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Frontiers in Bacteriology ·

Volume 5 - 2026 | https://doi.org/10.3389/fbrio.2026.1757036

Offense-defense in bone infection: interferon regulation and the immune evasion of Staphylococcus aureus

  • Jinrong Qian1
  • Weiwei Qian2
  • Xiaoyu Tang1
  • Yin Yang3*corresponding author
  1. 1Emergency Department, The First Orthopedic Hospital of Chengdu, Chengdu, China
  2. 2Emergency Department, West China Hospital, Sichuan University, Chengdu, China
  3. 3The First Orthopedic Hospital of Chengdu, Orthopedics Department of Xi’an Central Hospital, Xi’an, China
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Abstract

Bone infection is a severe disease caused by microbial invasion of bone tissue, characterized by inflammatory responses, bone destruction, and impaired repair. Its high recurrence rate and refractory nature have posed significant challenges in clinical treatments. Pathogens such as Staphylococcus aureus (S. aureus) establish a highly immune-evasive microenvironment by intracellular latency, biofilm formation, and secretion of multiple virulence factors, which interfere with complement activation, phagocytic clearance, and T-cell responses. Host immune responses in bone infections exhibit multidimensional, multi-cell synergistic characteristics. During this process, interferons (IFNs), particularly type I (IFN-I) and type II (IFN-γ), play a central regulatory role through signaling pathways. They not only directly activate the bactericidal functions of innate immune cells such as macrophages and neutrophils but also precisely coordinate antigen presentation by dendritic cells, cytotoxic activity of NK cells, adaptive immunity of T cells, and antibody responses of B cells, collectively constructing an anti-infective defense network. In the early stages, timely activation of these factors is crucial for controlling infection. However, their sustained or excessive expression during chronic phases may lead to immune dysregulation, excessive inflammation, and exacerbated osteoclast-mediated bone destruction. This review focuses on the primary pathogen spectrum and immunological characteristics of bone infections, emphasizing the hierarchical regulatory roles of IFN-I and IFN-γ in neutrophils, macrophages, dendritic cells, NK cells, and T/B cells. Key escape strategies employed by S. aureus against the interferon network are summarized, providing theoretical foundations and potential approaches for immune intervention and targeted therapies in chronic, refractory bone infections.

Keywords

1 Introduction

Bone infection, also known as osteomyelitis, refers to a severe infectious disease caused by microbial invasion of bone tissue. It can affect bone marrow, cortical bone, and periosteum, thereby leading to local inflammatory responses, bone tissue destruction, and impaired bone remodeling (Sax and Lew, 1999; Masters et al., 2019). With relatively high incidence and mortality rates, it has been one of the most significant complications and risks in orthopedic surgery (Li et al., 2013). Epidemiological studies indicate that approximately 22 cases of osteomyelitis occur per 100,000 person-years in the United States, with an increasing incidence trend, particularly among the elderly and diabetic patients (Kremers et al., 2015). Pathways for bone infection primarily include direct spread from adjacent infection sites, exogenous contamination via surgery or trauma, and hematogenous dissemination from bacteremia (Mader et al., 1999; Trampuz and Zimmerli, 2006; Peltola et al., 2010; Dancer et al., 2012). The pathological process is frequently characterized by bone necrosis, sequestrum formation, involucrum, and chronic inflammatory response (Birt et al., 2017).

