Keywords: Tuberculosis, genetics, susceptibility, T cells, macrophages, latency, chemokine
The global incidence of tuberculosis (TB) is rising, with 8.8 million new cases and 2 million deaths each year. The rate of progression from infection to disease is highly variable, and approximately 90% of infected individuals never develop clinical disease. About half of the 10% of Mycobacterium tuberculosis-infected individuals who do develop overt clinical disease are diagnosed with TB within 2 years of infection and can be considered fast progressors. This 'primary' TB is particularly common in children and is often disseminated due to early haematogenous spread of the mycobacterium with miliary and/or extra-pulmonary disease.
About 50% of TB patients who develop clinical disease more than two years after infection are commonly described as cases of 'reactivation' or post-primary TB. Post-primary TB is predominantly a pulmonary disease of adults, involving extensive damage to the lungs and efficient airborne transmission of bacteria. Although neonatal immunisation with the Mycobacterium bovis-derived Bacillus Calmette-Guérin (BCG) vaccine can provide protection against childhood TB, BCG is relatively ineffective in preventing disease in older children and adults.
Latently infected individuals run a lifelong risk of reactivation. The risk is particularly high when these individuals are immunocompromised, as the result of either HIV infection or of immunosuppressive treatment.
Tightly controlled genetically determined interactions between the mycobacteria and different host target cells that are regulated by the host innate and adaptive immune responses dictate the outcome of mycobacterial infection in humans, ranging from an asymptomatic infection to a life-threatening disease.
HOMITB proposes to identify novel host genes involved in control of bacterial load, and regulation of inflammation and immune responses, and bacterial molecules involved in escape from such immune regulatory and effector mechanisms. Both targeted and genome-wide explorations will be employed to identify susceptibility of genes involved either in the immunological control or pathogenesis of primary M. tuberculosis infection in children and secondary pulmonary TB in adults, as well as in the control of mycobacterial infection in the mouse model. Immunological validation of the novel host susceptibility genes will be performed. In parallel, the M. tuberculosis strains collected in field studies will be typed by the most recent and discriminatory molecular typing method, based on Mycobacterial Interspersed Repetitive Units (MIRUs).
Mycobacterium host interactions in macrophages, dendritic cells and non-haematopoietic cells such as epithelial cells will also be studied both in human and mouse models. The role of chemokines, chemokine receptors and key intracellular signalling molecules in response to mycobacterial infection will be analysed. Mice with human lymphoid and myeloid lineages de novo developed after transplantation of haematopoietic stem cells will be used to explore the human immune responses to infection with Mycobacterium.
HOMITB 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, the project will investigate such responses using a third model based on mice reconstituted de novo with human haematopoietic-derived cell lineages. Finally, targeted and genome-wide explorations will be employed to identify novel susceptibility genes involved in the immune control of primary M. tuberculosis infection and secondary pulmonary TB.
Advanced knowledge of molecular and cellular interactions between host and mycobacteria is crucial for the design of novel vaccination or immunotherapeutic strategies and for the discovery of better diagnostic markers.
Prof. Martin Rottenberg
Microbiology and Tumorbiology Center, Karolinska Institute
|Official Address||Other Information|
|1||Carmen Fernandez||University of Stockholm
|2||Foo Y Liew||University of Glasgow
|4||Enrico Proietti||Instituto Superiore di Sanità
|5||Camille Locht||Institute Pasteur de Lille
|6||Francois Mascart||Université Libre de Bruxelles
|7||Jamila El Baghdadi||University Center of Rabat
|8||Mahavir Singh||Lionex Diagnostics & Therapeutics