Bacterial pathogens must acquire iron to replicate and survive in mammalian hosts. The iron-porphyrin heme, bound to circulating hemoglobin, contains up to 80% of bodily iron. This fact has led to the hypothesis, which is backed by experimental evidence, that heme serves as a source of iron during infection. However, in the anthrax-causing bacteria B. anthracis, deletion of iron-regulated surface determinant (Isd) genes, which code for surface proteins that bind heme, did not reduce B. anthracis virulence in animal models of infection. These results suggest other factors contribute to iron uptake in this deadly pathogen. A hallmark of Isd systems is the presence of a conserved protein module termed the near-iron transporter (NEAT) domain, which mediates the transfer of heme into Gram-positive pathogenic bacteria. In silico analysis of the genome of B. anthracis indicates a non-Isd gene, designated BAS0520, is annotated to encode for a single NEAT-domain protein. The objective of this proposal is to determine if BAS0520 represents the missing link mediating heme uptake during anthrax infection. Specifically, we hypothesize BAS0520 is a surface protein that extracts heme from host hemoglobin, thereby promoting heme transport into the bacterial cell and enhancing iron-dependent replication in mammalian hosts. This hypothesis will be tested with two aims: 1. Determine the mechanistic function of BAS0520. Biochemical approaches will define the molecular and structural factors of the NEAT domain of BAS0520. 2. Determine the role of BAS0520 in iron acquisition and anthrax disease. Growth studies and animal infection models using fully virulent strains will be used to define which mechanisms of iron uptake are important for anthrax disease.
Bacterial pathogens require iron in order to replicate. The goal of this proposal is to understand how B. anthracis, a potential weapon of bioterrorism and the causative agent of anthrax disease, acquires iron during infection. Understanding how bacteria survive, grow, and spread inside mammalian hosts will lead to the discovery of new targets for drug development.
|Balderas, Miriam A; Nguyen, Chinh T Q; Terwilliger, Austen et al. (2016) Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease. Infect Immun 84:3408-3422|
|Chan, Albert H; Yi, Sung Wook; Terwilliger, Austen L et al. (2015) Structure of the Bacillus anthracis Sortase A Enzyme Bound to Its Sorting Signal: A FLEXIBLE AMINO-TERMINAL APPENDAGE MODULATES SUBSTRATE ACCESS. J Biol Chem 290:25461-74|
|Green, Sabrina I; Ajami, Nadim J; Ma, Li et al. (2015) Murine model of chemotherapy-induced extraintestinal pathogenic Escherichia coli translocation. Infect Immun 83:3243-56|
|Terwilliger, Austen; Swick, Michelle C; Pflughoeft, Kathryn J et al. (2015) Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins. J Bacteriol 197:2400-11|
|Nguyen, Chinh T Q; Shetty, Vivekananda; Maresso, Anthony W (2015) Global metabolomic analysis of a mammalian host infected with Bacillus anthracis. Infect Immun 83:4811-25|
|Ma, Li; Terwilliger, Austen; Maresso, Anthony W (2015) Iron and zinc exploitation during bacterial pathogenesis. Metallomics 7:1541-54|
|Nobles, Christopher L; Clark, Justin R; Green, Sabrina I et al. (2015) A dual component heme biosensor that integrates heme transport and synthesis in bacteria. J Microbiol Methods 118:7-17|
|Honsa, Erin S; Maresso, Anthony W; Highlander, Sarah K (2014) Molecular and evolutionary analysis of NEAr-iron Transporter (NEAT) domains. PLoS One 9:e104794|
|Honsa, Erin S; Owens, Cedric P; Goulding, Celia W et al. (2013) The near-iron transporter (NEAT) domains of the anthrax hemophore IsdX2 require a critical glutamine to extract heme from methemoglobin. J Biol Chem 288:8479-90|
|Nobles, Christopher L; Green, Sabrina I; Maresso, Anthony W (2013) A product of heme catabolism modulates bacterial function and survival. PLoS Pathog 9:e1003507|
Showing the most recent 10 out of 12 publications