Electron microsopy image of Mycobacterium tuberculosis bacteria
Image courtesy of Centers for Disease Control and Prevention (J. Carr, R. Butler)
The Agency for Science, Technology and Research (A*STAR) supports a number of research projects tackling various infectious diseases.
In August 2010, tuberculosis (TB) was selected as the agency’s latest investment target with the announcement of a new collaboration between the A*STAR Singapore Immunology Network (SIgN) and French bioindustrial group Institut Mérieux along with its diagnostics subsidiary bioMérieux.
The collaboration, which comes with a joint investment of S$3 million (US$2.18 million), aims to identify new biomarkers for the disease that could help in diagnosis and therapy1.
Since its discovery in 1882, TB has remained one of the most prevalent infectious diseases on Earth, with one third of humanity estimated to be infected with the TB bacterium, Mycobacterium tuberculosis. The host–pathogen interaction is very complex, and only about one in ten TB-infected individuals will develop active TB at some point in their life.
According to the World Health Organization (WHO), about 1.8 million people died of TB worldwide in 2008, and those with HIV are at greatest risk: over a quarter of TB deaths occur among HIV-infected patients.
Tackling multidrug-resistant strains
Tuberculosis has almost been forgotten thanks to the development of effective antibiotics that can cure patients of the disease. But TB remains a major threat for people in developing countries, and worryingly, “the bacterium is rapidly becoming multidrug resistant,” says Paola Castagnoli, professor and scientific director of the SIgN and one of the leading members of the new initiative. In March 2010, the WHO urged countries to seek new and innovative measures to counter the spread of TB.
Paola Castagnoli, scientific director of the SIgN
Singapore has taken the advice seriously. Over 1,400 new cases were reported in Singapore in 2009 — a figure higher than that for most European countries.
With this new agreement, the SIgN, Institut Mérieux and bioMérieux will establish a joint laboratory at the SIgN’s headquarters in the Biopolis in Singapore to study immune cells in the blood of infected individuals without active TB and compare the results with those for individuals with active TB and non-infected, healthy people. Through analysis of gene expression and metabolism in these immune cells, the team hopes to identify biomarkers linked with TB infection and activation.
The information obtained through this new initiative could prove to be essential for clinicians and researchers to develop new therapies, Castagnoli says, and will establish the SIgN as an international research hub for human immunology. Already the SIgN infectious disease program has attracted two new researchers internationally renowned for their work on TB: Gennaro De Libero and Lucia Mori from Basel University in Switzerland.
The diagnostic tests for TB have remained almost unchanged for decades, involving skin tests and X-ray examinations. It can take up to a month to determine whether a patient is infected with TB, and it is currently very difficult to tell whether individuals with a latent infection could be at risk of developing active disease later in life. “We don’t know why nine out of ten infected people are protected from the disease, or what the correlates of protection may be,” says Castagnoli. “We need to find good biomarkers to unveil this mechanism. But a single biomarker is not sufficient because it may work for Caucasians, for example, but not Asians.”
Unveiling host–pathogen interactions
In 2008, Castagnoli and her collaborators in France and the UK made an important step toward understanding the interaction between the bacterium and its human host.
Using advanced microarrays, they succeeded in simultaneously characterizing the transcriptome of M. tuberculosis and the cells, macrophages and dendritic cells of the host for the first time2. They identified a number of common and dissimilar gene regulation patterns that suggest that the bacteria interact with the host in different ways and can recognize whether they are within a dendritic cell or a macrophage.
This is relevant because these two cell types have quite different functional properties. Although the findings are a small first step in a long investigation, the research has become an important backbone for future study at the SIgN.
“What we need is to develop new approaches to study host–pathogen interactions, and ultimately find new ways to vaccinate people,” says Castagnoli.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network.
