TNF-alpha in Tuberculosis

The mechanisms by which latent tuberculosis is established and subsequently reactivates are poorly understood. We have used the low dose model of persistent murine tuberculosis to examine the effects of tumor necrosis factor (TNF)-alpha on host immune response in the quiescent phase of infection. Results of these studies demonstrate that persistently infected mice undergo reactivation when neutralized for TNF-alpha by the administration of the monoclonal antibody MP6- XT22. This reactivation is characterized by increased mortality associated with severe inflammatory reaction in the lungs despite only a moderate tissue bacterial load. The severe pathology may result from progressive disorganization of the granulomas and unfocused inflitrating cells in the lungs. In addition, expression of interleukin (IL)-10 is enhanced in TNF-alpha neutralized, persistently infected mice. TNF-alpha and IL-10 can modulate the expression of chemokines and chemokines receptors, molecules that play a criticalrole in cell migration. Fibronectin-bound TNF-alpha can anchor trafficking T cells thereby halting migration. IL-10 has been reported to block inflammatory molecule-triggered chemokine receptor switch and uncouple signaling through these receptors in monocytes. Consequently, IL-10 can render inflammatory monocytes unresponsive to specific chemokines. Therefore, we propose that TNF-alpha neutralization in persistently infected mice results in aberrant cell migration secondary to dysregulation of localized chemokine and chemokine receptor expression. In addition, the TNF-alpha neutralization may lead to deficiency in the formation of TNF-alpha- fibronectin complex, thereby altering cell trafficking. Finally, enhanced IL-10 expression in TNF-alpha neutralized mice may cause aberrant cell migration because of its ability to modulate the expression and uncoupling of chemokine receptors. The goal of this proposal is to rigorously test these hypotheses. Results obtained from these studies should enhance our understanding of the effects of TNF-alpha on the hose immune response in persistent infection, particularly those pertaining to cell migration to and within the granuloma and pathology. This, in turn , will illuminate the mechanisms by which TNF-alpha exert its antimycobacterial effects in persistent infection.