The role of the activated macrophage in clearing Listeria monocytogenes infection

Abstract

Macrophage activation often contributes to the strong immune response elicited upon infection. The ability of macrophages to become activated was discovered when sub-lethal primary infections of mice with the bacterium Listeria monocytogenes provided protection against secondary infections through non-humoral immunity. L. monocytogenes infect and propagate in macrophages by escaping the phagosome into the cytosol, where they avoid humoral immune mediators. Activated macrophages kill L. monocytogenes by blocking phagosomal escape. The timing of the antimicrobial activities within the phagosome is crucial to the outcome. In non-activated macrophages, bacterial factors generally prevail, and L. monocytogenes can escape from the vacuoles and grow within cytoplasm. Activated macrophages generate reactive oxygen or nitrogen intermediates early after bacterial uptake, which prevent the bacteria from escaping vacuoles into cytoplasm. The heterogeneity in the interactions between L. monocytogenes and the macrophage indicate a complex relationship between the host and the pathogen governed by chemistries that promote and inhibit escape from vacuoles. This review examines the mechanisms used by activated and non-activated macrophages to kill microbes, and how those mechanisms are employed against L. monocytogenes.

Figure 1

Macrophages phagocytose foreign particles into membrane-bounded compartments that undergo fusion events guiding their maturation. After phagosome closure, the phagosome resembles an early endosome that transitions into a late endosome and fuses with the lysosomes.

Figure 2

In RAW 264.7 macrophages, wild-type L. monocytogenes vacuoles recruit and escape from Rab7-and PI3P- positive compartments. Wild-type L. monocytogenes also delay lysosome fusion, relative to hly-L. monocytogenes vacuoles. hly- L. monocytogenes vacuoles also label with Rab7 and PI3P. They eventually also acquire LAMP-1, an indication of their failure to escape.

Figure 3

Macrophages activated with IFN-gamma and LPS generate reactive oxygen (ROI) and nitrogen (RNI) intermediates within or near the L. monocytogenes vacuole, thereby blocking the early perforations by LLO that otherwise allow L. monocytogenes to escape the vacuole.