Jan. 30, 2013 Tuberculosis is a devastating disease that kills nearly 2 million people worldwide each year. Although antibiotics exist that can ameliorate the symptoms, the courses of therapy last for months and don't completely eradicate the disease, which frequently recurs years or decades after the initial treatment.
Now, in a classic case of bench-to-bedside research, scientists at the Stanford University School of Medicine have discovered a possible reason for the disease's resistance: The ability of the tuberculosis bacteria to infiltrate and settle down in a particular class of stem cell in the bone marrow. By doing so, the bacteria take advantage of the body's own mechanisms of self-renewal.
"Cancer scientists have noted that self-renewing stem cells like these in the bone marrow have properties -- such as natural drug resistance, infrequent division and a privileged immune status -- that make them resistant to many types of treatment," said Dean Felsher, MD, PhD, professor of oncology and of pathology. "Now it turns out that this ancient organism, Mycobacterium tuberculosis, figured out a long time ago that, for the same reasons, these cells are ideal hosts to invade and in which to hide."
Not only did the scientists find genetic material from the bacteria inside the stem cells, they were also able to isolate active bacteria from the cells of human patients with tuberculosis who had undergone extensive treatment for the disease. The findings raise the possibility that other infectious agents may employ similar "wolf-in-stem-cell-clothing" tactics. And, although any new human treatments are likely to still be years away, they suggest a new possible target in the fight against tuberculosis, which infects nearly 2.2 billion people worldwide.
"We now need to learn how the bacteria find and infect this tiny population of stem cells, and what triggers it to reactivate years or decades after successful treatment of the disease," said postdoctoral scholar Bikul Das, MBBS, PhD.
Felsher is a co-senior author of the study, which was published online Jan. 30 in Science Translational Medicine. Das is the lead author. The research was conducted in collaboration with scientists from the Forsyth Institute in Cambridge, Mass.; the Hospital for Sick Children in Toronto; and several research groups in India.
The research focuses on a subset of stem cells in the bone marrow called mesenchymal stem cells. These cells are multipotent, meaning they can become several different types of specialized cells, including bone, fat and cartilage. Although the mesenchymal stem cells are most often found in the bone marrow, they are known to be able to migrate to sites in the lungs, where the tuberculosis bacteria thrive.
"Hematopoeitic cells, especially macrophages, have long been thought of as the primary intracellular niche for M. tuberculosis, even when the infection is present at a very low levels and the individual is asymptomatic," said Kevin Urdahl, MD, PhD, an assistant professor at Seattle Biomedical Research Institute, the country's largest independent organization devoted to the study of infectious diseases. Urdahl was not involved in the research. "However, this study shows that the bacteria also has the capacity to reside within mesenchymal stem cells, and may even persist in these cells after drug treatment. Although further studies will be needed to establish the relative importance of this niche during latent infection, the immunoprivileged nature of the bone marrow and the ability of mesenchymal stem cells to express drug efflux pumps make this an intriguing possibility that could have important clinical implications."
Although tuberculosis is most commonly known as a disease of the lungs, it can infect many parts of the body, including the abdomen, bone, skin and brain. The respiratory form of the disease is spread through infectious particles aerosolized when an infected person coughs or sneezes. Many cell types have been found to harbor tuberculosis bacteria, but the location of the bacteria's primary (and highly successful dormant variant) hideout has remained unclear. However, Das noticed a clue during his years as a physician in India.
"Fifteen years ago, I was treating hundreds of tuberculosis cases," said Das. "At the time, we noticed we were finding tuberculosis bacteria in bone marrow biopsies that had been obtained from some of these patients for other reasons. This was a totally unexpected and accidental finding, but it gave me the idea that the bacteria could be infiltrating these cells."
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Tuberculosis may lurk in bone marrow stem cells of infected patients