Regulation of autoinducer-2 production in Salmonella enterica serovar Typhimurium

Infections by members of the salmonellae can result in a wide range of clinical symptoms including gastroenteritis, enteric fever or a carrier state. The intercellular signaling molecule, autoinducer-2 (AI-2) establishes cell-cell communication in many bacteria including the foodborne pathogen S. enterica serovar Typhimurium (S. typhimurium). AI-2 signal generation in the S. typhimurium is highly regulated, where maximal signaling activity is observed during rapid growth in the presence of a preferred carbohydrate. Two proteins Pfs and LuxS are required to generate AI-2 from S-adenosylhomocysteine.{09}The results describe the regulation of AI-2 production by Salmonella and are summarised below. It was determined that pfs expression (but not luxS) is correlated to AI-2 production in several growth conditions and is linked to carbohydrate availability. AI-2 production is likely regulated at the level of Pfs substrate concentration (S-adenosylhomocysteine), as overexpression of Pfs and LuxS proteins does not result in increased signal production. It was also determined that the carbohydrate-dependent regulation of AI-2 production was restricted to Salmonella strains in subgroup I (causing >99% of all human infections), suggesting that the environmental composition of the host may contribute to the regulation of AI-2 production. Due to the correlation of pfs expression to AI-2 production, specific regulators of pfs expression were identified. Mutations in hha, leuO and yojN, encoding global regulatory proteins as well as yifA and gidA resulted in significant increases or decreases in pfs promoter activity. The cAMP receptor protein (CRP) and adenylate cyclase required for cAMP generation were examined specifically and mutations in either gene resulted in increases in both pfs expression and AI-2 production. Lastly, it was determined that the Pfs substrate, S-adenosylhomocysteine is exported from the cell during growth, consistent with the hypothesis that altered flow of substrate through the Pfs/LuxS pathway leads to differences in AI-2 production. Studies on the regulation of AI-2 signal production by S. typhimurium will further our understanding of how this pathogen relays environmental conditions to induce a population response.