TRANSFORMING GROWTH-FACTOR-BETA AS A VIRULENCE MECHANISM FOR LEISHMANIA-BRAZILIENSIS

Transforming growth factor beta (TGF-beta) has potent down-regulating effects on macrophages and is thus capable of influencing the fate of intramacrophage parasites, including leishmanias. We report the develo pment of a mouse model for the study of the human pathogen Leishmania braziliensis and demonstrate, both in vitro and in vivo, a key regulat ory role for TGF-beta in the pathogenesis of infection with this paras ite. Recombinant TGF-beta added to cultures of murine peritoneal macro phages led to increased intracellular L. braziliensis replication, whe reas addition of neutralizing anti-TGF-beta monoclonal antibody decrea sed levels of infection. Macrophages infected with L. braziliensis pro duced biologically active TGF-beta, with a direct correlation between amounts of TGF-beta induced by two parasite isolates and their relativ e virulence. In vivo, treatment with recombinant TGF-beta rendered avi rulent parasites virulent and activated latent L. braziliensis infecti on. Activation of parasite replication was observed in mice which had been infected with L. braziliensis 15 weeks previously but had not dev eloped lesions or had healed lesions, depending on the parasite isolat e used to infect the mice. The exacerbation of L. braziliensis infecti on in vivo was associated with an increase of interleukin 10 mRNA in t he draining lymph node. These results demonstrate that TGF-beta is abl e to alter the course of in vitro and in vivo infections with L. brazi liensis, the latter being characterized by an increase in interleukin 10, an important T(h2) helper-T-cell cytokine.