Activation of Macrophages to Kill Rickettsiae and Leishmania: Dissociation of Intracellular Microbicidal Activities and Extracellular Destruction of Neoplastic and Helminth Targets

Abstract

Analysis of Listeria infection in mice (Mackaness, 1962) clearly defined host-cell interactions that occur during resolution of this infectious disease: T lymphocytes develop specific immune responses to the invading microorganism, but macrophages are the proximate effector cells that eliminate the pathogen. Parenthetically, these early studies also showed that macrophages recovered from infected animals can destroy microorganisms antigenically unrelated to Listeria. In fact, these “activated” macrophages develop the capacity to kill a variety of intracellular and extracellular targets. The observation that mediators released by specifically sensitized T lymphocytes confer enhanced but entirely nonspecific killing properties on macrophages focused attention on a new group of important immunoregulatory mechanisms. Initial attempts to demonstrate activation of macrophages for enhanced microbicidal activities in vitro,however, were frustrated by a variety of technical difficulties inherent in these facultative intracellular bacteria: adherence to macrophage surfaces, extracellular replication, and short generation times obscured important details of intracellular events. Only recently have we and several other groups developed techniques to analyze macrophage antimicrobial activities in vitro (Anderson and Remington, 1974; Hinrichs and Jerrels, 1976; Nogueira and Cohn, 1978; Mauel et al.,1978; Nacy and Meltzer, 1979; Nacy et al., 1981b). The key to success of these later studies is the target cell: obligate intracellular microorganisms. The use of obligate intracellular parasites circumvents the major problem associated with facultative microorganisms—extracellular replication—and permits quantitative analysis of events that lead to macrophage activation for microbicidal activities.