Journal article
Disruption of Glycolysis by Nutritional Immunity Activates a Two-Component System That Coordinates a Metabolic and Antihost Response by Staphylococcus aureus
mBio, Vol.10(4), e01321-19
08/06/2019
DOI: 10.1128/mBio.01321-19
PMCID: PMC6686040
PMID: 31387906
Abstract
During infection, bacteria use two-component signal transduction systems to sense and adapt to the dynamic host environment. Despite critically contributing to infection, the activating signals of most of these regulators remain unknown. This also applies to the
ArlRS two-component system, which contributes to virulence by coordinating the production of toxins, adhesins, and a metabolic response that enables the bacterium to overcome host-imposed manganese starvation. Restricting the availability of essential transition metals, a strategy known as nutritional immunity, constitutes a critical defense against infection. In this work, expression analysis revealed that manganese starvation imposed by the immune effector calprotectin or by the absence of glycolytic substrates activates ArlRS. Manganese starvation imposed by calprotectin also activated the ArlRS system even when glycolytic substrates were present. A combination of metabolomics, mutational analysis, and metabolic feeding experiments revealed that ArlRS is activated by alterations in metabolic flux occurring in the latter half of the glycolytic pathway. Moreover, calprotectin was found to induce expression of staphylococcal leukocidins in an ArlRS-dependent manner. These studies indicated that ArlRS is a metabolic sensor that allows
to integrate multiple environmental stresses that alter glycolytic flux to coordinate an antihost response and to adapt to manganese starvation. They also established that the latter half of glycolysis represents a checkpoint to monitor metabolic state in
Altogether, these findings contribute to understanding how invading pathogens, such as
, adapt to the host during infection and suggest the existence of similar mechanisms in other bacterial species.
Two-component regulatory systems enable bacteria to adapt to changes in their environment during infection by altering gene expression and coordinating antihost responses. Despite the critical role of two-component systems in bacterial survival and pathogenesis, the activating signals for most of these regulators remain unidentified. This is exemplified by ArlRS, a
global regulator that contributes to virulence and to resisting host-mediated restriction of essential nutrients, such as manganese. In this report, we demonstrate that manganese starvation and the absence of glycolytic substrates activate ArlRS. Further investigations revealed that ArlRS is activated when the latter half of glycolysis is disrupted, suggesting that
monitors flux through the second half of this pathway. Host-imposed manganese starvation also induced the expression of pore-forming toxins in an ArlRS-dependent manner. Cumulatively, this work reveals that ArlRS acts as a sensor that links nutritional status, cellular metabolism, and virulence regulation.
Details
- Title: Subtitle
- Disruption of Glycolysis by Nutritional Immunity Activates a Two-Component System That Coordinates a Metabolic and Antihost Response by Staphylococcus aureus
- Creators
- Paola K Párraga Solórzano - Departmento de Ciencias de la Vida, Universidad de las Fuerzas Armadas ESPE, Sangolquí, EcuadorJiangwei Yao - St. Jude Children's Research HospitalCharles O Rock - St. Jude Children's Research HospitalThomas E Kehl-Fie - University of Illinois Urbana-Champaign
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.10(4), e01321-19
- DOI
- 10.1128/mBio.01321-19
- PMID
- 31387906
- PMCID
- PMC6686040
- ISSN
- 2161-2129
- eISSN
- 2150-7511
- Grant note
- R37 GM034496 / NIGMS NIH HHS K22 AI104805 / NIAID NIH HHS R01 GM034496 / NIGMS NIH HHS R01 AI118880 / NIAID NIH HHS
- Language
- English
- Date published
- 08/06/2019
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984618646902771
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