Tuberculosis is a leading killer world-wide, and the proportion of Paediatric tuberculosis is expanding. Although the BCG vaccine triggers specific T and B cell responses in neonates, it only confers protection from severe forms of tuberculosis in the firs t years of life. BCG does not significantly protect adults from pulmonary tuberculosis. There is therefore an urgent need to develop novel vaccines against tuberculosis, which would provide a long lasting protection following neonatal inoculation. One appr oach to this crucial aim is to decipher the mechanisms involved in neonatal immune responses to mycobacteria. For this purpose, we have established a consortium of experts in Genetics, Immunology, Microbiology and Paediatrics, as well as a biotechnology co mpany. Our objective is to dissect the molecular and cellular immune responses in neonates and infants, combining three complementary models, namely mice, humanized mice, and human patients. We will compare the innate and adaptive immune responses, with an emphasis on dendritic cells and T-cells. We will investigate neonatal and adult mice during mycobacterial infection and following inoculation of a novel and promising candidate vaccine, methylated HBHA. In addition, we will investigate such responses usin g mice reconstituted de novo with human lymphoid and myeloid hemopoietic-derived cell lineages, allowing for the first time an experimental dissection of human immunity to mycobacteria. The immune responses of naturally infected humans in the corresponding age groups will also be monitored and compared. Finally, the human molecular basis of hyper-susceptibility to live BCG in rare neonates with disseminated BCG disease will be investigated, in order to discover novel mycobacterial susceptibility genes, whic h will then be tested in the humanized mouse model. The feasibility of this research programme is attested by the high scientific quality and remarkable complementarity of the participants.
Call for proposal
See other projects for this call