Keywords: Tuberculosis; neonatal; infant; T-cells; Dendritic cells; T-regulatory cells; vaccine; type I interferons; forward genetics; humanised mice; HBHA; Toll-like receptors
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.
Tuberculosis is a major infectious disease estimated to kill over 2 million people annually worldwide. Although TB is more frequent in adults than in children, due to the chronic nature of the disease, it is still common in childhood, including the neonatal period.
Attempts over the years to vaccinate adults against pulmonary tuberculosis with the attenuated BCG vaccine have proved disappointing. While neonatal BCG vaccination can provide protection against childhood manifestations of the disease, the protection wanes over time and an immunologic explanation for the lack of efficacy of BCG is unavailable.
The failure to produce an improved vaccine against TB is probably because most vaccine strategies concentrate on structural proteins of the microorganism that target the adaptive memory responses and do not consider other aspects of the host/microorganism relationship.
The aim of NEOTIM is to compare the neonates/infants and adults in terms of protective responses generated during mycobacterial infections or vaccination with novel mycobacterial antigens in murine experimental systems and in humanised mice, reconstituted with human lymphoid and myeloid cellular populations.
The innate and adaptive immune responses, with an emphasis on dendritic cells and T-cells will be compared. The consortium will investigate neonatal and adult mice during mycobacterial infection and following inoculation of a novel and promising candidate vaccine, methylated HBHA. In addition, it 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 humanised mouse model.
The result of this project will provide conclusive assessment of the role and regulation of the neonatal/infant immune system in determining the outcome of mycobacterial infections.
Data obtained will also determine whether the use of selected mycobacterial antigens, together with innate immunomodulatory molecules, will offer significant protection against human tuberculosis.
This project aims to expand our knowledge significantly in the immune protection of neonates and children against M. tuberculosis. The knowledge gained here will allow for a combined targeting of innate and adaptive immune systems. This will be highly relevant in the rational design of vaccines. The research will be of further value for a better general understanding of pathogen/host relationships and of the basic mechanisms of the immune system and immune protection.
Microbiology and Tumor Biology Center
171 77 Stockholm
Tel: +46 8 5248 6711
Fax: +46 8 32 8878
|Official Address||Other Information|
|2 ||Carmen Fernandez ||Department of Immunology |
The Wenner Gren Institute
|Tel: +46 8 16 4599 |
Fax: +46 8 15 4163
|3 ||Foo Yew Liew ||Department of Immunology & Bacteriology |
University of Glasgow
UK-G11 6NT Glasgow
|Tel: +44 141 211 2695 |
Fax: +44 141 337 3217
|4 ||Jean Laurent Casanova ||Laboratory of Human Genetics of Infectious Disease |
University of Paris René Descartes – INSERM U550
Necker-Enfants Malades Medical School
|Tel: +33 1 40 61 56 87 |
Fax: +33 1 40 61 56 88
|5 ||Enrico Proietti ||Department of Cell Biology and |
Immune Regulation Unit
Istituto Superiore di Sanità
|Tel: +39 064990 3290 |
Fax: +39 064990 2097
|6 ||Camille Locht ||Laboratory of Molecular and Genetic Microbiology, U629 |
Institut Pasteur de Lille
FR-59019 Lille Cedex
|Tel: +33 3 20 87 11 21 |
Fax: +33 3 20 87 11 58
|7 ||Françoise Mascart ||Laboratory of Vaccinology and Mucosal Immunity |
Université Libre de Bruxelles
|Tel: +32 2 555 3467 |
Fax: +32 2 555 4499
|8 ||Mahavir Singh ||LIONEX Gmb |
Mascheroder Weg 1b
|Tel: +49 531 260 1266 |
Fax: +49 531 260 1159