Characterization of the two-component regulatory system ArlRS in Staphylococcus aureus

Parraga Solorzano, Paola K.

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https://hdl.handle.net/2142/115703 Copy

Description

Title

Characterization of the two-component regulatory system ArlRS in Staphylococcus aureus

Author(s)

Parraga Solorzano, Paola K.

Issue Date

2022-04-15

Director of Research (if dissertation) or Advisor (if thesis)

Kehl-Fie, Thomas E

Doctoral Committee Chair(s)

Kehl-Fie, Thomas E

Committee Member(s)

• Wilson, Brenda A
• Blanke, Steven R
• Metcalf, William W

Department of Study

Microbiology

Discipline

Microbiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Staphylococcus aureus, ArlRS, calprotectin, nutritional immunity, manganese, metabolism

Abstract

During infection, bacterial pathogens utilize two-component transduction systems to sense and respond to the environmental changes that they encounter in the human host. Despite the critical role of two-component systems in bacterial adaptation and virulence factor regulation, multiple aspects of their physiology remain unknown. This applies to ArlRS, a Staphylococcus aureus two-component system that coordinates virulence determinant expression and a metabolic response that enables this pathogen to overcome host-imposed manganese starvation. The restriction of essential nutrients, a response referred to as nutritional immunity, is a critical host defense during infection. In this thesis, expression analysis revealed that calprotectin-induced manganese limitation and the absence of glycolytic substrates activate ArRS. Calprotectin-imposed manganese limitation also actives ArlRS even in the presence of glycolytic carbon sources. A combination of metabolomics, mutational and feeding approaches revealed that alterations in metabolic flux occurring in the latter half of glycolysis activate ArlRS. ArlRS also induces the expression of staphylococcal leukocidins in response to calprotectin. Altogether, these findings indicate that ArlRS is a metabolic sensor that allows S. aureus to coordinate an anti-host response to environmental challenges that alter glycolytic flux. They also establish that the latter half of the glycolic pathway is a checkpoint that informs about the metabolic state. Two-component systems are canonically composed of a sensor histidine kinase and a response regulator that work as a pair. Therefore, it was assumed that ArlS activates ArlR in response to host-imposed manganese starvation and glucose limitation. However, it has been suggested that the sensor histidine kinase GraS can also activate ArlR, calling into question the assumption that ArlS contributes to the response of S. aureus to manganese and glucose limitation. Although the loss of ArlS does not eliminate the activity of ArlR, this response regulator no longer responds to manganese and glucose availability in the absence of its cognate kinase. Moreover, phosphorylation of ArlR by ArlS is required for S. aureus to respond to calprotectin-imposed metal starvation. Cumulatively these studies indicate that ArlS is necessary to activate ArlR in response to calprotectin-imposed manganese starvation and glucose limitation. In total, the work contained within this thesis contributes to a better understanding of ArlRS and how invading pathogens, such as S. aureus, adapt to the host during infection.

Graduation Semester

2022-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Paola Parraga Solorzano

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