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TB bacteria hide in stem cells, protected from drugs and immune system

Where do tuberculosis bacteria hide in the body, sheltered from powerful antibiotics? That is among the most important questions facing infectious disease experts today, as TB remains at epidemic levels world-wide despite decades of aggressive anti-TB campaigns.

Research published in the January 30, 2013 issue of Science Translational Medicine identifies bone marrow stem cells as the near-perfect hiding place for the TB pathogen. An international research team led by Dr Bikul Das, a former fellow at The Hospital for Sick Children (SickKids), recovered viable Tuberculosis mycobacterium from CD271+ (or CD271-plus) stem cells from the bone marrow of individuals who had been treated and ‘cured’ of TB.

Study co-author Dr. Herman Yeger of SickKids says, “The biggest problem with tuberculosis is its dormant phase. We bring out the heaviest, most comprehensive artillery possible for TB, and these antibiotics kill all the infection they find, but some pathogens escape by hiding out somewhere in the body. Much later these bacteria emerge to infect the person all over again. Our work shows that a few of the pathogens hijack bone marrow stem cells to escape from the antibiotics.” Dr. Yeger is a Senior Scientist in Developmental & Stem Cell Biology at SickKids and Professor of Laboratory Medicine & Pathobiology at University of Toronto.

Dr. Das forged a unique collaborative network in India, including the Idu-Mishmi people of northeast India, in whom TB remains endemic. They participated in the clinical part of the study.

“I first saw the TB bugs in bone marrow about 15 years ago while treating people with tuberculosis in Bhutan, and while at SickKids I applied for the Bill and Melinda Gates Foundation grant to test the idea,” says Dr. Das.

Currently a post-doctoral fellow at Stanford University, Dr. Das initiated the stem cell part of the project while a post-doctoral fellow at Dr. Yeger’s laboratory in SickKids. The other study collaborator is a group at Forsyth Institute, a Harvard University-affiliated research centre, which specialized in the biology of dormant TB. “It is a great satisfaction that our multi-centre collaborative approach led to the discovery of the stem cell type where the bacteria hide,” says Dr. Das.

Ideal hiding place

TB specialists have long tried to find the bacteria’s hiding places, investigating other likely areas both within and outside various cell types. Previous investigators had recovered DNA of TB from different cell types, but had failed to recover viable bacteria. This is the first study to test stem cells for TB, and it found both the DNA and viable TB bacteria.

Dr. Das and his team speculated that some qualities of bone marrow stem cells could make them ideal for sequestering the tiny mycobacterium tuberculosis pathogen. The CD271+ stem cells are self-replicating, reside in secured niches in the bone marrow virtually inaccessible to the immune system, and are largely impervious to drug molecules. For much of their life cycle the stem cells stay in the bone marrow, eventually emerging into the bloodstream to circulate throughout the body. “A pathogen that hijacks a CD271+ stem cell has the best of both worlds,” says Dr. Das. “It can hide from drugs and the body’s own immune defenses. Then, when the coast is clear, it can travel throughout the body to choice sites for re-infection in the lungs and elsewhere.”

The team first compared stem cells from non-infected volunteers with that of individuals who had been treated and ‘cured’ of TB. It found dormant TB pathogen in the CD271+ bone marrow stem cells of this group. Additionally, it replicated the results from the human cells with mice under controlled laboratory conditions – a good example of comprehensive translational research.

The research could open up new treatment pathways for TB, says Dr. Yeger.  “Now that we know where TB hides out, we have a better chance of developing treatments that can actually target and destroy this terrible pathogen in its dormant stage.”  

Up to half of world population is infected

Estimates of TB infection  world-wide range from 2.2 to 4 billion people. The World Health Organization* states that “progress in responding to multi-drug resistant TB remains slow,” adding that “the global burden of TB remains enormous.” TB is one of the top killers of women and is also “a huge problem among children across India, South East Asia, and Latin America,” adds Dr. Yeger. WHO states that India and China have the largest number of cases, and cites an estimated 8.7 million new cases and 1.4 million deaths in 2011.
*WHO: Global Tuberculosis Report 2012, Executive Summary, p. 1.

The paper is titled “CD271+ Bone Marrow Mesenchymal Stem Cells May Provide a Niche for Dormant Mycobaterium  tuberculosis,” appearing in the January 30, 2013 issue of Science Translational Medicine.

The study was funded by SickKids Foundation, Canadian Cancer Society, Bill and Melinda Gates Foundation, KaviKrishna Foundation, Laurel Foundation, and several grants from the US Department of Defense and (US) National Institutes of Health.

The Hospital for Sick Children (Sic

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