RclA is a thermostable copper (II) reductase required for reactive chlorine resistance and host colonization in Escherichia coli

Academic Article

Abstract

  • ABSTRACT Inflammatory bowel diseases (IBDs) are a growing health concern and have been linked to changes in gut microbiome composition. Enterobacteria, including Escherichia coli , bloom to high levels in the gut during inflammation and strongly contribute to the pathology of IBDs. To survive in the inflamed gut, E. coli must tolerate high levels of antimicrobial compounds produced by the immune system, including toxic metals like copper and reactive chlorine oxidants such as hypochlorous acid (HOCl). The mechanisms by which both copper and HOCl kill bacteria are complex and poorly characterized. In this work, we show that the widely-conserved bacterial HOCl resistance enzyme RclA catalyzes the reduction of copper (II) to copper (I), and that this activity specifically protects E. coli against toxicity resulting from the combination of HOCl and intracellular copper, probably by preventing Cu(III) accumulation. Mutant E. coli lacking RclA were highly sensitive to killing by HOCl and were defective in colonizing an animal host. Consistent with the need for RclA to maintain activity under proteotoxic stress conditions, we found that RclA is remarkably thermostable and resistant to inactivation by HOCl. Our results indicate new complexity in the interactions between antimicrobial toxins produced by innate immune cells, and highlight that understanding copper redox reactions both inside and outside of cells is critical to our understanding of how bacteria evade innate immune factors during inflammation. SIGNIFICANCE STATEMENT During infection and inflammation, the innate immune system uses antimicrobial compounds to control bacterial populations. These include toxic metals like copper and reactive oxidants, including reactive chlorine species like hypochlorous acid (HOCl). We have now found that RclA, an enzyme strongly induced by HOCl in pro-inflammatory Escherichia coli and found in many bacteria inhabiting epithelial surfaces, reduces copper (II) to copper (I), and that this activity is required to resist killing by HOCl and for host colonization. This finding indicates that copper redox chemistry plays a critical and previously unappreciated role in bacterial interactions with the innate immune system.
  • Authors

    Digital Object Identifier (doi)

    Pubmed Id

  • 19901698
  • Author List

  • Derke R; Barron A; Chaple I; Lapi S; Broderick N; Gray M