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Title page for ETD etd-08222017-151211

Type of Document Dissertation
Author Juttukonda, Lillian Johnson
Author's Email Address lillian.juttukonda@vanderbilt.edu
URN etd-08222017-151211
Title Manganese Homeostasis in Bacterial-Host Interactions
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
David M. Aronoff Committee Chair
Aaron B. Bowman Committee Member
Eric P. Skaar Committee Member
Maria Hadjifrangiskou Committee Member
Richard M. Peek, Jr Committee Member
  • infection
  • nutritional immunity
  • calprotectin
  • diet
  • Acinetobacter baumannii
  • Staphylococcus aureus
Date of Defense 2017-07-11
Availability restricted
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.
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