- Research on the immunology underpinning host infectiousness in visceral leishmaniasis
- Molecular pathological studies on skin lesion diversity in tegumentary leishmaniasis
- Phase II clinical trials of a candidate leishmaniasis vaccine in Sudan
- Identification of targets for host directed therapy across the L. donovani disease spectrum, and
- The development of a human challenge model of cutaneous leishmaniasis.
Related work in the other groups includes studies on parasite cysteine peptidases and kinases and RNA binding proteins, on the role of non-coding RNAs in host immunity, on parasite genomics and on drug target identification.
Examples of current research projects:
Regulating the trans-regulators: investigating the PRMT7 molecular pathway as an epigenetic regulator of Leishmania virulence (P Walrad)Funded by the Medical Research Council
The single-cell Leishmania parasite differentiates in distinct forms during its lifecycle to adapt to different hosts; moving from mammals to sand flies and back to mammals by sand fly bites. Major changes to the parasite’s morphology, metabolism and virulence proteins occur during these transitions that enable them to survive. Leishmania gene expression relies almost exclusively upon mRNA regulation. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the adaptation of these parasites enable them to survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. We have recently isolated a major control panel “Regulator” protein, PRMT7, which controls Leishmania parasite virulence in mammalian infections. Very few Leishmania regulator proteins have yet been identified and this finding represents a major leap forward to isolate and examine this regulatory pathway and interfering with parasite virulence.
We have identified some downstream target proteins of PRMT7 and now seek to determine if they are regulated by PRMT7 and whether they participate in Leishmania parasite virulence. These Leishmania proteins are different from human proteins; therefore we can use these differences to target Leishmania – specific virulence factors, block their function and block leishmaniasis from developing. Significant findings may provide insight to leishmaniasis research. We propose to find more regulators of Leishmania virulence using the PRMT7 virulence pathway. We will identify how these regulators function, and test whether any are essential for parasite survival.
Leishmania virulence factors and host peptidases associated with visceral leishmaniasis (J Mottram, P Kaye)Funded by the Medical Research Council
The aim in this project is to characterise key biological processes of Leishmania chagasi, and so identify factors that influence the outcome of disease. The work will concentrate on three key areas of the biology of the parasite and its interaction with the host. The project will test if peptidases in the mammalian host are important for the pathogenesis of the disease. It will investigate the genome variation that occurs in different strains of Leishmania. It will sequence the genomes of L. chagasi parasites isolated from patients in the State of Piaui in Brazil with different clinical VL outcome and identify parasite genes that might influence the presentation of disease. It will integrate parasitological and immunological studies in animal models and humans and overall, with the expectation that the outcome from the study to be a greatly improved understanding on the roles of these biological processes in Leishmania, and the molecular mechanisms of the processes themselves – which will be relevant to many areas of biology.
Developing a human challenge model for Leishmania major infection as a tool for assessing vaccines against leishmaniasis (P Kaye, C Lacey, A Layton), Funded by the Medical Research Council and the Department for International Developmentwww.leishchallenge.org
The primary outcome of this project is the development of an effective Leishmania major human challenge model with 100% lesion clearance after treatment. The secondary outcomes include the measurement of immune response parameters and analysis of lesion development.
Leish Challenge is split into two stages.
Stage 1 develops the tools necessary to conduct a human challenge study comprising four elements: focus group discussions, validation /modification of a sand fly biting protocol using uninfected sand flies; establishment of a clinical parasite bank at GMP, to provide a source of parasites for sand fly infection and human challenge, submission for ethical review for the human challenge.
Stage 2 brings these elements together in a CHIM study.