Kosin Med J.  2024 Mar;39(1):5-17. 10.7180/kmj.24.104.

Clinical challenges and advancements in diagnosing Staphylococcus aureus-associated musculoskeletal infections

• Oh I

• KMID: 2556793
• DOI: http://doi.org/10.7180/kmj.24.104

Abstract

Musculoskeletal infections (MSKI) present a significant health challenge, with a rising incidence linked to the aging population and advancements in orthopedic surgical care. Staphylococcus aureus is the most prevalent pathogen associated with orthopedic infections. The conventional culture method for identification of pathogen frequently lacks accuracy and is challenged by false-positive or false-negative results. Inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein are not site-specific or accurate, as they can be confounded by other medical conditions. Identifying the dominant pathogen and monitoring treatment response following surgical debridement and antibiotics therapy continues to pose challenges. Understanding the pathogenesis of MSKI is crucial for the development of innovative diagnostics and alternative therapeutics. S. aureus immune evasion stands out as a key component of the pathogenic mechanism, complicating clinical decisions. Other unique mechanisms such as biofilm and abscess formation, as well as osteocyte-lacuno canalicular network invasion, underscore the need for aggressive debridement and the complete removal of infected implants and bone tissues. Ongoing efforts focus on exploring and developing innovative diagnostics, such as serum immunoassays, next-generation sequencing of infected tissue, transcriptomics of peripheral blood mononuclear cells, and serum proteomics. These endeavors offer promising avenues for improved diagnostics, medical management, and innovative therapeutics for MSKI.

Keyword

Biomarkers; Musculoskeletal infection; Orthopaedic infection

Figure

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  Fig. 1. Examples of musculoskeletal infections. (A) Diabetic foot infection, (B) implant-associated periprosthetic infection, (C) infected tenosynovitis of the flexor hallucis longus tendon, and (D) septic arthritis of the native ankle joint.

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  Fig. 2. Staphylococcus aureus pathogenesis in musculoskeletal infections. Various pathogenic mechanisms employed by S. aureus. Osteocyte-lacuno canalicular network (OLCN) invasion permits S. aureus to evade immune cells while propagating along the submicron channel. Biofilm formation on implant surfaces or necrotic bone provides biologic shield, aggregation, and growth of the microorganisms with increase antibiotic-resistant gene transfers. The process of abscess formation involves the aggregation of S. aureus to establish a colony and the development of a fibrous pseudocapsule, confining immune cells to the periphery and restricting their access to the center where bacteria replication persists.

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  Fig. 3. Staphylococcus aureus iron-regulated surface determinant (Isd) system. S. aureus utilizes the Isd system to strip iron from the host’s hemoglobin. IsdH, IsdB, and IsdA are anchored to the cell wall. Hemoglobin is captured by IsdH and IsdB through near iron transport (NEAT) domains. IsdB has two NEAT domains: NEAT1 binds to hemoglobin, and NEAT2 binds and transports the heme. The IsdB removes heme from hemoglobin and transports it to IsdA, which subsequently transfers the heme to the intracellular IsdC protein. The heme is degraded within the cell so that iron is released for utilization by S. aureus.

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  Fig. 4. Staphylococcus aureus immune evasion mechanisms. S. aureus secretes toxins—α-hemolysin (Hla), β-hemolysin, γ-hemolysin (HlgAB and HlgCB), leucocidin A/B (LukAB) and Panton-Valentine leukocidin (PVL)—that directly destroy neutrophils, macrophages and other antigen-presenting cells. S. aureus enterotoxin B and C (SEB, SEC) and toxic shock syndrome toxin 1 (TSST1) induce a shift in M2 macrophage polarization and promote formation of myeloid-derived suppressor cells. S. aureus utilizes microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) to facilitate its internal invasion of macrophages and neutrophils (ClfA, ClfB, fibronectin-binding protein A [FnBPA], fibronectin-binding protein B [FnBPB]). S. aureus also interferes with complement-mediated opsonization and phagocytosis through chemotaxis inhibitory protein of S. aureus (CHIPS), Staphylococcal complement inhibitor (SCIN), coagulase (CoA), and extracellular fibrinogen binding protein (Efb). SpA binds certain antibodies, blocking antibody-mediated phagocytosis and concurrently initiating proliferative B cell apoptosis. Staphylokinase (Sak) can directly degrade IgG.

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  Fig. 5. Transmission electron microscopy (TEM) evidence of Staphylococcus aureus invasion of the osteocyte-lacuno canalicular network. TEM investigation of an infected bone sample from a diabetic foot osteomyelitis patient demonstrated Staphylococcus deformation and invasion of the submicron osteocytic-canalicular system. Standard culture of the infected bone sample identified S. aureus. (A) TEM image of a dead osteocyte and its canaliculus colonized by deformed rod-shaped bacteria. (B) Higher-magnification TEM image show submicron-sized deformed and elongated bacteria [24].

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  Fig. 6. Development of novel diagnostics for musculoskeletal infections. Blood samples are obtained from patients with musculoskeletal infections (MSKI) to isolate peripheral blood mononuclear cells for transcriptome analysis. Upregulated ribonucleotide reductase regulatory subunit M2 (RRM2), a transcription factor in the Myb-related protein B (MYBL2), and a neutrophil-specific cell surface glycoprotein (CD177) have been detected, suggesting their potential role as biomarkers for MSKI diagnosis. Additionally, species-specific serum immunoassays are being explored to detect Staphylococcus aureus infection. Concurrently, research is underway on serum proteomics for the identification of protein biomarkers associated with MSKI. Isd, iron-regulated surface determinant; SCIN, Staphylococcal complement inhibitor; PBMC, peripheral blood mononuclear cell.

Reference

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