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Innate and adaptive immunity in clinical and experimental mycobacterial infection in neonates and infants

Final Report Summary - NEOTIM (Innate and adaptive immunity in clinical and experimental mycobacterial infection in neonates and infants)

Tuberculosis is a leading killer world-wide, and the proportion of pediatric tuberculosis is expanding. Although the Bacillus Calmette-Guérin (BCG) vaccine triggers specific T and B cell responses in neonates, it only confers protection from severe forms of tuberculosis in the first 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 approach 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 pediatrics, as well as a biotechnology company. The objective of NEOTIM was to dissect the molecular and cellular immune responses in neonates and infants, combining three complementary models, namely mice, humanized mice, and human patients.

We compared the innate and adaptive immune responses, with an emphasis on dendritic cells and T-cells and investigated neonatal and adult mice during mycobacterial infection and following inoculation of a novel and promising candidate vaccine, methylated HBHA.

In addition, we investigated such responses using 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 was also monitored and compared.

Finally, the human molecular basis of hyper-susceptibility to live BCG in rare neonates with disseminated BCG disease was investigated, in order to discover novel mycobacterial susceptibility genes, which was then be tested in the humanised mouse model. The immune parameters will be further compared to those observed in humans for the corresponding age group. Furthermore, human neonates with enhanced vulnerability to mycobacterial infections will be investigated to find novel susceptible genes using forward genetics.

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