HOMITB · Host and microbial molecular dissection of pathogenesis and immunity in tuberculosis

Tuberculosis (TB) is a leading public health problem. About half of the 10% of Mycobacterium tuberculosis-infected individuals develop overt clinical disease, do so within two years of primary infection. The remaining half of the TB patients, develop clinical disease later, owing to “reactivation” of pulmonary TB. Of importance, it is not understood why only 10% infected individuals develop active disease. In this project, we will investigate the molecular and cellular interactions between mycobacteria and host cells, and the regulation of such interactions by cellular immune responses. Such interactions dictate the outcome of infection, ranging from asymptomatic infection to life-threatening disease. For this purpose, we have established a consortium of experts in Genetics, Immunology, Microbiology and Paediatrics and a biotechnology company. We will dissect the molecular and cellular immune responses, combining mice models, and human patients. In both approaches, the responses of various host target cells regulating mycobacterial growth and the mycobacterial adaptation to different host cell responses to infection will be studied. The role of innate and adaptive immune responses in the control of mycobacterial growth and the regulation of inflammation will be studied as well. In addition, we will investigate such responses using a third model based on mice reconstituted de novo with human hematopoietic-derived cell lineages. Finally, targeted and genome-wide explorations will be employed in large familial samples to identify novel susceptibility genes involved in the immune control of primary M. tuberculosis infection and secondary pulmonary TB. The outcome of HOMITB will be an assessment of molecular and cellular interactions crucial for the design of novel vaccination, immunotherapeutic strategies and better diagnostic biomarkers. The feasibility of this programme is attested by the high scientific quality and remarkable complementarities of the participants.