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Role of tumor necrosis factor (TNF) and nitric oxide (NO) in mycobacterial infections and inflammation

English title Role of tumor necrosis factor (TNF) and nitric oxide (NO) in mycobacterial infections and inflammation
Applicant Garcia-Gabay Irène
Number 105914
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Endocrinology
Start/End 01.11.2004 - 31.10.2007
Approved amount 197'000.00
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Keywords (5)

Cytokines; TNF; Infectious diseases; tuberculosis; Nitric oxide

Lay Summary (English)

Lead
Lay summary
Tumor necrosis factor (TNF) is a pleiotropic factor associated with human immunopathologies and involved in physiological functions. Anti-TNF therapies which have shown their efficacy for the treatment of rheumatoid arthritis and Crohn’s disease, are today in expansion for many other inflammatory diseases. However, treatments resulting in total TNF blockade have confirmed the crucial role of TNF for control and resistance of tuberculosis infections which can be reactivated in patients treated with TNF inhibitors. TNF exists as a soluble TNF form as well as a membrane associated TNF form. We have studied the role of these two TNF forms during Mycobacterium bovis BCG and M. tuberculosis infections and showed that the membrane TNF is sufficient for total protection against M. bovis BCG and confers protection during an acute but not during a chronic infection by M. tuberculosis. Therefore, we postulate that selective inhibition of soluble TNF leaving functional membrane TNF may allow better approach for the treatment of inflammatory diseases while be sufficient for maintaining protective immunity against mycobacteria and other infectious pathogens. Thereby, the aim of this proposal is the analysis of the mechanisms involved in protection by membrane TNF and to propose candidate strategies to selective neutralisation of soluble TNF sparing membrane TNF or inhibiting TNF receptor activity that could be relevant for the development of second generation of specific TNF blockers. This project is relevant for second generation of TNF neutralizing strategies to obtain a better immunity of patients avoiding reactivation of latent tuberculosis infection. In addition, our studies are also designed to analyse the role of a lectin-domain of the TNF molecule, previously involved in reabsorption of alveolar edema, in tuberculosis. The role of TNF lectin-like domain in mycobateria host defense are unknown, however, this study can be of clinical relevance considering the development of pulmonary edema therapies using TNF lectin-like domain peptides.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
62026 Role of tumor necrosis factor, related ligands and receptors in infection and inflammation 01.10.2000 Project funding
118196 Role of tumor necrosis factor (TNF) in mycobacterial infections and inflammation 01.11.2007 Project funding

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