Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

In , the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in and other bacterial pathogens is still lacking. In the host, the essential tran...

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Published in:Infection and immunity Vol. 85; no. 7
Main Authors: Colomer-Winter, C, Gaca, A O, Lemos, J A
Format: Journal Article
Language:English
Published: United States American Society for Microbiology 01-07-2017
Subjects:
Enterococcus faecalis - growth & development
Enterococcus faecalis - metabolism
Gene Expression Regulation, Bacterial
Guanosine Pentaphosphate - metabolism
Homeostasis
Iron - metabolism
Manganese - metabolism
Microbial Viability
Molecular Pathogenesis
Virulence
Enterococcus
metal homeostasis
(p)ppGpp
nutritional immunity
manganese
oxidative stress
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Summary:In , the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in and other bacterial pathogens is still lacking. In the host, the essential transition metals iron (Fe) and manganese (Mn) are not readily available to invading pathogens because of a host-driven process called nutritional immunity. Considering its central role in adaptation to nutritional stresses, we hypothesized that (p)ppGpp mediates virulence through regulation of metal homeostasis. Indeed, supplementation of serum with either Fe or Mn restored growth and survival of the Δ Δ [(p)ppGpp ] strain to wild-type levels. Using a chemically defined medium, we found that (p)ppGpp accumulates in response to either Fe depletion or Mn depletion and that the (p)ppGpp strain has a strong growth requirement for Mn that is alleviated by Fe supplementation. Although inactivation of the nutrient-sensing regulator restored some phenotypes of the (p)ppGpp strain, transcriptional analysis showed that the (p)ppGpp/CodY network does not promote transcription of known metal transporters. Interestingly, physiologic and enzymatic investigations suggest that the (p)ppGpp strain requires higher levels of Mn in order to cope with high levels of endogenously produced reactive oxygen species (ROS). Because (p)ppGpp mediates antibiotic persistence and virulence in several bacteria, our findings have broad implications and provide new leads for the development of novel therapeutic and preventive strategies against and beyond.
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Citation Colomer-Winter C, Gaca AO, Lemos JA. 2017. Association of metal homeostasis and (p)ppGpp regulation in the pathophysiology of Enterococcus faecalis. Infect Immun 85:e00260-17. https://doi.org/10.1128/IAI.00260-17.
Present address: A. O. Gaca, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
ISSN:0019-9567
1098-5522
DOI:10.1128/iai.00260-17