New tool for TB: stem cells

New research may have discovered a new culprit that helps tuberculosis evade the immune system: stem cells.

Human lung granuloma from TB patient
Image: Wikimedia Commons/Mutleysmith

The research, conducted largely in vitro using mouse cells and linkurl:reported;http://www.pnas.org/content/early/2010/11/29/1007967107 in __PNAS__, suggests that stem cells recruited to sites of tuberculosis infection may suppress surrounding immune cells, thereby helping the bacterium establish a persistent infection."It's a novel finding," added linkurl:Joanne Flynn,;http://www.gradbiomed.pitt.edu/immunology/faculty.asp?ID=41 an immunologist at the University of Pittsburgh School of Medicine, who was not involved in the study. About one third of the human population carries __Mycobacterium tuberculosis__, but only around 10 percent of those infected go on to develop the often deadly pulmonary disease. In these individuals, actively replicating bacteria in the lungs and other organs encounter a slew of macrophages, epithelioid cells, and lymphocytes, which surround the bacteria and form a sphere of tightly bound cells known as granulomas. Unable to fully eradicate __M. tuberculosis__, the immune system reaches a stalemate with the quarantined pathogen—resulting in chronic infection.linkurl:Gobardhan Das,;http://www.icgeb.org/g-das-lab.html an immunologist at the International Centre for Genetic Engineering and Biotechnology in New Delhi, India, and his team set out to understand the host factors that allow the bacterium to remain, amid what should be a powerful and constant barrage of attacking immune cells. Because T cells form one of the host's primary defenses against __M. tuberculosis__, the team started off by testing how well T cells cultured from the spleens of infected mice were able to proliferate. They found that the T cells of infected mice did not divide as fast as those of uninfected mice when in the presence of the other spleen cells. But when these T cells were isolated from the bunch, they divided similarly. This suggested that another cell type, present in the spleens of infected mice, was suppressing the T cells. A closer look at the spleen cells derived from infected mice revealed that a significant number bore the signature membrane markers of mesenchymal stem cells(MSCs)—multipotent cells that originate in the bone marrow and can differentiate into a number of different cell types. These same cells were also present in the lung granulomas of mice infected with tuberculosis. MSCs have previously been known to travel to inflammation sites in tumor and Crohn's disease models, where they regulate the immune response, explained linkurl:David Lewinsohn,;http://www.ohsu.edu/vgti/lewinsohn.htm an immunologist at the Oregon Health & Science University, who was not involved in the study. They do so by producing substances such as nitric oxide and TGF-β, which can induce the production of T regulatory cells that in turn inhibit T cell activation. Indeed, nitric oxide levels in the cultured spleen cells of the infected mice were much higher than in those of uninfected mice. And to test if the nitric oxide produced by MSCs in the spleen was what was slowing down the T cell proliferation, the team grew the spleen cells of infected mice in the presence of a nitric oxide inhibitor and found that the defects in T cell division were reversed. As a result, the team proposed that MSCs inhibit T cell activation and proliferation by secreting nitric oxide in the periphery of the granulomas—in effect shielding the bacterium from the adaptive immune response. "What they're suggesting is that these stem cells are interposed between the T cells and the infected macrophages and that they're actually inhibiting and maybe preventing access of the T cells to the macrophages," said linkurl:Sam Behar,;http://www.hms.harvard.edu/dms/immunology/fac/Behar.html an immunologist at Harvard University who was not involved in the study."I don't think anybody has looked for stem cells in granulomas," Flynn said. But whether or not the presence of MSCs is ultimately detrimental to the host during the course of tuberculosis infection is not yet clear, she added. "They may be an important cell subset for balancing inflammation."Lewinsohn stressed, however, that the majority of these experiments were performed in vitro, and that until more rigorous experimentation in live mice is performed, the view of the microanatomy of the granulomas that the team is presenting may be a stretch.Behar agreed, noting that,ideally, the researchers would have looked at what happens when infected animals are deprived of their MSCs in vivo, he added. Lead scientist and last author of the paper Gobardhan Das could not be reached before deadline. The researchers did show that transgenic mice that are naturally resistant to tuberculosis had a higher concentration of __M. tuberculosis__ in the lungs and spleens during the first days of infection if they had been previously injected with MSCs isolated from susceptible strains of infected mice, suggesting the stem cells were helping to keep the immune system at bay. But these differences became much less pronounced as the infection progressed. However, by identifying a cell type, previously unknown to play a role to tuberculosis, the researchers opened up a whole new line of questioning for studying tuberculosis infection, Lewinsohn said. "This paper highlights ways in which other cells in the granuloma, which we haven't really thought about, may play a potentially important role."S. Raghuvanshi et al., "__Mycobacterium tuberculosis__ evades host immunity by recruiting mesenchymal stem cells," PNAS, doi:10.1073/pnas.1007967107, 2010.
**__Related stories:__***linkurl:TB or not TB?;http://www.the-scientist.com/2010/9/1/21/1/
[September 2010] *linkurl:Rethinking TB;http://www.the-scientist.com/blog/display/55325/
[8th January 2009] *linkurl:Turning back the tuberculosis tide;http://www.the-scientist.com/article/display/15477/
[23rd May 2005]