The factors instrumental in triggering latent tuberculosis (TB) infection to progress into active disease have long remained elusive to researchers. New insight into the mystery is provided by Professor David Russell, speaking at the Society for General Microbiology's spring meeting in Edinburgh today. His work could help develop innovative strategies for treating the disease.
Professor Russell and his group at Cornell University in New York, USA, have demonstrated that TB-causing bacteria are able to hijack fat metabolism in the host to drive the progression of the disease. The team's research shows that Mycobacterium tuberculosis (Mtb) is able to stimulate macrophages – the immune cells the bacterium infects – to accumulate fat droplets, turning them into “foamy” cells. This cellular transformation can trigger a reawakening of the TB infection from its latent state.
Following initial infection by Mtb, the infected immune cells in the body can clump together in the lungs in a cellular mass that is surrounded by a fibrous cuff. This containing structure, called a
tubercle, physically protects the bacteria from being destroyed by the immune system. This allows them to persist inside the host for years during a latent period in which the host shows no symptoms. The respiratory infection is reactivated only in a small percentage of individuals (often those who are immunosuppressed) in whom it progressively destroys lung tissue. Very little is known about the exact causes of reactivation and the relative roles of the host and the pathogen.
Professor Russell's group discovered that inside the tubercle, surface molecules of Mtb prompted host macrophage cells to take up vast quantities of cholesterol-type lipids from the surrounding blood
vessels. “We think that the lipids in the newly-formed foamy cell are then expelled into the cellular environment, which contributes to the collapse of the tubercle,” he said.
Once freed from their containing structure, the infectious bacteria are able to leak out into the airways where they can progressively destroy lung tissue. “If our model is correct, it has huge implications for
vaccines and chemotherapy programmes. A more detailed knowledge of the bacterium's life cycle and its host interactions will allow us to spot new targets for drugs – opening up new possibilities for treatment,” said Professor Russell.
One article warns that the absence of major investments in new technology and prevention and treatment tools could make drug-resistant strains of TB the “dominant” form of TB over the coming decades, according to the news service (5/18). The article notes “that India and China had around 50 percent of the global MDR-TB burden, followed by Russia with 9 percent,” Reuters writes. The authors write, “The future possibility of strains that are totally resistant to all anti-tuberculosis drugs is not inconceivable.”
“In other studies in the series … scientists said the combined impact of new drugs, vaccines, and diagnostic tests could cut worldwide incidence of TB by 94 percent by 2050,” the news service reports. According to experts, only about a quarter of the funding needed for drug research and development is available.
“Development of new drugs for TB is lengthy, expensive, and risky, and the expected revenues are too small to justify commercial investment,” Zhenkun Ma of the Global Alliance for TB Drug Development and co-authors write in a paper. “New financing and market incentive mechanisms are needed.”
The journal also notes that “there are 11 potential TB vaccines being tested in human trials and up to 10 experimental medicines in the TB drug 'pipeline.' Since many drugs fail in late-stage trials, this handful of possibilities is unlikely to be enough,” Reuters reports (Kelland, 5/18).
The series also focused on the broader issues that contribute to the spread of TB, the Associated Press reports. “Experts said TB isn't only a medical problem, but is intertwined with poverty, as it spreads widely among people living in overcrowded, dirty places. They said TB programs need to go beyond health and include other sectors like housing, education and transportation,” the news service writes. Philip Stevens, a health policy expert at the International Policy Network, said the disease “cannot be tackled in isolation,” noting that the focus of control efforts should be on “economic growth, which is outside the control of the U.N.” (Cheng, 5/18).
“In the eighth and final paper … a call to action is made to a wide range of sectors to assist scale-up TB service delivery, research and control. The launch of The Lancet TB Observatory, which will monitor progress on key indicators on an ongoing basis, is also announced,” according to a Lancet press release. The Observatory, which is a collaboration between the Lancet, the Stop TB Parternship, the WHO and the Global Fund to Fight AIDS, Tuberculosis, and Malaria, “will assess and monitor” TB research, financing and other information. In a comment discussing the Observatory, Lancet Editor-in-Chief Richard Horton and Executive Editor Pamela Das observe that currently “there is no formal mechanism to assess this information critically and independently. Nor is there any means to hold the various stakeholders in tuberculosis control to account” (5/18).
The series also includes comments about how to scale-up an integrated TB and HIV response, the burden of the disease in women and children and how migration patterns within and between countries contribute to the spread of TB.