[Mechanisms of intracellular microbicide]

The understanding of mechanisms whereby phagocytic cells destroy intracellular microorganisms has progressed considerably in recent years. The interaction of phagocytes with microbes starts with binding of the latter to the phagocyte. This binding can be mediated by opsonins on the microorganisms, which then interact with appropriate receptors on the phagocyte surface. Other types of receptors, such as lectins, may also be involved in this process. Following internalization, the microbe will be enclosed in a vesicle (the phagosome), whose membrane is derived from the plasma membrane of the phagocytic cell. The phagosome will then normally undergo fusion with primary or secondary lysosomes. Various mechanisms can then lead to intracellular killing; some depend on oxidative processes, whereas other are independent of the oxidative metabolism. The former involve the activation of membrane enzyme systems that lead to a stimulation of oxygen uptake (the "respiratory burst"), and its reduction to molecular species that are highly toxic for microorganisms. Differences appear to exist in this regard between alveolar macrophages and other phagocytes, in which the respiratory burst is of higher magnitude. Oxygen-independent microbicidal mechanisms are based on the production of acid, on the secretion of lysozyme, on iron-binding proteins, and on the synthesis of toxic cationic polypeptides. Both oxygen-dependent and independent mechanisms appear to be increased in activated macrophages. Certain microorganisms have evolved countermeasures which enable them to avoid being destroyed by phagocytes; these are well illustrated by studies of the interaction between macrophages and protozoan parasites. Parasites such as Toxoplasma gondii (as well as certain mycobacteria) are able to inhibit fusion of phagosomes with lysosomes, thus escaping from the potentially harmful action of lysosomal hydrolases. Other microorganisms are able to resist the effect of such enzymes, perhaps by secreting inhibitory substances. Other still avoid lysosomes by leaving the phagocytic vacuole, to reach the cytosolic matrix where their development is unhindered. Finally, some microbes have enzymes to detoxify oxygen metabolites formed during the respiratory burst. Intracellular death or survival will thus depend on a delicate balance between several factors, some of which appear to be under genetic control.