# Pathobiology of heme inducible transporters in Gram positive pathogens

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $511,950

## Abstract

SUMMARY
Staphylococcus aureus and Bacillus anthracis are pathogenic members of the order Bacillales that each
represent a considerable threat to global public health. The rise of S. aureus strains resistant to all known
antimicrobials has the potential to eliminate available treatment options whereas the successful use of B.
anthracis as an agent of bioterror threatens national security. Identifying novel therapeutic targets against
these organisms is critical to our continued ability to protect against these infections. Promising antimicrobial
targets include bacterial stress sensing and detoxification systems as both processes are required for infection.
Alterations in gene expression in response to stress can be orchestrated by signal transduction proteins known
as two-component regulatory systems (TCSs). Bacteria typically encode many TCSs that are responsible for
recognizing and responding to distinct signals, enabling adaptation to diverse environments. We have
identified and functionally characterized two TCSs named EdsRS and HitRS that trigger the response to cell
envelope damage as a strategy to defend against phagocyte-dependent killing. EdsRS is conserved in both S.
aureus and B. anthracis whereas HitRS is only present in B. anthracis, suggesting that HitRS may have
evolved to enable the intracellular lifecycle of this organism. In this proposal, we describe the discovery of
additional regulatory factors that govern signal transduction through EdsRS and HitRS, including known
enzymes as well as previously unstudied factors involved in RNA expression and stability. The combined
activities of these regulatory factors enable transcriptional, post-transcriptional, and post-translational control of
TCS signaling. Based on these discoveries, we propose a model whereby HitRS and EdsRS signal
transduction is controlled by accessory proteins that enable a coordinated and tightly controlled response to
host-mediated barrier damage. We propose that tight regulation of EdsRS and HitRS is required for survival
within macrophages and subsequent pathogenesis. This model uncovers new regulatory proteins that control
TCS signal transduction, expanding the small but rapidly growing catalogue of known TCS accessory proteins.
We will test this model through a series of interconnected specific aims that define the mechanism of control of
HitRS and EdsRS signal transduction, elucidate the cascade of events leading to HitRS and EdsRS activation
during infection, and uncover host factors that target the cell envelope of Gram positive bacteria and trigger
HitRS and EdsRS signaling. Due to the fundamental requirement for TCS in bacterial stress sensing, these
studies will be universally relevant to the field of microbial signal transduction.

## Key facts

- **NIH application ID:** 10407650
- **Project number:** 5R01AI073843-13
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Eric P Skaar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $511,950
- **Award type:** 5
- **Project period:** 2008-12-05 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407650

## Citation

> US National Institutes of Health, RePORTER application 10407650, Pathobiology of heme inducible transporters in Gram positive pathogens (5R01AI073843-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10407650. Licensed CC0.

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