# Engineering the innate immune response to Staphaureus infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $378,106

## Abstract

ABSTRACT
Staphylococcus aureus (SA) is a major cause of cutaneous infections. Virulent
community-acquired methicillin-resistant SA (MRSA) is the most common source of skin
and soft tissue infections in U.S. hospitals. Prompt recruitment of polymorphonuclear
(PMN) leukocytes in sufficient numbers to the site of infection is critical for controlling
MRSA infection and preventing dissemination to vital organs. Unexpectedly, we recently
discovered that hematopoietic stem and progenitor cells (HSPCs) are also recruited to
wounds, and these cells detect bacterial antigens and virulence factors, and augment
PMN numbers necessary to resolve a MRSA infected wound. The signaling process
eliciting an increase in myeloid recruitment and differentiation of HSPC within the wound
was found to involve toll-like receptor 2 (TLR2) detection of peptidoglycans derived from
the gram-positive cell wall and released within the wound. We propose that this newly
discovered host immune trait is an adaption to effectively overcome immune
suppression by MRSA virulence factors such as α-hemolysin toxin (AT) that blocks PMN
recruitment by lysing perivascular macrophages that help guide them to sites of
infection. The central hypothesis governing this proposal is that immune-modulation that
tunes PMN number and antibacterial activity against MRSA infection can hasten
clearance and healing. This proposal will utilize our innovative model of wound infection
that employs genetically-engineered bioluminescent bacteria and a transgenic lysozyme-
M-EGFP knock-in mouse that produces fluorescent mature PMN. This model will be
used in conjunction with advanced in vivo whole animal optical imaging to noninvasively
and longitudinally monitor bacterial burden and immune responses. A translational goal
will be the implementation of human CD34+ HSPC myeloid expansion to evaluate the
therapeutic potential of local PMN expansion to combat MRSA infection in an
immunodeficient (NSG) mouse wound model.

## Key facts

- **NIH application ID:** 10212940
- **Project number:** 5R01AI129302-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** J. Kent Leach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,106
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212940

## Citation

> US National Institutes of Health, RePORTER application 10212940, Engineering the innate immune response to Staphaureus infection (5R01AI129302-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212940. Licensed CC0.

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