# The Role and Regulation of Extracellular Proteases in Staphylococcus aureus

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $429,644

## Abstract

Abstract
A number of studies performed by ourselves and others have investigated the contribution of S.
aureus extracellular proteases to disease causation. Until recently, these data proved inconclusive,
however work by our group has definitively shown that secreted protease are key mediators of
S. aureus disease. Their role appears to be biphasic as: i) Secreted protease deletion leads
hypervirulence in infected animals; whilst ii) A complete protease-null strain has impaired survival
in human blood, decreased resistance to phagocytosis, increased sensitivity to AMPs and impaired
ability for dissemination and/or survival during infection. An explanation for these findings stems
from their differing roles, and substrates, during infection. Specifically, the enhanced mortality is
driven by an increased abundance of virulence factors, which exist unchecked upon secreted
protease deletion. Conversely, the virulence attenuation is mediated by these enzymes
attacking the host, cleaving proteins that facilitate nutrition, immune evasion, and dissemination.
However, despite this, much remains unknown about how these enzymes are regulated, how
they themselves regulate infection, and how they enhance the fitness of S. aureus in vivo. To fill in
these gaps we will explore: 1. Regulation by Secreted Proteases During S. aureus Infection.
We currently do not know which proteases cleave which virulence factors, or how this influences
the progression of infection. As such, in this aim we will connect in vitro virulence factor proteolysis
to the pathogenic potential of S. aureus in vivo. 2. The Regulation of Secreted Proteases During
S. aureus Infection. Although secreted proteases are produced alongside virulence factors, their
synthesis must be (and indeed is) tightly controlled, so as to tailor virulence factor abundance
during disease causation. Accordingly, in this aim we will fill in major knowledge gaps regarding
secreted protease regulation in vitro, and connect this to what happens in vivo. 3. The Role of
Secreted Proteases During S. aureus Infection. The next frontier of protease biology in the
context of pathogenic bacteria is an understanding of the host degradome (the complete set of
host proteins cleaved by bacterial proteases). Therefore, in this aim we will use cutting edge
proteomic techniques to gain insight into the infectious process, and interaction of host with
pathogen. Through these studies we will define specific pathways that directly govern S. aureus
disease, providing a unique and detailed insight into the molecular events that occur during
infection. This will produce key findings regarding S. aureus pathogenesis that has potential to be
used for the future generation of novel anti-virulence based therapeutics.

## Key facts

- **NIH application ID:** 9978697
- **Project number:** 5R01AI124458-04
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Lindsey Neil Shaw
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,644
- **Award type:** 5
- **Project period:** 2017-08-08 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978697

## Citation

> US National Institutes of Health, RePORTER application 9978697, The Role and Regulation of Extracellular Proteases in Staphylococcus aureus (5R01AI124458-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978697. Licensed CC0.

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