Intracellular survival of Staphylococcus aureus in macrophages during osteomyelitis

ABSTRACT Staphylococcus aureus, traditionally viewed as an extracellular pathogen, is increasingly recognized for its ability to persist intracellularly, particularly within macrophages. This intracellular lifestyle is central to osteomyelitis, a chronic bone infection characterized by persistent inflammation, bone destruction, and impaired repair. Within bone, S. aureus exploits macrophage plasticity by driving a shift from pro-inflammatory, bactericidal M1-like states to anti-inflammatory, tissue-reparative M2-like phenotypes. This polarization suppresses immune clearance and promotes an environment conducive to bacterial survival and dissemination. Additional strategies – including biofilm formation, small colony variants, and inhibition of phagolysosomal killing – further enhance persistence and immune evasion. While these mechanisms are well studied in extracellular infections, their role in intracellular survival is increasingly evident. This review synthesizes emerging insights into how S. aureus manipulates macrophage function to establish chronic bone infection and highlights therapeutic opportunities targeting macrophage polarization to improve immune-mediated clearance and bone repair in osteomyelitis. GRAPHICAL ABSTRACT

• Publication year

  2025

• Venue

  Virulence

• Publication date

  2025-09-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1080/21505594.2025.2553789PMID 40888369PMCID 12408055
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis

  2022cited by this paper
• Intracellular Habitation of Staphylococcus aureus: Molecular Mechanisms and Prospects for Antimicrobial Therapy

  2022cited by this paper
• Osteomyelitis: Diagnosis and Treatment.

  2021cited by this paper
• The Role of Macrophages in Staphylococcus aureus Infection

  2021influential reference
• Selective Host Cell Death by Staphylococcus aureus: A Strategy for Bacterial Persistence

  2021cited by this paper
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  2021cited by this paper
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  2020cited by this paper
• Emerging Evasion Mechanisms of Macrophage Defenses by Pathogenic Bacteria

  2020cited by this paper
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  2020cited by this paper
• Tissue-Resident Macrophages in the Control of Infection and Resolution of Inflammation.

  2020cited by this paper
• The Process of Osteoblastic Infection by Staphylococcus Aureus

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• Inhibition of pyroptosis attenuates Staphylococcus aureus-induced bone injury in traumatic osteomyelitis.

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• Infection of Primary Human Alveolar Macrophages Alters Staphylococcus aureus Toxin Production and Activity

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• Staphylococcal Osteomyelitis: Disease Progression, Treatment Challenges, and Future Directions

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• Prosthetic Joint Infections

  2018cited by this paper
• Microbiology of Acute and Chronic Osteomyelitis and Antibiotic Treatment.

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• The Role of Antibiotics in Modulating Virulence in Staphylococcus aureus

  2017cited by this paper
• Macrophage Migration Inhibitory Factor (MIF): A Glucocorticoid Counter-Regulator within the Immune System.

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• Apoptosis induced by Staphylococcus aureus toxins.

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• Antimicrobial Activity against Intraosteoblastic Staphylococcus aureus

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• Cytoplasmic replication of Staphylococcus aureus upon phagosomal escape triggered by phenol‐soluble modulin α

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• Staphylococcus aureus: determinants of human carriage.

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• Staphylococcus aureus persistence in non-professional phagocytes.

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• Staphylococcus epidermidis agr Quorum-Sensing System: Signal Identification, Cross Talk, and Importance in Colonization

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• Macrophage activation and polarization: nomenclature and experimental guidelines.

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• Macrophage plasticity and polarization: in vivo veritas.

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• Immunity against Staphylococcus aureus cutaneous infections

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• Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection

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• Monocyte recruitment during infection and inflammation

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• Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence.

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