Scientists have found a hiding place in the body where bacteria that cause tuberculosis may take refuge—a clue that could one day help them target treatments more effectively and surmount a major obstacle to eradicating the global epidemic.
The tuberculosis microbe’s ability to hang around, dormant, for as long as a lifetime has long been a mystery and a public health problem; 2.2 billion people worldwide are infected with TB, 90 percent with latent infections that cause no symptoms but could be reawakened later. Now, a team of stem cell specialists and infectious disease researchers from the Forsyth Institute, a research center in Cambridge, Stanford University School of Medicine, and India have found evidence the bacteria may take shelter in bone- and cartilage-forming stem cells in the bone marrrow, where they are protected from the immune system and drugs that would normally wipe out the bacteria.
“Anybody, it seems to me, who has any insight into how a bug can hang out for that period of time and remain viable is doing good things,” said Barry Bloom, an infectious disease and global health specialist at the Harvard School of Public Health who was not involved in the research. “This paper offers one such bit of evidence, that it could hide in a relatively privileged part of the bone marrow.”
In the study, published Wednesday in the journal Science Translational Medicine, researchers first showed that it was possible to infect a certain subset of bone marrow stem cells grown in laboratory dishes with TB bacteria. Then, they infected mice with an engineered strain of the bacteria that would not grow unless it was activated by a drug. They wanted to know whether bacteria that was not actively growing could reside in various repositories in the body, and found it in the lungs and in the subset of bone marrow stem cells they had studied in previous experiments.
When they looked in the bone marrow cells of nine people from a remote Indian village who had been treated for TB and deemed cured, they were able to grow TB bacteria from the bone marrow stem cells of two of the people.
The study comes with a number of cautions. Researchers still don’t know, for example, whether this population of stem cells is an important reservoir for the infection. Other theories of how infections can recur and persist are being examined, such as the possibility that bacteria enter a zombie-like “persister” state, in which they are able to evade drug attack and then revive an infection later.
But it does suggest new ways to attack the disease. The course of medication currently given to patients with TB may spare bacteria that shelter in the stem cells; thus, future treatments might also need to target the bacteria inside its hiding place. Continued research will have to be done to better understand how the infection could be reactivated from the stem cells, how they entered those cells in the first place, and the key differences between the bacteria that go dormant and those that cause active infections.
“For understanding tuberculosis vaccine development, diagnostic development, and treatment development, it’s very, very important we understand what are the situations that distinguish these two different phases of the disease,” said Dr. Antonio Campos-Neto, director of the Forsyth Institute’s Center for Global Infectious Diseases and one of the leaders of the work. “In some cases, the infection just moves to an active pathology, and in other cases, it stays latent forever.”
Bloom said understanding the particulars of the latent infections is especially critical because it is the TB microbe’s unusual ability to enter a long latent period that has made it so difficult to eradicate. Unlike the measles epidemic, which has been virtually wiped out in a decade by an effective vaccine, he said it would take a century to get rid of TB with an equivalent vaccine. People who harbor the latent infection from a childhood infection could, in their 80s, have an infection flare up and infect everyone else in their nursing home, for example.
Bloom said that the study was interesting, although he added that the evidence from human patients was tentative. He said it was possible that the hiding-out strategy could also be used by other infections that have long periods of dormant infection.
Kim Lewis, director of the Antimicrobial Discovery Center at Northeastern University, said the study raised some interesting questions for further research including whether, in a larger group of patients, bacteria could be found in bone marrow stem cells.
He said the paper presented preliminary evidence about a major global health mystery.
“It is an enormous problem indeed. Where exactly those pathogens hide within the body is not exactly clear, and this study tries to address this question,” Lewis said.