An international collaboration including researchers from Perth's The Kids for Child Health Research has identified a critical genetic risk factor for a potentially fatal parasitic disease that affects up to 400 thousand people a year, mostly children.
The results have just been published online in the prestigious international journal Nature Genetics and are an important step towards the development of a vaccine against the disease known as visceral leishmaniasis.
The study, involving 6,000 people living in areas of India and Brazil endemic for the disease, identified variation in a specific region of the major immune response locus, known to immunologists as the major histocompatibility complex (MHC), as the single most important genetic risk factor for disease.
Scientists from India, Brazil, UK, Australia and USA worked together as the LeishGEN Consortium to undertake the study jointly with the Wellcome Trust Case Control Consortium.
For the teams in Australia, UK and USA, the results are being used in a targeted way in vaccine research to study the way the immune system interacts with the disease in mice.
Professor Jenefer Blackwell, who led the LeishGEN Consortium first from the Cambridge Institute for Medical Research at the University of Cambridge and now from The Kids for Child Health Research as a Winthrop Professor of the University of Western Australia, says: "Earlier genetic studies of visceral leishmaniasis in inbred mice allowed us to clearly demonstrate the importance of the MHC in regulating this disease. Now, major advances in human genetics, and the ability to compare the genomes of large numbers of people with and without the disease, have allowed us to identify the precise molecular basis to this MHC control in humans. This will have a major impact on refining research towards the ultimate goal of a vaccine."
Leishmania are single-celled parasites that have adapted to living in macrophages. These are central cells of the immune system whose normal role is to gobble up and kill invading micro-organisms.
Leishmania parasites are transmitted by the bite of sand flies and cause disfiguring as well as fatal forms of disease in sub-tropical/tropical regions of Old and New Worlds.
Leishmaniasis is classified by the World Health Organization as one of the neglected tropical diseases. It affects 12 million people and there are an estimated 1.5 million new cases annually. Of these, 200-400,000 are cases of potentially fatal visceral leishmaniasis caused by the Leishmania donovani complex, 90% of which occurs in three foci in India/Bangladesh/Nepal, Sudan/South Sudan/Ethiopia, and Brazil.
Now, a study comparing genomes of 1346 people suffering from disease in India and Brazil against those of 2,702 healthy controls has identified a single major genetic region implicated in disease. The findings were confirmed in an independent cohort of 941 cases and 990 healthy controls from India.
Professor Peter Donnelly from the University of Oxford, Chair of the Wellcome Trust Case Control Consortium, says: "Thanks to the hard work of clinicians and scientists in the endemic areas of India and Brazil, and the 6,000 people from those countries who have provided DNA samples, we were able to undertake the largest genetic study of this potentially fatal infectious disease. The signal of association at the MHC was decisive, and focuses attention on a genetic interval containing particular immune-system variants which must have a biologically important role in determining the outcome of the infection. It was striking to find the same human genetic factors involved in different continents where disease is caused by different species of the parasite."
Professor Shyam Sundar from Banaras Hindu University in Varanasi, India, says: "Our team has been excited to participate in this important research. In our region we have been World leaders for drug trials of new therapies for leishmaniasis, but development of resistance means that the parasites keep getting one step ahead of us. What we really need is a vaccine. This genetic study has influenced the path of research to identify potential vaccine candidates that will target the susceptible individuals."
Professor Selma Bezerra Jeronimo from the Universidade Federal do Rio Grande do Norte, Natal, Brazil, is also excited about the results of this research. She said: "Through the international team that LeishGEN has brought together, and the collaboration with the Wellcome Trust Case Control Consortium, we are now more confident that we might be able to develop vaccines that will work against the disease across the divides of geography and parasite species."
The study was funded by the Wellcome Trust and the National Institutes of Health.
-ends-
Notes to editors:
200-400,000 new cases of potentially fatal visceral leishmaniasis caused by the Leishmania donovani complex occur annually, 90% of which occurs in three foci in India/Bangladesh/Nepal, Sudan/South Sudan/Ethiopia, and Brazil. A large percentage of the disease burden falls on children under 12 years old. See the latest WHO review of leishmaniasis in the open access online publication: Alvar, J. et al. Leishmaniasis Worldwide and Global Estimates of Its Incidence. PLoS One 7, e35671 (2012).
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
About Oxford University's Medical Sciences Division
Oxford University's Medical Sciences Division is recognized internationally for its outstanding research and teaching, attracting the brightest minds from all over the world. It is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students, and brings in around two-thirds of Oxford University's external research income. Listed by itself, that would make it the fifth largest university in the UK in terms of research grants and contracts. Oxford is home to the UK's top-ranked medical school, and partnerships with the local NHS Trusts enable patients to benefit from the close links between medical research and healthcare delivery. 14 winners of the Nobel Prize for Physiology or Medicine worked or were educated at Oxford, and the division is home to 29 Fellows of the Royal Society and 68 Fellows of the Academy of Medical Sciences. www.medsci.ox.ac.uk
About the Cambridge Institute for Medical Research
University of Cambridge School of Clinical Medicine: The Cambridge Institute for Medical Research (CIMR) is a cross-departmental institute, within the University of Cambridge School of Clinical Medicine, that is housed in the Wellcome Trust/MRC Building on the Addenbrooke's Hospital Site of the Cambridge Biomedical Campus. It provides a unique interface between basic and clinical science that underpins its high level objective of determining and understanding the molecular mechanisms of disease. Currently, CIMR comprises approximately 250 scientists, about a quarter of whom are graduate students. They are organised into around 40 research groups each led by a Principal Investigator (PI) who, along with their group members, is also a member of one of seven home University departments (Medicine, Pathology, Medical Genetics, Clinical Biochemistry, Haematology or Clinical Neurosciences). Jenefer Blackwell was the founding director of CIMR in 1998. Since this time the institute has maintained a healthy proportion (around 40%) of PIs who are medically qualified and clinically active, and a strong base of cross-disciplinary collaborative research. CIMR receives core support from the Wellcome Trust in the form of a strategic initiative award. The Wellcome Trust is the major source of funding for the individual research groups with approximately 70% of grant income coming from the Wellcome Trust and close to 20% from the MRC. www.cimr.cam.ac.uk