1. Singapore’s Agency for Science, Technology and Research (A*STAR) and the UK’s Medical Research Council (MRC) announce today that they have jointly awarded S$4.5m in grants to six collaborative research projects in infectious diseases such as gastric flu, hepatitis B, dengue fever and tuberculosis. Each project aims to contribute towards developing a treatment, vaccine or antimicrobial product to address disease infection. This is the first joint grant call between A*STAR and MRC and involves collaboration between UK-based and Singapore-based public research organisations.
2. Said Executive Director of A*STAR’s Biomedical Research Council, Prof Lee Eng Hin, “We are pleased and excited to announce the results of our first joint grant call with MRC. The awarded projects in highly relevant areas of infectious disease are a result of collaborative efforts between teams with Singapore and UK’s top capabilities in both biomedical and engineering research. By bringing the two communities together, we aim to accelerate knowledge creation with the goal of treating, eradicating and preventing infectious disease, and improving human health.”
3. Wendy Ewart, Director of Strategy for the MRC said: “Supporting this breadth of research projects will tackle some of the most important diseases across the globe that kill millions of people each year. From pioneering new treatments to unlocking the genetics behind these diseases, this international partnership will fund the highest quality science to deliver a wealth of knowledge, helping to develop future treatments and ultimately save thousands of lives each year.
Outsmarting bacteria that cause gastric flu in young and old
4. Under one grant, researchers from A*STAR’s Institute of Medical Biology (IMB) and UK’s Imperial College London aim to shed light on the signalling pathways employed by two rogue strains of the gut bacteria Escherichia coli. One strain is the leading cause of infantile diarrhoea, morbidity and mortality in developing countries, while the other is predominant in developed countries and can cause gastroenteritis (better known as ‘gastric flu’) or haemolytic-uraemic syndrome (HUS) – the young, elderly and immuno-compromised are most at risk.
5. Said IMB Principal Investigator, Dr Sohail Ahmed, “There are currently no vaccines or specific treatments against such bacterial infections. HUS patients may require dialysis and in severe cases, kidney transplantation. Better understanding of the bacteria and their means of infection is thus essential for the development of specific and effective treatments. Working together with Imperial College, our team will use an award-winning infection research model to identify proteins and signal transduction pathways targeted by specific virulence proteins produced by the rogue bacteria, and thus elucidate their infection strategies.”
Training immune cells to outlast viral infections
6. Another grant, shared by researchers from A*STAR’s Singapore Institute of Clinical Sciences (SICS) and UK’s University College London, is targeted at redirecting the body’s T cells to overcome tolerance in chronic hepatitis B infection. Hepatitis B remains one of the top ten killers in the world today, causing around a million deaths every year from chronic liver disease. A vaccine exists, but is of no use to the 400 million people estimated to already be chronically infected. There is also no effective drug therapy for the end-stage complications of liver failure and liver cancer.
7. Said SICS Principal Investigator, Dr Antonio Bertoletti, “Our goal is to develop a treatment for hepatitis B virus infection by harnessing the natural ability of T cells to control this virus. Hepatitis B patients have very few T cells left that can fight the virus in the body, so we will genetically engineer their T cells to regain their ability to fight. We will look into how effectively these genetically engineered T cells combat the hepatitis B virus in the liver by mimicking this situation in vitro and in vivo. Our findings will provide valuable information for the potential application of this approach to hepatitis and other chronic infections and tumours.”
8. The other projects awarded funding are:
• Collaboration between National University of Singapore and University of Liverpool to study and optimise the interaction between drugs used to treat tuberculosis and HIV, which are commonly co-inherited diseases;
• Collaboration between A*STAR’s Singapore Immunology Network and Imperial College London to examine the interplay between regulatory T cells and the Streptococcus bacterium;
• Collaboration between Singapore’s Nanyang Technological University and UK’s National Institute for Medical Research to investigate how the malaria-causing Plasmodium parasite evades the immune system; and
• Collaboration between National University of Singapore and University of Birmingham to study how multi-antibiotic resistant bacteria responsible for hospital-acquired infections actively pump out drugs from their interiors.
9. The A*STAR-MRC Joint Grant Call is the first to be held under the A*STAR-MRC Collaborative Research Fund, which was established in 2008 following productive workshops and travel grants under the “UK-Singapore Partners in Science” programme. The programme aims to promote R&D collaboration between UK-based public institutes and Singapore public sector research organisations via joint scientific projects in areas of common interest.
ANNEX
INFORMATION ON GRANTS AWARDED
1. Subversion of actin signaling pathways by enterohaemorrhagic and enteropathogenic E. coli Singapore PI: Sohail Ahmed (Institute of Medical Biology, A*STAR)
UK PI: Gad Frankel (Imperial College of Science, Technology and Medicine)
Escherichia coli (E.coli), otherwise a harmless part of intestinal flora, can acquire additional genes that enable them to cause gastroenteritis (better known as gastric flu) when they inject specific virulence proteins, or effectors, into the mammalian cell. Enteropathogenic E. coli (EPEC) is the leading cause of infantile diarrhoea, morbidity and mortality in developing countries, while enterohaemorrhagic E. coli (EHEC, particularly E. coli O157:H7) is predominant in developed countries and causes diarrhoea, haemorrhagic colitis and haemolytic uraemic syndrome (HUS); the young and the elderly are most at risk. About 73,000 and 1,000 human EHEC infections occur in the US and the UK each year, respectively. There are no vaccines currently available for such E. coli infections; better understanding of the bacteria is thus essential for the development of specific and effective treatments.
