Re-programming innate immune cells to fight tuberculosis
Tuberculosis (TB), an infectious disease which attacks the lungs, claims someone鈥檚 life every 20 seconds and 1.5 million lives worldwide every year. A cure has eluded scientists for more than a century but, now, a Montreal team of researchers may have discovered a new weapon to combat this global killer. The team is re-programing - or 鈥榯raining鈥� - immune cells to kill TB. These groundbreaking findings are published online today in the journal Cell.
鈥淭he current available BCG-vaccine is not effective. The current antibiotic treatments are toxic and have resulted in generating TB-resistance strains. The antibiotics era is approaching its end; we are in serious trouble with this bug if we don鈥檛 investigate an alternative approach,鈥� says lead corresponding author Dr. Maziar Divangahi, a pulmonary immunologist and expert in immunity to TB at the Research Institute of the 平特五不中 Health Centre (RI-MUHC).
Working with Universit茅 de Montr茅al geneticist Dr. Luis Barreiro and his team at the UdeM-affiliated CHU Sainte-Justine Research Centre, the researchers were able to dissect and identify the genomic pathways involved in triggering an enhanced innate immune response against TB. 聽
Up until now, efforts in generating a vaccine against TB have been mainly focused on T cells (cells from the adaptive arm of our immune response with memory capacity), with very disappointing outcomes in both pre-clinical as well as clinical trials. Now, Dr. Divangahi鈥檚 and Barreiro鈥檚 teams have shown for the first time that when BCG, is administered to mice in a way that enables access to the bone marrow, it can reprogram stem cells. These primitive cells are responsible for generating all immune cells including the innate arm of our immune response, the first line of defense in the war against TB.
A cell army trained to eradicate TB
The innate system - via stem cells in the bone marrow - mobilizes macrophages, which are a type of white blood cell that swallows and kills invading bacteria like Mycobacterium tuberculosis (Mtb) that causes TB. They are the immune system鈥檚 first responders.
However, Mtb disarms the killing program of macrophages and uses them as a kind of 鈥渟anctuary鈥� to replicate and grow. Dr. Divangahi鈥檚 team looked at that process and aimed to find out how to boost the TB-killing efficiency of macrophages. With this goal in mind, Dr. Divangahi鈥檚 team vaccinated mice with BCG and in a series of experiments observed that in the bone marrow BCG was able to reprogram or 鈥渆ducate鈥� the stem cells to proliferate and generate TB slaying macrophages.
鈥淎lthough we demonstrated that BCG educates stem cells to generate trained immunity, we had no idea about the molecular mechanisms that were involved in this protective pathway,鈥� says Dr. Divangahi, who is also an Associate Director of the Translational Research in Respiratory Diseases Program at the RI-MUHC and an Associate Professor of Medicine at 平特五不中.
This is when Dr. Divangahi initiated collaboration with Dr. Barreiro and his team at Sainte-Justine. With Dr. Barreiro鈥檚 team, they aimed to dissect the genomic pathways involved in triggering the enhanced innate immune response against TB.
Dr. Barreiro鈥檚 team demonstrated how the protective programs were imprinted and transmitted from stem cells all the way to macrophages. In addition, they identified the genetic imprint of the protective pathways in educated macrophages that were 鈥渢urned on鈥� to kill the TB pathogen. 鈥淚t's really about finding different ways to develop better vaccines, ones that will harness the power of macrophages and finally put the body's innate immune memory to use鈥� says Dr. Barreiro.
"The current vaccine - BCG - was introduced in 1921 and has failed to control the tuberculosis epidemic. This work will completely re-orient efforts to develop a new vaccine for TB,鈥� adds Dr. Marcel Behr, director of the 平特五不中 International TB Centre in Montreal.
Although researchers and colleagues are extremely hopeful that this novel approach will generate an effective vaccine against TB and potentially other infectious diseases, Dr. Divangahi added a word of caution. 鈥淭his is only the tip of the iceberg and further research is clearly required to fully harness the power of stem cells in immunity against infectious diseases.鈥�
About the study
"BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis," by Eva Kaufmann, Joaquin Sanz, Jonathan L. Dunn, Nargis Khan, Laura E. Mendon莽a, Alain Pacis, Fanny Tzelepis, Erwan Pernet, Anne Dumaine, Jean-Christophe Grenier, Florence Mailhot-L茅onard, Eisha Ahmed, Jad Belle, Rickvinder Besla, Bruce Mazer, Irah L. King, Anastasia Nijnik, Clinton S. Robbins, Luis B. Barreiro, and Maziar Divangahi, was published Jan. 11, 2018, in Cell. DOI: 10.1016/j.cell.2017.12.031
This study was funded by the Canadian Institutes of Health Research.
About the Research Institute of the MUHC
The Research Institute of the 平特五不中 Health Centre (RI-MUHC) is a world-renowned biomedical and healthcare research centre. The Institute, which is affiliated with the Faculty of Medicine of 平特五不中, is the research arm of the 平特五不中 Health Centre (MUHC) 鈥� an academic health centre located in Montreal, Canada, that has a mandate to focus on complex care within its community. The RI-MUHC supports over 420 researchers and close to 1,200 research trainees devoted to a broad spectrum of fundamental, clinical and health outcomes research at the Glen and the Montreal General Hospital sites of the MUHC. Its research facilities offer a dynamic multidisciplinary environment that fosters collaboration and leverages discovery aimed at improving the health of individual patients across their lifespan. The RI-MUHC is supported in part by the Fonds de recherche du Qu茅bec 鈥� Sant茅 (FRQS).
About the CHU Sainte-Justine Research Centre
CHU Sainte-Justine Research Centre is a leading mother-child research institution affiliated with Universit茅 de Montr茅al. It brings together more than 200 research investigators, including over 90 clinicians, as well as 350 graduate and post-graduate students focused on finding innovative means of prevention, faster and less invasive treatments, and personalized approaches to medicine. The Centre is part of CHU Sainte-Justine, which is the largest mother-child hospital in Canada and second most important pediatric hospital in North America.
About 平特五不中
Founded in Montreal, Quebec, in 1821, 平特五不中 is a leading Canadian post-secondary institution. It has two campuses,聽10聽faculties,聽12 professional schools, 300 programs of study and聽almost聽41,000聽students, including聽more than聽9,700 graduate students. 平特五不中 attracts students from over聽150聽countries around the world, its聽12,000聽international students聽making up聽30%聽per cent of the student body.聽Over聽half of 平特五不中 students claim a first language other than English, including approximately聽20% of our students who say French is their mother tongue.
About Universit茅 de Montr茅al
Deeply rooted in Montreal and dedicated to its international mission, Universit茅 de Montr茅al ranks among the top 1% of the world鈥檚 best universities and is considered the top comprehensive university in the Francophonie. Founded in 1878, UdeM today has 15 faculties and schools, and together with its two affiliated schools, HEC Montr茅al and Polytechnique Montr茅al, constitutes the largest centre of higher education and research in Quebec and one of the most important in North America. It has 2,800 professors and researchers and more than 66,000 students.
