Cracking the stem cells' code in vaccination against TB

• Applicant: Dr. Eva Kaufmann
• Subject Area: Immunology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 333604363

The ability of Mycobacterium tuberculosis (Mtb) to persist in individuals with apparently normal immune systems implies that it has developed strategies to evade, subvert and even specifically stimulate innate and adaptive immunity. As a result, Mtb remains one of the most successful human pathogens. Approximately 1.5 million people die of tuberculosis (TB) annually and nearly 10 million new cases of active TB occur due to the large reservoir of asymptomatic persons chronically infected with Mtb. Undoubtedly, an effective vaccine is essential for control of the epidemic. Unfortunately, so far no vaccine proved superior to BCG - a live attenuated M. bovis strain with a highly variable efficacy which only confers reliable protection against severe forms of TB in infants but not against the pulmonary main manifestation of the disease in adults. This underscores the urgent need to generate a highly efficient vaccine against TB through employment of novel and innovative approaches. So far, vaccine development mainly focused on strengthening adaptive cellular immune responses through enhanced provision of dominant antigens. However, the potential contribution of innate immunity to successful vaccination against TB has not yet been well understood.The route of entry of Mtb is mainly via the respiratory tract and the first cells to encounter the bacterium are alveolar macrophages. Mtb has evolved into a pathogen of the naturally hostile, intracellular milieu of the alveolar macrophages, where it not only survives but even replicates. These cells, which normally excel at destroying the biological particles they engulf by phagocytosis, are killed by Mtb, enabling the bacterium to spread to bystander cells and to propagate the infectious process. Furthermore, the presence of Mtb is not only limited to the lungs, but it can also be isolated from the peripheral lymphoid organs and even the bone marrow (BM). Considering the BM is home to hematopoietic stem cells (HSCs), the earliest precursors of immune cells including monocytes and macrophages, and lacks a physical barrier to exclude already differentiated immune cells, translocation of Mtb to this privileged site may have significant consequences on the pathogenesis and chronicity of TB. Although we know a great deal about the immune response to Mtb in the lung, our understanding of the HSC response to mycobacterial infection and vaccination is extremely limited. The overall goals of the proposed study are therefore to dissect the immune response to Mtb in the BM and to develop novel vaccination strategies against this devastating disease.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Maziar Divangahi, Ph.D.