When people get exposed to the mycobacterium responsible for tuberculosis (TB), some will become sick with a disease that is a major cause of mortality around the world while others simply don't. Now, researchers reporting in the March 5th issue of the journal Cell, a Cell Press publication, can point to one important reason for this variation in susceptibility or resistance: genetic differences among individuals in levels of an immune enzyme (LTA4H) that is involved in the production of leukotriene B, a pro-inflammatory fatty acid immune signaling molecule.
It turns out individuals who are heterozygous for LTA4H, meaning they carry two versions of the enzyme-encoding gene and produce an average amount of the enzyme (not too little or too much), are less likely to succumb to tuberculosis. They also appear to gain protection against leprosy, a disease which is also caused by mycobacterial infection.
"TB is obviously a big problem," said Lalita Ramakrishnan of the University of Washington. "There isn't a good vaccine, notwithstanding the fact that the TB vaccine has been administered to more people than any other. On top of that, it requires long-term treatment for cure and there is an epidemic of drug-resistant TB. Increasingly, people are becoming infected with strains that are resistant to every antibiotic. On this backdrop, it made sense to go back to the drawing board and try to understand the pathogenesis of the disease."
In the new study, Ramakrishnan and her colleague David Tobin did just that, in an unbiased screen for TB susceptibility genes in the zebrafish. They then collaborated with University of Washington human geneticists Jay Vary, Thomas Hawn and Mary-Claire King and others in Vietnam and Nepal to validate their findings in human populations.
A second study in the same issue of Cell approached the question in another way. Kanury Rao and his colleagues at the International Centre for Genetic Engineering and Biotechnology in India used a genome-wide analysis to produce what now becomes a resource for TB researchers everywhere. They uncovered all of the "cellular machinery" within human macrophages - the cells primarily targeted by TB - that interact with the infectious mycobacteria and allow the infection to stably persist.
Rao's team uncovered 275 players within host cells that interact with each other to form a dense network. That picture allowed the researchers to make a detailed molecular-level description of what he refers to as "functional modules" within host cells that are engaged and perturbed by TB infection. Interestingly, they showed that the shape of that interaction varies depending on which isolated strain of TB one considers, suggesting that the different strains rely on somewhat different tactics for successful infection.
Rao's findings offer new leads in the fight against TB, he says. "We identify a core set of molecules which can be targeted through drug development efforts to treat both drug sensitive and multiple drug resistant forms of TB infection. Rather than targeting the pathogen itself, our studies highlight an alternate strategy wherein the host factors required to support pathogen survival can be used as targets for TB therapy."
The discovery of LTA4H as a TB susceptibility gene may have clinical implications too, even if it doesn't offer a direct path to a better vaccine, Ramakrishnan says. For one thing, the finding that medium activity of the immune enzyme is best when it comes to TB might help to explain something that has been known but not well understood in clinical circles: people with hard-to-treat TB sometimes improve when they are given anti-inflammatory, immunosuppressive therapies along with more standard drug treatments alone.
Ramakrishnan also notes that the same polymorphisms in LTA4H they uncovered were earlier linked to heart disease. That suggests that drugs that target this pathway in heart disease might be useful in the context of TB, she says.
The connection between infectious disease and heart disease also has implications for understanding the evolution of the immune system's inflammatory responses. "In general, people have thought that inflammation is a positive when it comes to fighting infection, but then it can cause modern-day disease," Ramakrishnan says. The finding that it is heterozygotes - with intermediate activity of the immunity enzyme - who fare best in the context of TB and leprosy suggests that in these infections also, inflammation has to be finely tuned for optimal protection.
The researchers include David M. Tobin, University of Washington, Seattle, WA; Jay C. Vary, Jr., University of Washington, Seattle, WA; John P. Ray, University of Washington, Seattle, WA; Gregory S. Walsh, Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA; Sarah J. Dunstan, Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, Oxford University, Oxford, UK; Nguyen D. Bang, Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam; Deanna A. Hagge, Mycobacterial Research Laboratory, Anandaban Hospital, Kathmandu, Nepal; Saraswoti Khadge, Mycobacterial Research Laboratory, Anandaban Hospital, Kathmandu, Nepal; Mary-Claire King, University of Washington, Seattle, WA; Thomas R. Hawn, University of Washington, Seattle, WA; Cecilia B. Moens, Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA; and Lalita Ramakrishnan, University of Washington, Seattle, WA.