# Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $678,065

## Abstract

Abstract
Infectious osteomyelitis (OM) is an inflammation-driven disease of bone that culminates in pathological
alterations in skeletal architecture. Bone infections are multifactorial and reflect a complex interaction between
microorganisms and host cells. Staphylococcus (S.) aureus, a pathogen that has developed antibiotic resistance,
is the leading cause of bacterial-induced OM and has been identified as one of the greatest bacterial threats to
global public health. These infections are painful, debilitating and can become chronic or recur years after the
initial event. The pathogen’s ability to damage bone tissue and evade clearance by the immune system, even
with appropriate antibiotics, impose significant obstacles to treatment of OM. The first and most critical level of
host defense against infection by S. aureus is innate immunity, primarily mature myeloid lineage cells such as
neutrophils and macrophages; the success of this pathogen is dependent on its ability to evade and exploit these
responses. While much has been learned about interactions between myeloid cells and S. aureus, relatively little
work has specifically focused on infections of bone. This microenvironment presents unique features, including
relative hypoxia, abundant immature myeloid cells, and the presence of unique bone cells – osteoclasts (OCs),
osteoblasts, and osteocytes - that interact with both the bacteria and innate immune cells. Furthermore, the route
of infection - via injury or direct soft tissue extension, surgical implants, or hematogenously spread – can
significantly alter the interactions between bacteria and bone, especially during early stages of infection. Notably,
OCs differentiate from monocytic precursors, providing an inherent link between immature myeloid lineage cells
and bone homeostasis. The overall goal of this application is to understand the host-pathogen interactions
between the bone’s OC and neutrophil lineage cells and S. aureus during the establishment, progression, and
resolution of OM. Our preliminary studies strongly implicate the interleukin-1 (IL-1) signaling axis as a driver of
both antibacterial immunity and pathologic bone changes during OM. Following infections such as with S. aureus,
IL-1 family members including IL-1β are canonically generated through the activation of multi-protein complexes
known as inflammasomes. However, little is known about the role of inflammasomes in the pathogenesis of OM.
We have found that, compared to their uncommitted precursors, OCs have lower inflammasome activation and
are permissive of intracellular S. aureus proliferation. We hypothesize that differences in inflammasome activity
within myeloid lineage cells present in bone affect the pathogenesis of OM, with S. aureus exploiting those cells
with weaker inflammasome and antimicrobial responses as a proliferative niche while leading host cells with an
excessive inflammatory response to cause tissue damage. Aim 1: Define host and pathogen deter...

## Key facts

- **NIH application ID:** 10899448
- **Project number:** 5R01AI161022-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JAMES E CASSAT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,065
- **Award type:** 5
- **Project period:** 2021-09-24 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899448

## Citation

> US National Institutes of Health, RePORTER application 10899448, Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis (5R01AI161022-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899448. Licensed CC0.

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