This proposal investigates the responses of the model Gram positive bacterium Bacillus subtilis to metal ion starvation. When cells are starved for essential metals, such as iron or zinc, they express complex adaptive responses. These responses include the elaboration of high affinity uptake systems to obtain metals from the environment. Perhaps even more important, cells reprogram their metabolism to block the synthesis of unneeded proteins and enzymes that will consume the limiting nutrient. In the case of iron, this """"""""iron-sparing response"""""""" leads to large scale changes in the protein composition and metabolic potential of the cell and has wide-ranging ramifications for cell physiology. Iron-sparing responses have evolved multiple times in various organisms and are mediated by a variety of RNA- and protein-based regulators. In B. subtilis, the iron-sparing response requires a regulatory, small RNA that functions in collaboration with three genes encoding small, basic peptides. These small proteins are postulated to function, at least in part, as RNA chaperones. Preliminary results suggest that the response to zinc starvation is also complex and multifaceted. Repression of the synthesis of non-essential zinc metalloproteins provides a """"""""zinc-sparing response"""""""" and the expression of a set of alternative ribosomal proteins displaces small, Zn-containing peptides from the ribosome to provide zinc for the cell. In addition to the expression of high affinity metal ion uptake (acquisition) and the repression of non-essential metalloproteins (sparing), cells also express alternative isozymes for some essential functions that might otherwise be compromised (substitution). This proposal will focus on the characterization of these and related adaptive responses that enable cells to compete effectively even in severely metal-limited environments.

Public Health Relevance

Project Narrative Metal ions are essential for life and function as cofactors for numerous enzymatic and electron transfer processes. This proposal seeks to understand how the model Gram positive bacterium Bacillus subtilis adapts to limitation for iron and zinc. These studies will provide significant insights into the adaptive processes which enable Gram positive pathogens (e.g. Staphylococcus aureus, streptococci, and enterococci) to survive in the metal-limited environments encountered in the host.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059323-12
Application #
8245128
Study Section
Special Emphasis Panel (ZRG1-IDM-Q (03))
Program Officer
Chin, Jean
Project Start
2000-02-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$298,793
Indirect Cost
$97,872
Name
Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Chandrangsu, Pete; Loi, Vu Van; Antelmann, Haike et al. (2018) The Role of Bacillithiol in Gram-Positive Firmicutes. Antioxid Redox Signal 28:445-462
VanderWal, Arica R; Makthal, Nishanth; Pinochet-Barros, Azul et al. (2017) Iron Efflux by PmtA Is Critical for Oxidative Stress Resistance and Contributes Significantly to Group A Streptococcus Virulence. Infect Immun 85:
Huang, Xiaojuan; Shin, Jung-Ho; Pinochet-Barros, Azul et al. (2017) Bacillus subtilis MntR coordinates the transcriptional regulation of manganese uptake and efflux systems. Mol Microbiol 103:253-268
Chandrangsu, Pete; Rensing, Christopher; Helmann, John D (2017) Metal homeostasis and resistance in bacteria. Nat Rev Microbiol 15:338-350
Pi, Hualiang; Helmann, John D (2017) Ferrous iron efflux systems in bacteria. Metallomics 9:840-851
Makthal, Nishanth; Nguyen, Kimberly; Do, Hackwon et al. (2017) A Critical Role of Zinc Importer AdcABC in Group A Streptococcus-Host Interactions During Infection and Its Implications for Vaccine Development. EBioMedicine 21:131-141
Shin, Jung-Ho; Helmann, John D (2016) Molecular logic of the Zur-regulated zinc deprivation response in Bacillus subtilis. Nat Commun 7:12612
Pi, Hualiang; Patel, Sarju J; Argüello, José M et al. (2016) The Listeria monocytogenes Fur-regulated virulence protein FrvA is an Fe(II) efflux P1B4 -type ATPase. Mol Microbiol 100:1066-79
Chandrangsu, Pete; Helmann, John D (2016) Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in Bacillus subtilis. PLoS Genet 12:e1006515
Price, Ian R; Gaballa, Ahmed; Ding, Fang et al. (2015) Mn(2+)-sensing mechanisms of yybP-ykoY orphan riboswitches. Mol Cell 57:1110-1123

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