NO produced by activated macrophages inhibits expression of the Salmonella SPI2 system, which destines the bacteria (green) for degradation in late endosomes/lysosomes (red).

Macrophages use nitric oxide (NO) to gain the upper hand against Salmonella infection, according to a study on page 625. McCollister and colleagues show that NO released by macrophages foils Salmonella's attempts to avoid degradation in lysosomes.

Salmonella is an enteric pathogen that infects macrophages and causes illnesses ranging from mild gastroenteritis to potentially fatal systemic disease. Once inside macrophages, Salmonella avoid the cells' antimicrobial defenses using a specialized protein secretion system. This system, known as the Salmonella pathogenicity island 2 (SPI2) type III secretion system, injects proteins from the bacteria-containing phagosome into the cytosol of the infected cell. These proteins disrupt normal vesicular trafficking and prevent the fusion of the phagosome with the degradative lysosomes where the bacteria would be digested. Salmonella with a defective SPI2 system survive poorly in macrophages and are unable to cause systemic disease.

Previous studies have shown that interferon (IFN)-γ–induced activation of macrophages is essential for effective defense against Salmonella infections. McCollister and colleagues now show that IFN-γ helps outsmart the bacteria by inducing the sustained production of NO by macrophages. Macrophage-produced NO inhibited transcription of the sensor kinase that controls the SPI2 system. Without the SPI2 system in place, the Salmonella-containing phagosomes were free to fuse with lysosomes and the bacteria were destroyed.