This project aims to investigate the physiological role of key E. coli proteins that interfere with intracellular signaling mechanisms. The mechanism by which these effectors subvert signalling will initially be studied in vitro in human cells in culture.
2. Redirecting T cells to overcome tolerance in chronic HBV infection Singapore PI: Antonio Bertoletti (Singapore Institute of Clinical Sciences, A*STAR) UK PI: Mala Maini (University College London)
Hepatitis B virus remains one of the top ten killers in the world today, causing around 1,000,000 every year from chronic liver disease. A vaccine exists but is of no use to the 400 million people already infected with the disease. There are now a number of drugs available to treat Hepatitis B infection, but these only suppress the virus rather than remove it; when patients stop treatment the virus returns to pathogenic levels. There is also no effective drug therapy for the end-stage complications of liver failure and liver cancer.
The goal is to develop a treatment to safely boost the immune system’s ability to control Hepatitis B virus infection by harnessing the natural ability of T cells in the immune system. Hepatitis B patients have very few T cells left that can fight the virus in the body. By genetically engineering patients’ T cells, it is hoped that more cells will regain their ability to fight the Hepatitis B virus. The project, by replicating Hepatitis B infection of the liver in in vitro as well as in vivo mouse models, will look at how effective these genetically engineered T cells will be at combating the Hepatitis B virus. Its findings will provide essential information for the possible future application of this approach to hepatitis and other chronic infections and tumours.
3. Modulation of TB-HIV drug interaction by host genetic influences Singapore PI: Lawrence Lee (National University of Singapore) UK PI: Saye Khoo (University of Liverpool)
Tuberculosis (TB) and HIV are leading causes of death worldwide. Co-infection is common and concurrent treatment of both diseases is complex because of drug interactions. One common combination of drugs is Rifampicin (RIF) and Efavirenz (EFV) - RIF is used to treat TB while EFV is used to treat HIV. However, it is known that RIF decreases the effectiveness of EFV. In addition, the effectiveness of such drug treatments is strongly affected by genetic variation, which is particularly common amongst black Africans, South Indians and Southeast Asians, populations where HIV-TB co-infection is also widespread.
This project investigates how a specific genetic variation affects the impact of RIF on the effectiveness of EFV. Knowledge gained will allow more informed design of treatment guidelines for HIV-TB co-infection and optimisation of disease management through a personalised medicine approach. It will also have an impact on the design and selection of drugs for HIV-TB co-infection.
4. Cellular and transcriptomic analysis of regulatory T cells in streptococcal infection Singapore PI: Olaf Rotzschke (Singapore Immunology Network, A*STAR) UK PI: Daniel Altmann (Imperial College of Science, Technology and Medicine)
This project will examine the role of regulatory T cells (Tregs), a type of white blood cell, in infections involving Streptococcus pyogenes (S. pyogenes). This particular species of bacteria causes diseases ranging from sore throat to scarlet fever, rheumatic heart disease, sepsis and necrotizing fasciitis (‘flesh-eating bacteria’). The interplay between body and bacterium is a complex one: on the one hand, a robust immune response is required to defend the body; on the other, over-exuberant immunity is responsible for many of the manifestations of the disease.
Tregs are responsible for ‘dampening’ the response of other immune cells, thereby preventing inflammatory ‘overshoot’. It has already been shown in mice that there is rapid upregulation of Tregs and associated molecules at the site of S. pyogenes infection. This project aims to build up an understanding of the immunological factors affecting the diseases listed previously. It makes use of a powerful DNA microarray technology, which provides a gene-by-gene comparative analysis of cells and allows scientists to obtain a detailed understanding of how the human body operates in response to disease.
5. Variant surface antigens of Plasmodium chabaudi as a model to study antigenic variation in Plasmodium vivax Singapore PI: Peter Preiser (Nanyang Technological University) UK PI: Jean Langhorne (National Institute for Medical Research)
Plasmodium vivax (P. vivax) is the most frequent and widely distributed cause of chronic malaria. One reason for their persistence in the human body is their ability to avoid the antibody response. This malarial parasite lives for much of its life in red blood cells (RBC) and would otherwise be invisible to the immune system but for proteins it produces on the surface of the RBC that allow it to communicate with the external environment.
In order to avoid detection by the immune system, P. vivax constantly changes the proteins at the RBC surface by switching on and off genes that code for different variants. By using a mouse model of malaria to investigate how the production of these proteins is regulated, whether they are recognised by antibodies, and whether they are responsible for the pathogenic effects of the parasite, the group hopes to gain knowledge that will lead to the development of vaccines as well as other treatments for malaria.
6. Significance of efflux pumps in multidrug resistance and pathogenesis of Acinetobacter spp. Singapore PI: Chua Kim Lee (National University of Singapore) UK PI: Laura Piddock (University of Birmingham)
Hospital-acquired infections caused by Acinetobacter spp. are a serious problem because of the rapid increase in multi-antibiotic resistant Acinetobacter spp. strains. This project aims to increase understanding of how multi-resistance to antibiotics is caused.
Researchers will investigate how certain types of molecular pumps actively remove drugs from the interior of the bacterium, thereby decreasing the effectiveness of the drugs. The study of how these pumps function and what kinds of molecules they transport will hopefully lead to the discovery of novel antimicrobials as well as inhibitors of these pumps.
