Mechanisms of anaerobic nitric oxide detoxification by Salmonella enterica serovar Typhimurium
Salmonella is the cause of millions of food- and water-borne infections worldwide. Systemic infection and gastroenteritis are the main diseases and often prove fatal to immunocompromised patients. Key to Salmonella’s pathogenicity is the survival of several components of the innate immune system encountered during infection. Reactive oxygen and nitrogen species (ROS and RNS) are an integral part of this antibacterial defence of the immune system. Exposure to ROS and RNS occurs within phagocytic immune cells such as macrophages, where such generation of radicals is used to combat pathogens. NO is a radical belonging to the group of RNS that damages bacterial DNA and proteins. Detoxification of NO is essential during infection to allow Salmonella to survive and replicate within macrophages. Three enzymes are currently known to help Salmonella to detoxify NO, but their deletion, however, does not eliminate Salmonella’s survival. Therefore, it is predicted that further mechanisms for NO detoxification exist. In this study, the core NO regulon has been identified: Expression of nine genes is significantly increased during endogenous and exogenous NO exposure of S. Typhimurium. Their functions range from carbon starvation, cytochrome oxidation, iron-sulphur repair and NO reduction to putative proteins with unknown function, some of which contain domains for tellurite resistance. Single and combination deletion strains have shown that these genes are important to decrease anaerobic NO sensitivity of S. Typhimurium and for intracellular survival in murine macrophages. Furthermore, we have shown for the first time that the core NO regulon also provides protection against tellurite. Tellurite is toxic and requires detoxification when encountered. Reducing tellurite to yield the elemental tellurium results in the release of ROS, which then need to be detoxified further. Deletion strains sensitive to tellurite have also shown increased sensitivity to NO. Concurrently, tellurite resistance genes also facilitate the defence against NO.
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