How does the oxidative burst of macrophages kill bacteria? Still an open question

TLDR: The Barras and Méresse labs use a GFP fusion to an OxyR regulated gene to show that phagocyte‐derived H2O2 is gaining access to the Salmonella cytoplasm, suggesting that ROS are not diminished in this modified phagosome.

Abstract: Macrophages engulf and kill bacteria. Although the overall role of macrophages has been known for over 100 years, we understand surprisingly little of the actual mechanisms by which bacteria are destroyed. The cell biology of phagolysosomal formation is fairly well understood. Macrophages recognize and engulf bacteria into phagosomes, which subsequently acidify. These phagosomes mature into phagolysosomes upon vesicle-mediated delivery of various antimicrobial effectors, which include proteases, antimicrobial peptides, and lysozyme (Garin et al., 2001)(Figure 1). The phagolysosome is also a nutrient-limiting environment. Reactive oxygen species and reactive nitrogen species are produced in this compartment. The multi-subunit NADPH-dependent phagocytic oxidase (Phox or NOX2) is assembled on the phagolysosome membrane and pumps electrons into the compartment to reduce oxygen to superoxide anion (O2−). The inducible nitric oxide synthase uses arginine and oxygen as substrates to produce nitric oxide (Fang, 2004). Figure 1 Reactive oxygen species in the Salmonella containing vacuole Most bacteria are rapidly killed and degraded in the phagolysosome, making it difficult to dissect the mechanism of death. But a few bacteria have evolved to survive in macrophages. Salmonella use a type III secretion system to affect vesicular trafficking and maturation of the phagolysosome (Holden, 2002). It is presumed that the bacteria within this modified “Salmonella containing vacuole” (SCV) are subjected to a less intense antimicrobial response. However, the phagocytic arsenal still has a role in Salmonella pathogenesis and the bacteria must also be resistant to these antimicrobial factors. This balance between survival and killing makes Salmonella a powerful model to understand the mechanisms of action of the phagocytic effectors. Reactive oxygen species (ROS) are critical weapons in the phagocyte arsenal. In theory, O2− and nitric oxide can combine to form highly reactive peroxynitrite (ONOO−). But the roles of Phox and iNOS are both temporally (Vazquez-Torres et al., 2000a) and genetically (Craig and Slauch, 2009) separable during Salmonella infection, suggesting that ONOO− is irrelevant when combating this pathogen. Studies by Aussel et al. (2011), reported in this volume, provide important information regarding Salmonella resistance to the ROS produced by Phox, and suggest that Salmonella relies less on blocking ROS formation than on scavenging.