Nitric Oxide Increases Susceptibility of Toll-like Receptor-Activated Macrophages to Spreading Listeria monocytogenes

Caroline Cole et al., Immunity 36:807–820 (2012)

Speaker: Miao-Huei Cheng (鄭妙慧)                    Time: 15:00~16:00, Sep. 19, 2012

Commentator: Dr. Pei-Jane Tsai (蔡佩珍老師)    Place: Room 601

Abstract

The Gram-positive bacterium Listeria monocytogenes is a threatening pathogen that can cause an overall 30% mortality rate in human infection [1]. Infection by L. monocytogenes occurs almost exclusively after ingestion of contaminated food and then causes gastroenteritis in susceptible individuals, severe septicemia in the newborn, and meningoencephalitis in immunocompromised or elderly people. This pathogen has the amazing ability to cross three tight barriers in humans, because this pathogen could escape extracellular defense mechanism and remain in intracellular through cell-to-cell spread (move directly from the primary infected ‘‘donor’’ cell to a secondary uninfected ‘‘recipient’’ cell) to disseminate and lead to severe disease. Previous studies indicate that Toll-like receptors (TLR) activation could increase the ability of macrophages to killphagocytosed bacteria. However, many intracellular pathogens, including Listeria, are able to overcome early TLR-dependent immune cell activation to establish infection in susceptible hosts [2]. The results in this study show that after infecting with L. monocytogenes, TLR-activated macrophages can produce nitrite oxide (NO) to kill cell-free L. monocytogenes but fail to prevent infection by spreading L. monocytogenes. Instead, TLR signaling increases the efficiency of L. monocytogenes spread from “donor” to “recipient” macrophages through delaying the maturation ofphagosomes. The spreading data also show that TLR-induced NO increases infection of the recipient macrophages which contain membrane-like particles that mimic L. monocytogenes–containing pseudopods. Furthermore, NO promoted L. monocytogenes spread during systemic in vivo infection, and treatment with the NOS2 inhibitor reduced spread-dependent L. monocytogenes burdens in mouse livers. According to these fundings, they suggest that NO is not only for killing phagocytosed bacteria but also important for regulating the spread of L. monocytogenes.

References

1.          Lecuit M and Cossart P. Genetically-modified-animal models for human infections: the Listeria paradigm. Trends Mol Med. 8:537-542 (2002)

2.          Myers JT, Tsang AW and Swanson JA. Localized reactive oxygen and nitrogen intermediates inhibit escape of Listeria monocytogenes from vacuoles in activated macrophages. J Immunol. 15:5447-5453 (2003)