# Overcoming nutritional immunity: Staphylococcal adaptation to host-imposed manganese and zinc starvation

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $373,843

## Abstract

Project Summary/Abstract:
 Bacterial infections are of serious concern to human health because of the continued emergence and
spread of antibiotic resistance. Reports by both the Centers for Disease Control and World Health Organization
have stated that the end of the antibiotic era is upon us. They also called for the development of new
therapeutic strategies for treating bacterial pathogens, such as Staphylococcus aureus. A powerful strategy
utilized by the host to combat invading pathogens is the restriction of essential nutrients, such as manganese
(Mn) and zinc (Zn). Despite experiencing Mn and Zn starvation during infection, S. aureus and other successful
pathogens remain capable of causing disease. Elucidating how bacteria adapt to this host defense has the
potential to identify new targets for therapeutic intervention, the disruption of which will enhance the efficacy of
the host immune response. Recent work revealed that a critical component of the nutrient withholding
response is the Mn- and Zn-binding immune effector protein calprotectin (CP). This finding allowed the creation
of novel reagents based on CP that can be used to impose highly specific and biologically relevant metal
starvation in culture. Utilizing these reagents revealed that the bacterial two-component signal transduction
system ArlRS is a critical regulator of the staphylococcal response to host-imposed metal starvation.
Surprisingly, while ArlRS is known to contribute to staphylococcal virulence, the signal that activates the
system and the direct vs. indirect targets of the system are unknown. Further investigations suggest that Mn
and Zn sequestration prevents S. aureus from utilizing sugars, but not amino acids, as an energy source. This
observation suggests that Mn and Zn starvation disrupts glycolysis in S. aureus. Recent work in other species
has shown that glycolysis can be dependent on these metals. They also revealed that the expression of two
putatively Mn-dependent superoxide dismutases, which is unique to S. aureus, promotes resistance to host-
imposed nutrient metal starvation. In total, these results lead to the hypothesis that S. aureus profoundly alters
how it generates energy and expresses alternative enzymes in order to adapt to host-imposed Mn and Zn
starvation. The Aims of this proposal will evaluate this hypothesis and elucidate how S. aureus adapts to Mn
and Zn starvation. Aim I. Elucidate the direct vs. indirect targets of the ArlRS regulatory network and the
environmental signals that modulate activity of the system. Aim II. Determine the impact of Mn and Zn
starvation on staphylococcal central metabolism and carbon source preference. Aim III. Elucidate how metal
availability impacts the contributions of SodA and SodM to staphylococcal disease. To accomplish these aims
an interdisciplinary approach utilizing techniques taken from microbiology and biochemistry, as well as
advanced elemental quantification and whole cell paramagnetic spectroscopy...

## Key facts

- **NIH application ID:** 9927982
- **Project number:** 5R01AI118880-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Thomas Everett Kehl-Fie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,843
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927982

## Citation

> US National Institutes of Health, RePORTER application 9927982, Overcoming nutritional immunity: Staphylococcal adaptation to host-imposed manganese and zinc starvation (5R01AI118880-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927982. Licensed CC0.

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