Survival of Intracellular Pathogens within Macrophages

Reactive oxygen metabolites produced during phagocytosis are important for the microbicidal activity of granulocytes and probably of monocytes as well (1, 2). Although the role of reactive oxygen metabolites in the microbicidal activity of macrophages is not established, recent studies (3-6) suggest that they may be important because activated macrophages that exhibit enhanced antimicrobial activity produce increased amounts of these metabolites in response to various stimuli. Because reactive oxygen metabolites are potentially lethal, organisms that survive within phagocytes must either fail to stimulate production of such substances or must be resistant to or fail to encounter them. One such intracellular organism is Toxoplasma gondii. This organism survives and replicates in vitro within human monocyte-derived macrophages and within normal mouse macrophages (7-10). However, other mononuclear phagocytes can kill or inhibit multiplication of Toxoplasma. For example, we recently have observed that Toxoplasma is rapidly destroyed by freshly isolated human blood monocytes (11). In addition, macrophages can be activated to kill or inhibit intracellular replication of Toxoplasma (7-9), and normal macrophages can kill the organism if it is coated with antibody (12, 13). Because the ability of Toxoplasma to survive within mononuclear phagocytes depends upon the stage of differentiation or state of activation of mononuclear phagocytes and also depends upon whether the organism is opsonized, we studied the oxidative metabolic burst by different mononuclear phagocytes during phagocytosis of Toxoplasma. These studies were performed to determine the relationship between survival of this intracellular pathogen and production of toxic oxygen metabolites by these cells. The results revealed that the ability of this organism to survive within certain mononuclear phagocytes is dependent in part upon its being phagocytosed without stimulating production of reactive oxygen metabolites by these cells.