A New Link Between Stress and Infection

Abstract

We have known for a long time that stress increases the risk of bacterial infections by weakening the immune system. However, that is only one side of the story. Could bacteria be actively sensing stress to identify where and when to invade?During conditions of stress, key markers such as the hormones norepinephrine (NE) and epinephrine are secreted into the gut by gut associated lymphoid tissue (GALT). Under normal circumstances, these tissues function as the watchtowers of the immune system. However, numerous studies have shown that GALTs are also the preferred sites for initiation of infections in the gut. We therefore hypothesized that bacteria might specifically locate GALTs by sensing the hormones as chemoattractants and this formed the basis of our studies.We conducted chemotaxis assays with wild‐type and mutant strains of E. coli K12 (RP437) and found that NE is not a chemoattractant. Instead, we discovered that these bacteria convert NE to 3,4‐dihydroxymandelic acid (DHMA), and that DHMA is a highly potent chemoattractant. We have shown that E. coli use TynA and FeaB to convert NE to DHMA, and Tsr to sense DHMA as a chemoattractant (Pasupuleti et al. (2014) J Bacteriol. 196, 3992).In this report, we show that DHMA is not only an attractant for enterohemorrhagic E. coli O157:H7, but it also induces virulence in this pathogen. Exposure to DHMA increased expression of LEE genes up to 35‐fold and increased attachment to HeLa cells over two‐fold. We also show that DHMA is present in the gut and that it is likely produced by gut microbiota. Using LC‐MS, DHMA could be detected and quantified in metabolite extracts from fecal samples as well as cecal contents of normal mice whereas no DHMA could be detected in fecal extracts of germfree mice.Our studies lead us to hypothesize that normal gut microbiota convert stress hormones such as NE into DHMA. This DHMA then acts as a beacon to other bacteria, including pathogens, directing them to NE rich sites such as the GALTs, thus playing an important role in initiating infections during stress. We are now investigating the detailed molecular mechanisms involved in the activity of DHMA as a chemoattractant and a virulence factor. Our studies could help identify new strategies to fight against intestinal infections.Support or Funding InformationNational Science Foundation award MCB 1121916