PI: Ferric Fang;Grant # 1R01AI 77629-01A2 Revised Abstract Section Iron is essential for virtually all forms of life and plays a central role in cellular metabolism. Microbes have developed complex strategies for the acquisition, storage, trafficking, utilization and detoxification of iron. One of the primary biochemical roles of iron is to serve as an intermediate electron carrier in oxidative reactions catalyzed by proteins containing iron-sulfur clusters. Our central hypothesis is that innate immunity exploits microbial iron dependence by targeting essential microbial iron and iron-containing proteins with phagocyte-derived reactive oxygen and nitrogen species. This project will examine a novel BaeSR-regulated efflux pump we have discovered which mediates iron excretion when intracellular iron levels are elevated from iron-sulfur cluster damage.
The specific aims of this research plan are to analyze the following aspects of the BaeSR system in Salmonella enterica: (1) Activation of BaeSR and characterization of the BaeSR regulon; (2) Identification of the novel chelator responsible for iron efflux; (3) Importance of the BaeSR regulon in iron homeostasis and Salmonella virulence. This work will have fundamental implications for understanding the strategies by which pathogenic microbes evade innate immunity by minimizing iron- dependent cell damage and maintaining iron homeostasis.
Iron is essential for living organisms. During infection, the host restricts the availability of iron to invading microbial pathogens, which employ iron in a variety of metabolic reactions. This project examines specific mechanisms used by the food-borne pathogen Salmonella to acquire and utilize iron in the host environment. The understanding gained from this research can be used to develop novel strategies for the treatment and prevention of a broad range of infectious diseases.
| Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Bacterial Stress Responses during Host Infection. Cell Host Microbe 20:133-43 |
| Fang, Ferric C; Weiss, Günter (2014) Iron ERRs with Salmonella. Cell Host Microbe 15:515-6 |
| Velayudhan, Jyoti; Karlinsey, Joyce E; Frawley, Elaine R et al. (2014) Distinct roles of the Salmonella enterica serovar Typhimurium CyaY and YggX proteins in the biosynthesis and repair of iron-sulfur clusters. Infect Immun 82:1390-401 |
| Frawley, Elaine R; Fang, Ferric C (2014) The ins and outs of bacterial iron metabolism. Mol Microbiol 93:609-16 |
| Nairz, Manfred; Schleicher, Ulrike; Schroll, Andrea et al. (2013) Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. J Exp Med 210:855-73 |
| Bäumler, Andreas; Fang, Ferric C (2013) Host specificity of bacterial pathogens. Cold Spring Harb Perspect Med 3:a010041 |
| Brown, D E; Libby, S J; Moreland, S M et al. (2013) Salmonella enterica causes more severe inflammatory disease in C57/BL6 Nramp1G169 mice than Sv129S6 mice. Vet Pathol 50:867-76 |
| Frawley, Elaine R; Crouch, Marie-Laure V; Bingham-Ramos, Lacey K et al. (2013) Iron and citrate export by a major facilitator superfamily pump regulates metabolism and stress resistance in Salmonella Typhimurium. Proc Natl Acad Sci U S A 110:12054-9 |
| Deriu, Elisa; Liu, Janet Z; Pezeshki, Milad et al. (2013) Probiotic bacteria reduce salmonella typhimurium intestinal colonization by competing for iron. Cell Host Microbe 14:26-37 |
| Karlinsey, Joyce E; Bang, Iel-Soo; Becker, Lynne A et al. (2012) The NsrR regulon in nitrosative stress resistance of Salmonella enterica serovar Typhimurium. Mol Microbiol 85:1179-93 |
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