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Neotim

Tuberculosis

Innate and adaptive immunity in clinical and experimental mycobacterial infection in neonates and infants
Framework programme:
6
Call:
3
Project number:
LSHP-CT-2005-018736
EC contribution:
€ 2 000 000
Duration:
36 months
Type:
STREP
Starting date:
November 2005

Keywords: Tuberculosis; neonatal; infant; T-cells; Dendritic cells; T-regulatory cells; vaccine; type I interferons; forward genetics; humanised mice; HBHA; Toll-like receptors

Summary:

Tuberculosis is a leading killer worldwide, 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 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. The objective is to dissect the molecular and cellular immune responses in neonates and infants, combining three complementary models, namely mice, humanised 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 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 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, which will then be tested in the humanized mouse model.

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