Translational activities

Overview of Translational work in Immunology and Infection.

Many members of the Institute are actively engaged in translational work, which can be divided into three themes: disease intervention methods, diagnostics and policy formulation.

Disease Intervention (vaccine and drug development)

The integration of basic research into infectious disease research in the Institute is apparent in the wealth of translational work being conducted by several groups. In particular, the tradition of malaria research in the University of Edinburgh is represented by work on vaccine development in at least 4 laboratories.

The Cavanagh lab

The Cavanagh lab is involved in the development and clinical evaluation of vaccines for the parasites causing malaria, in collaboration with industrial partners in Europe and India. The Cavanagh lab have identified a novel target for malaria vaccine development in the N-terminal region of merozoite surface protein 1 (MSP-1) and demonstrated its association with protection in both human and experimental models.

They have developed a novel, stable and easily produced multivalent vaccine based on MSP1 Block 2 sequences that targets all known MSP1 variants of Plasmodium falciparum.

The Cavanagh lab is collaborating with two industrial partners to optimize recombinant vaccine expression and delivery, and are producing and pre-clinically evaluating a new malaria vaccine based on a novel parasite antigen.

The Rowe lab is involved in the development of drugs and vaccines to treat and prevent life-threatening malaria. They are targeting rosetting - the ability of malaria-infected red blood cells to form clumps with uninfected red cells.

Rosetting malaria parasites clog up blood flow in small blood vessels in vital organs, and cause tissue damage and disease that can be fatal.

Together with 2 other universities, they are investigating the ability of sulfated glycoconjugate compounds to reverse, as well as the potential for an anti-rosetting vaccine by raising antibodies to the parasite rosetting ligand PfEMP1.

The Matthews lab has been conducting research on important veterinary pathogens.

They have developed a non-pathogenic trypanosomatid organism, Trypanosoma (megatrypanum) theileri as a vaccine delivery system for cattle pathogens.

Trypanosoma theileri is a ubiquitous trypanosomatid of cattle found in all or most cattle throughout the UK, Europe, US and globally. Using knowledge from their work focussed on pathogenic trypanosomes of sub Saharan Africa they have developed methods to engineer T. theileri to express heterologous proteins and antigens that stimulate the immune response of cattle and vaccinate them against bovine infections.

The system promises to be a safe, flexible and cost effective vaccination system that can combat infections such as bovine TB, FMDV, Salmonella and brucellosis, as examples.

The Mutapi lab works on a different parasite, the helminth Schistosoma haematobium which causes bilharzia/snail fever and has been involved not only in identification of candidate vaccine antigens but also in researching the most effective vaccine protocol, generating data indicating that schistosome vaccine efficacy would be improved by integrating anti-helminthic treatment into vaccination protocols.

This recommendation has been taken up by both the World Health Organization and the Schistosome Vaccine Initiative. The lab is also searching for reliable markers of immune-mediated resistance to infection/pathology for evaluating schistosome vaccine clinical trials. In addition, the Mutapi Lab was involved in clinical trial studies investigating the potential use of helminth infection in controlling allergic rhinitis in Danish volunteers.

On the molecular front, basic research on intervention targets in virus and protozoa is being harnessed for application in human diseases. Following the discovery of specific microRNAs that reduce the replication capacity of multiple viral families, the Buck lab is focusing on developing and testing the antiviral therapeutic capacity of microRNAs against cytomegalovirus and other viruses. Currently they are developing antiviral microRNAs for treatment of respiratory virus infections.

The Schnaufer lab is pursuing two essential trypanosome enzymes as novel drug targets in these organisms. The first one is RNA editing ligase 1 (REL1), involved in a unique post-transcriptional RNA processing pathway in the mitochondrion of these organisms.

In collaboration with Prof Rommie Amaro, a computational biologist in the US, they have used state-of-the-art in silico drug screening techniques and have already identified a number of single-digit micromolar REL1 inhibitors, one of which kills the African trypanosome T. brucei with an IC50 in the low micromolar range.

They have also developed a biochemical high-throughput screening assay for REL1 and won support from SULSA, Wellcome Trust, GSK and the NIH in the USA for screening campaigns.

These campaigns are currently underway and hits are being evaluated for medicinal chemistry follow up in collaboration with Prof Rommie Amaro (University of California San Diego) and Prof Michael Greaney (University of Manchester).

The second target is the mitochondrial ATP synthase, which in the disease-causing stage of T. brucei functions in a unique way. Here they are piggy backing on efforts in the pharmaceutical industry to develop ATP hydrolase-specific inhibitors.

In collaboration with Dr Greaney they have synthesized some of these compounds and are currently testing them in the laboratory.

The Potocnik lab works on the mouse model of malaria (P. chabaudi). Using this system, they discovered that early dyserythropoiesis in acute malaria precedes the peak of parasitaemia and anaemia.

The functional inability of early erythroid progenitors to respond towards Epo is largely related to IFN γ signaling. They are investigating the effect of blocking IFN γ signaling genetically and by small molecule inhibitors of the Jak-Stat pathway, and pursuing therapeutic protocols to eliminate the cellular source of IFN γ during acute infection with the hope of reducing acute malaria.

They are also working towards the generation of mouse models with humanized receptors to all them to define the exact mechanism of one of the pathways leasing to clinical malaria symptoms and then screen agonistic/antagonistic peptides against distinct receptors involved in the pathway thus interrupting the development of pathology.

Diagnostics

A spin-off from of the Cavanagh lab’s work on malaria vaccines is that their recombinant Plasmodium falciparum antigens are now being used in an anti-malaria antibody detection kit employed as a front line donor screening assay by the National Blood Transfusion Services in the UK and abroad.

More reliable malaria antigen and antibody diagnostics are also being developed by the Cavanagh lab, in collaboration with a small biotech company in England. Other groups in the institute continue to work on markers for diseases which can be used for diagnosis, for example, the Potocnik lab is also working on biomarkers of malaria pathology.

The Buck lab identified microRNA biomarkers associated with a range of infection conditions, including Schistosoma mansoni-induced fibrosis and now they are testing the capacity of parasite miRNAs to detect River blindness.

The Mutapi lab is evaluating serological assays for schistosome infection as well as identifying reliable morbidity markers of paediatric S. haematobium infection to inform organisations and partners involved in schistosome control.

Policy formulation

The Mutapi Lab has been working with the World Health Organisation to formulate an evidence-based policy on the control of paediatric schistosomiasis in pre-school children. They are also involved in monitoring and evaluation of Zimbabwe’s National Schistosomiasis Control Programme.

The Schnaufer lab is part of the Non-Tsetse Transmitted Animal Group (NTTAT) which meets annually and advises the World Organisation for Animal Health (OIE) on policies concerning animal trypanosomes.