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Tumor necrosis factor (TNF or TNF?) is a pleiotropic cytokine associated with the development of human immunopathologies, involved in physiological functions and host defense mechanisms against many pathogens. Anti-TNF therapies have shown their efficacy for the treatment of autoimmune inflammatory diseases such as rheumatoid arthritis and Crohn’s disease and are being expanded to treatment of other inflammatory diseases. However, complete TNF blockade has confirmed its critical role in the control of tuberculosis and other infections. Our previous work has been devoted to the study of the role of soluble TNF (solTNF) or membrane TNF (mTNF) in host immunity during the course of Mycobacterium bovis BCG and M. tuberculosis infections and inflammatory diseases. These studies have shown that mTNF can mediate several functions of solTNF during infection but exerts limited pathogenic activity during inflammatory liver diseases. According to this data, we have established that while total inhibition of TNF by non-selective inhibitors leads to fatal infection, selective inhibitors blocking only solTNF can be active in vivo in mice preventing acute inflammation but not inhibiting host immunity to mycobacterial infections. The identification of cellular sources of TNF begins to be defined, while cells responding to TNF mediating host protective immunity triggered by mycobacterial infections are unknown. This proposal explores interactions between TNF and TNFRs, mainly TNFR1, triggered by mycobacterial infection and investigates immunoregulatory and antimicrobial activities of TNF responses required for host immune responses against intracellular bacterial infection. Our first aim is the identification of specific cell types expressing TNFRs, responding to mycobacterial-induced TNF, and required for host protection mechanisms against mycobacteria. A combination of mouse models including mice deficient in TNFRs and bone-marrow chimeric mice will be used to determine whether TNF-responsive cells are from hematopoietic and/or nonhematopoietic origin and to identify cells relying on protection and sensitivity to the infection and associated immunopathology. As a model for interaction of TNF with TNFR1, we will explore host immunity in human TNF KI mice in which mouse TNF has been replaced by human TNF. The contribution of T cells and macrophages/neutrophils in host protection against M. bovis BCG and M. tuberculosis infections will be analyzed in mice with cell specific inactivation or activation of TNFR1. To understand underlying mechanisms involved in the interaction between TNF and TNF receptors, gene expression by microarray analysis will be carried out on selected infected lungs which may provide new targets for clinical intervention. Our second aim is the investigation of TNFR1 blockade as adjunctive therapy to treat virulent M. tubeculosis infection and underlying mechanisms. We will determine whether inactivation and blockade of TNFR1 improve lung immunopathology and bacterial clearance after M. tuberculosis chemotherapy and study the underlying mechanisms using gene expression profile by microarray analysis. These studies will extend our understanding of TNF-dependent host defense mechanisms based on the identification of cells and gene products that can be potential targets for designing new therapies for infectious diseases.