July 24, 2007 Sleuthing through soil has led University of British Columbia researchers to a key discovery about the world’s most lethal infection -- tuberculosis (TB).
Lindsay Eltis, a microbiologist and biochemist, spent the first part of his career in soil bacteria research, looking at how microbes in dirt degrade or break down pollutants such as polychlorinated biphenyls (PCBs). He has expert knowledge of a process called biocatalysis, where enzymes activate or accelerate chemical reactions.
TB scientists had earlier identified genes that helped Mycobacterium tuberculosis -- the bacterial agent that causes TB -- to survive, but no one knew exactly how the process worked. TB bacilli are unusual in that they can survive in macrophages -- large immune cells that normally devour invading pathogens.
Eltis, UBC colleague Bill Mohn and co-investigators from UBC and Europe looked at similarities in the function of enzymes involved in PCB degradation and enzymes involved in TB. What they uncovered helps explain how TB survives. They found a suite of genes that contain the information required to make enzymes that degrade the cholesterol found in macrophage cell membranes. The bacilli use the degraded cholesterol for fuel to survive. In most infections, the macrophage is the enemy. In TB it’s dinner.
The discovery offers the potential for an entirely new class of therapeutics -- answering a critical need for new treatments to combat emerging drug resistant strains. Now that scientists know cholesterol is essential for TB bacilli’s survival, they can work to inhibit the enzymes that are responsible for cholesterol degradation. In effect, they would be taking cholesterol off the menu and starving the infection to death.
UBC’s University Industry Liaison Office has filed a patent application for the technology leading to the discovery, and the work was published recently in the Proceedings of the National Academy of Science.
“This is a classic example of the serendipitous nature of discovery,” says Eltis, a UBC alumnus and professor of microbiology and immunology. “You just can’t predict the benefits that spin off from good research. This work re-inforces the need for funding basic research.”
Next steps for the researchers include purifying the cholesterol-degrading enzymes and developing and testing compounds to inhibit the action of the enzymes.
TB is the leading killer among infectious diseases and is responsible for one in four adult preventable deaths, according to the World Health Organization (WHO). One-third of the world’s population is currently infected. Particularly susceptible include those with a compromised immune system, elderly, homeless and undernourished people, and those living in overcrowded environments with poor ventilation such as some hospitals or prisons. In Canada, individuals of Aboriginal and Inuit heritage have a higher incidence of TB than the general population.
There have been no new drugs for TB in the last 40 years and the bacilli have developed drug resistance over time. Current treatment usually involves taking drugs over a period of six to18 months. Patients generally feel better within weeks and often stop taking the drugs, allowing drug-resistant strains to develop.
One in 10 cases of TB are resistant to some first-line drugs and are described as multi-drug resistant TB or MDR-TB. The treatment for such cases involves using second-line drugs that must be taken for a year or more. TB resistant to both first- and second-line drugs is called extensive drug resistant TB or XDR-TB.
“XDR-TB is now virtually untreatable,” says Eltis, who joined UBC in 1999 from Quebec’s Université Laval. “It’s on every major continent, and developed countries are making a serious mistake by not dealing with it aggressively. This disease is going to bite us.”
The WHO reports that TB takes an annual toll of two million lives, with eight million people developing TB every year. The highest rates per capita are in Africa with 29 per cent of all TB cases, often affecting HIV/AIDS patients. Half of all new cases are in six Asian countries: Bangladesh, China, India, Indonesia, Pakistan, and the Philippines.
In Canada, approximately 1,600 new cases of active TB are diagnosed annually and 63 per cent of those cases are found in people born outside of the country, according to the Canadian Lung Association.
Eltis and colleagues are working to create a multidisciplinary TB research centre at UBC, involving investigators in areas such as microbiology, chemistry and immunology. Their objective is to establish a “pipeline” for the development of new therapies. Eltis cites UBC strengths such as top investigators, special lab facilities being constructed for biocontaminant research, and the Centre for Drug Research and Development that helps ready new therapies for commercialization.
“UBC is uniquely positioned to make a major contribution to a global threat,” says Eltis.
There are currently only two centres for TB research -- in Lausanne, Switzerland and in Seattle, WA.
Along with UBC colleagues Yossef Av-Gay, Richard Stokes, Charles Thompson and others, Eltis envisions the centre offering shared services to enable targeted gene studies and development of inhibitors and vaccines.
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