIs, PDRAs and PhD students in the foremost technologies and expertise available worldwide. Studies will be focused on understanding parasite genetic diversity in the context of variations of Leishmania infectivity and virulence factor expression, mechanisms of immune evasion, diversity of host response, resultant immunopathology and sustained activation that drives chronic disease. We will investigate novel molecular targets of vulnerable pathways that are essential to Leishmania viability, optimise techniques and diagnostic markers to predict and definitively categorize patient pathology profiles to inform more bespoke, effective treatment design. Our JCPiL will create new collaborations in order to build sustainable, fundable future projects and make an impact on this deadly disease.

Planned Impact

The primary aim of this project is to attain new knowledge, innovation, scientific advancement and the development of a sustainable UK:Brazil Joint Centre Partnership. The work aims to investigate fundamental aspects of the biology of Leishmania species, which cause some of the world's most prevalent neglected infectious diseases (NIDs), the Leishmaniases, as well as the response of the host (human) to infection. A deeper understanding of the interaction of the pathogen with its hosts, the human and the phlebotomine fly vector, is expected to lead to the development of new treatment regimens in South America. Thus, the ultimate beneficiaries of the work will be those in endemic areas of the world who are infected with Leishmania. The project is likely to lead to the development of new resources and tools that can be utilized by other researchers for their own investigations into NIDs. In particular, much of the research will be highly relevant to Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi. As both Leishmania and T. cruzi are trypanosomatid, kinetoplastid parasitic protozoa knowledge gained on leishmaniasis research is applicable to other NIDs in South America.

This project will support the achievement of Sustainable Development Goals 1 (no poverty) and 3 (good health) in Lower Middle Income Countries of South America, through research contributing to the improvement of treatments for tegumentary and visceral leishmaniasis. Leishmaniasis is a neglected tropical disease with substantial and complex links with poverty. The burden of leishmaniasis falls disproportionately on the poorest segments of the global population, including within Brazil, where there are 30,000 cases/year. 90% of VL cases are found in six countries, Brazil, Ethiopia, India, Somalia, South Sudan and Sudan. Diagnosis and treatment of leishmaniasis is expensive and many of the drugs used are not fit for purpose; drug resistance is an increasing problem. Public investment in treatment and control would decrease the leishmaniasis disease burden and help to alleviate poverty, yet more research is required to understand the parasite and host and environmental factors that contribute to clinical outcome of disease. This project aims to integrate the strengths of Brazilian and UK science in Leishmania biology and response of the host to infection to increase capacity in both Brazil and the UK for fundamental research into the factors that influence leishmaniasis disease progression.

Publications

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