©2007 Copyright Landes Bioscience. Not for Distribution. CHAPTER 16 *Corresponding Author: João S. Silva—Depto of Biochemistry and Imunology, School of Medicine-USP, Av. Bandeirantes, 3900, CEP 14049-900; Ribeirão Preto, SP, Brazil, Email: jsdsilva@fmrp.usp.br. Protozoans in Macrophages, edited by Eric Denkers and Ricardo Gazzinelli. ©2007 Landes Bioscience. Effector Mechanisms of Macrophages Infected with Trypanosoma cruzi Fredy R.S. Gutierrez, Flavia S. Mariano, Isabel K.F. Miranda-Santos and João S Silva* Abstract T he main effector mechanisms that control infection by T. cruzi depend upon activa- tion of macrophages. These cells are activated soon after infection by mechanisms that are dependent on production of several cytokines and chemokines. Once activated, macrophages, as well other cells of the innate immune system, including cardiomyocytes pro- duce several oxidative molecules, such as nitric oxide. These free radicals kill the intracellular parasites by chemically modifying the structural properties of their proteins and inactivating catalytic sites of their enzymes. Some of these molecules present systemic effects and activate other cells of the innate and adaptive immune responses, recruiting them to the inflammatory site, hence improving the host’s immune response to infection. These energy-consuming re- sponses must be controlled in order to avoid damage to host tissues and macrophages also participate in this aspect of homeostasis. Here we discuss the mechanisms that lead to activa- tion of macrophages, killing of parasites and migration of cells, as well as the consequences of the inflammatory reaction caused by infection with T. cruzi. The Clinical Outcome of Infection with Trypanosoma cruzi and its Preference for an Intracellular Habitat Trypanosoma cruzi, the causative agent of Chagas’ disease, is classified as an intracellular parasite, in reference to its preferential location for development within the mammalian host. The term “intracellular” also refers to the escape strategies that it have evolved in order to deal with the effector or killing mechanisms of the host’s phagocytes, the cell that the amastigote form of this parasite is very adept at living in. In fact, parasite escape mechanisms underscore the relevant host defenses that are important for maintaining pathogen numbers in check. These effector mechanisms and T. cruzi’s preference for the very cell that is supposed to destroy it must be reconciled with the pathology and clinical presentations of infections caused by this parasite. Most patients infected with T. cruzi survive the acute infection and progress to the so-called indeterminate phase. Of these, less than 30% develop the clinical complications of chronic disease such as carditis and organomegally. The different outcomes of the initial infec- tion reflect the stochastic nature of the interplay between parasite and host, which is affected by their genetic makeup.