Manganese Homeostasis in Bacterial-Host Interactions

Abstract

Bacterial pathogens must acquire nutrients from the host during infection. The transition metal manganese (Mn) is an essential nutrient for both bacteria and vertebrates. Molecular mechanisms by which the opportunistic pathogen Acinetobacter baumannii acquires Mn and regulates Mn homeostasis were investigated. The Nramp-family transporter MumT was defined as a Mn acquisition system in A. baumannii that contributes to infection in the lung. The transcriptional regulator MumR was identified as a transcriptional activator of Mn import machinery. MumR was found to be important for defense against hydrogen peroxide. The importance of dietary Mn in Staphylococcus aureus infections was also interrogated. Excess dietary Mn enhances S. aureus infection of the heart. Mn is bioavailable to S. aureus in the heart, and S. aureus utilizes Mn to detoxify reactive oxygen species and escape neutrophil killing. The host Mn-binding protein calprotectin does not sequester Mn in the heart. Instead, calprotectin promotes S. aureus infection of the heart by modulating neutrophil recruitment. Finally, a small molecule was identified that targets metal homeostasis and is toxic to Gram-positive bacteria. Together, this Thesis establishes a role for Mn during A. baumannii infection, defines dietary Mn intake as a critical factor modulating S. aureus virulence, and presents a potential therapeutic targeting Mn homeostasis.