Nitrate Utilization Promotes Systemic Infection ofTyphimurium in Mice.

Abstract

Typhimurium is an invasive enteric pathogen that causes gastroenteritis in humans and life-threatening systemic infections in mice. During infection of the intestine,Typhimurium can exploit nitrate as an electron acceptor to enhance its growth. However, the roles of nitrate onTyphimurium systemic infection are unknown. In this study, nitrate levels were found to be significantly increased in the liver and spleen of mice systemically infected byTyphimurium. Mutations in genes encoding nitrate transmembrane transporter () or nitrate-producing flavohemoprotein () decreased the replication ofTyphimurium in macrophages and reduced systemic infection in vivo, suggesting that nitrate utilization promotesTyphimurium systemic virulence. Moreover, nitrate utilization contributes to the acidification of theTyphimurium cytoplasm, which can sustain the virulence ofTyphimurium by increasing the transcription of virulence genes encoding onpathogenicity island 2 (SPI-2). Furthermore, the growth advantage ofTyphimurium conferred by nitrate utilization occurred only under low-oxygen conditions, and the nitrate utilization was activated by both the global regulator Fnr and the nitrate-sensing two-component system NarX-NarL. Collectively, this study revealed a novel mechanism adopted byto interact with its host and increase its virulence.