Tuberculosis Genes Reveal Secrets to Disease Success

A tuberculosis patient receives medication. The bacteria’s success at mutation for survival has led to a strain of multidrug resistant TB that is an increasing health threat.

Washington — The bacteria that cause tuberculosis have plagued humankind for millennia, but scientists are just getting to know the pathogen at the genetic level. Research published August 21 offers insight into how this microscopic organism is so successful at causing human disease and death.

Analyses of dozens of tuberculosis genomes from disease strains gathered around the world offer clues on why TB is so prevalent and how it evolves to defend against human attempts to fight it.

“It’s as though the bacterium places bets on human behavior,” said Caitlin Pepperell, a University of Wisconsin-Madison microbiologist who is the lead author on the work published in PLOS Pathogens. The TB bacterium “always bets that humans will go to war, send people to refugee camps and gather in miserable places. Historically, that’s been a winning bet on the bacterium’s part.”

These are conditions in which TB thrives. The pathogen is transmitted only by humans and cannot survive in the environment on its own. TB has proven to be the greatest threat in the crowded conditions of prisons, slums and refugee camps.

That survival technique has enabled TB to follow humans over the last several centuries and flourish in historical periods marked by urbanization, migration and expansion into new territories, the researchers find.

The World Health Organization (WHO) calls TB the world’s second most deadly disease pathogen after HIV, causing 1.4 million deaths in 2011 and 8.7 million cases of illness.

The research team — which included scientists from Stanford University, the University of Iowa, the University of Sydney and the Broad Institute, which is supported by the Massachusetts Institute of Technology and Harvard University — analyzed the genetic diversity of 63 TB strains and related pathogens.

The scientists found that the disease strains had two common characteristics that contribute to longevity. They are very good at casting off mutations that are harmful to their survival, while they are tolerant of beneficial mutations that strengthen their defensive genes. Mutations that allow the organism to fend off attacks from the human immune system or resist the pharmacological onslaught of medications are readily adapted.

Those traits have apparently contributed to TB’s great longevity, Pepperell said. “It must have some incredibly clever strategies and tricks to hang on.”

These observations about the TB genome will provide the platform for further research, Pepperell expects, because they will help other researchers identify vulnerabilities that could be new drug targets. The U.S. National Institutes of Health provided funding for the work conducted by Pepperell and her colleagues.

More than 95 percent of TB deaths occur in low- and middle-income countries, where it is among the top three causes of death for women aged 15 to 44.

After concerted efforts to improve treatment access by the United States and other donor nations, the TB death rate is down by 41 percent between 1990 and 2011, WHO reports.

Through this period, an estimated 20 million lives have been saved through use of a TB-stopping strategy recommended by WHO. The estimated number of people falling ill with tuberculosis each year is declining, although very slowly. Based on that trend, predictions indicate that the world is on the way to achievement of a goal to reverse the spread of TB by 2015.

Under the Obama administration’s Global Health Initiative, the United States is committed to contributing to that goal, as well as supporting TB testing and treatment for millions of vulnerable individuals worldwide.