# The impact of hypoxia on Staphylococcus aureus metabolism and virulence during osteomyelitis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $376,701

## Abstract

PROJECT SUMMARY / ABSTRACT
 Staphylococcus aureus is an important human pathogen, capable of causing life-threatening infections
in a variety of host tissues. Osteomyelitis, an invasive and debilitating infection of bone, is one of the most
common manifestations of staphylococcal disease. Indeed, osteomyelitis accounts for approximately 2-3 of
every 1,000 admissions to pediatric hospitals in the United States, and complicates up to 25% of open
fractures. Bone infections are notoriously refractory to treatment due to widespread antimicrobial resistance
and pathogen-induced bone remodeling, which limits penetration of antibiotics into the infectious focus. S.
aureus is by far the most common cause of musculoskeletal infection, yet the mechanisms by which
staphylococci survive within and ultimately destroy bone are poorly understood. The overarching objective of
this proposal is to understand how S. aureus regulates its virulence and metabolic programs to survive within
bone during osteomyelitis.
 Bone, like most mammalian tissues, is inherently hypoxic. Moreover, maintenance of skeletal health
requires constant bone turnover by resident bone-forming osteoblasts and bone-resorbing osteoclasts. These
skeletal cells, in turn, require a specialized metabolism characterized by high rates of glucose uptake, which is
expected to limit the carbon sources available to invading pathogens. In order to better understand how S.
aureus thrives within this hypoxic and metabolically unique environment, we created a powerful murine model
of osteomyelitis capable of precise quantification of both bacterial burdens and bone turnover. By applying
transposon sequencing (TnSeq) to this osteomyelitis model, we identified >200 staphylococcal genes
important for survival in bone. Importantly, bacterial responses to hypoxia were found to be critical
determinants of survival during osteomyelitis, as hypoxic growth not only dictates the energy production
strategies used by staphylococci, but also augments the production of quorum-dependent virulence factors that
participate in bone destruction. Based on these preliminary data, we hypothesize that S. aureus survival in
bone is facilitated by (a) quorum-regulated virulence factor expression in response to hypoxia, and (b) specific
nutrient utilization programs that enable growth in the unique metabolic environment of bone. The proposed
Aims will test this hypothesis to determine (i) the mechanism by which hypoxic growth triggers increased
staphylococcal virulence, (ii) the metabolic pathways that support bacterial growth in bone, and (iii) the role of
host hypoxic signaling pathways in antibacterial immunity and bone remodeling during osteomyelitis.
Completion of these studies will elucidate microbial survival strategies during invasive infection, determine the
impact of hypoxia on bacterial pathogenesis, and help to meet a critical need for new osteomyelitis
therapeutics by defining putative antimicrobial and anti-virulence ta...

## Key facts

- **NIH application ID:** 9901431
- **Project number:** 5R01AI132560-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** JAMES E CASSAT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,701
- **Award type:** 5
- **Project period:** 2017-05-10 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901431

## Citation

> US National Institutes of Health, RePORTER application 9901431, The impact of hypoxia on Staphylococcus aureus metabolism and virulence during osteomyelitis (5R01AI132560-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901431. Licensed CC0.

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