The development of bone infections results from the interactions between pathogens and the host immune system (Hofstee et al., 2020; Maimaiti et al., 2023). Bone marrow functions both as a hematopoietic organ and an immune organ. Within the bone marrow microenvironment, hematopoietic stem cells differentiate into erythrocytes, granulocytes, platelets, and various immune cells, including monocytes, dendritic cells, T cells, B cells, and natural killer (NK) cells (Gallagher, 2008; Costa et al., 2018). The host immune system exhibits multidimensional characteristics in the response to bone infection: neutrophils serve as the first line of defense, rapidly eliminating pathogens through phagocytosis and NET formation (Sollberger et al., 2018); macrophages polarize toward a pro-inflammatory M1 phenotype via signals like IFN-γ to enhance bactericidal activity (Wang et al., 2018); dendritic cells bridge innate and adaptive immunity through antigen presentation (Palucka and Bancherea, 1999); NK cells release effector molecules driven by interferon (IFN) signaling (Madera et al., 2016; Chen et al., 2024); while T and B lymphocytes establish long-term defense through cellular and humoral immunity, respectively (Chi et al., 2024). Within this network, IFNs—particularly type I (IFN-I) and type II (IFN-γ)—play a central regulatory role. IFN-I signal through IFNAR, whereas IFN-γ signals through IFNGR, both triggering the JAK–STAT signaling cascade and driving the transcription of interferon-stimulated genes (ISGs) via STAT1/STAT2 and their associated transcriptional complexes (Gao et al., 2007; Li et al., 2024). Through this pathway, interferon signaling enhances antimicrobial effector functions and modulates inflammatory intensity in phagocytes, promotes dendritic cell maturation and the upregulation of MHC molecules and costimulatory factors to improve antigen-presenting capacity, and reinforces Th1 polarization and cytotoxic activity at the T-cell and NK-cell level, thereby establishing a coordinated immune defense that links innate and adaptive immunity (Mcnab et al., 2015). In the context of bone infection, interferon signaling is not merely an epiphenomenon but exerts a causal influence on disease outcome: genetic ablation or pharmacological blockade of this pathway alters bacterial burden, inflammatory cell recruitment, and the extent of bone destruction (Martin et al., 2009; Klopfenstein et al., 2021), whereas exogenous interferon supplementation can reshape immune responses and infection trajectories. Notably, interferon signaling exhibits a stage- and magnitude-dependent “double-edged sword” effect: appropriately regulated signaling during the early phase of infection facilitates pathogen control (Mcnab et al., 2015), whereas sustained or dysregulated interferon activity suppresses protective inflammation, promotes the accumulation of immunosuppressive cell populations, and exacerbates bone damage by enhancing osteoclast activation (Kim et al., 2003; Place et al., 2021). This dual protective and pathological role of interferons has been substantiated by experimental evidence.

However, pathogens, such as S. aureus, have evolved sophisticated immune evasion mechanisms. They disrupt host immune recognition and response by secreting virulence factors including protein A, pore-forming toxins, and superantigens (Ahmad-Mansour et al., 2021; Cheung et al., 2021); form biofilms to resist antibiotics and immune clearance (Ricciardi et al., 2018); and induce T-cell exhaustion by modulating immune checkpoint molecules such as MHC-II and PD-L1 (Mellergaard et al., 2023). Staphylococcus aureus can actively disrupt IFN axis through complementary mechanisms. On the one hand, it modulates the release and host recognition of its pathogen-associated molecular patterns (PAMPs), thereby altering the induction of interferon responses (Parker and Prince, 2012; Askarian et al., 2018). On the other hand, S. aureus exploits virulence factors to induce negative regulatory mediators, including suppressor of cytokine signaling (SOCS) proteins and the anti-inflammatory cytokine interleukin-10 (IL-10), which collectively dampen JAK–STAT signaling and impair downstream immune cell functions (Li et al., 2017). This coordinated, multi-level disruption of the IFN-mediated defense system ultimately undermines effective host immune responses. These strategies subvert IFN-coordinated immune defenses, ultimately leading to chronic and refractory infections. Although antibiotic therapy and surgical debridement significantly improve patient outcomes, persistent pathogen immune evasion and host immune imbalance make bone infections prone to recurrence and difficult to cure completely, especially in complex cases such as implant-associated infections and diabetic foot-related osteomyelitis (Seebach and Kubatzky, 2019; Fan et al., 2023). Therefore, it is of great significance to elucidate the IFN-mediated immune regulatory network in bone infections and the mechanisms by which pathogens subvert for developing novel immunomodulatory strategies and therapeutic approaches.

2 Pathogens and immune evasion of bone infections

The occurrence and progression of bone infections is a complex dynamic process driven by pathogen invasion, adhesion, colonization, and dissemination, coupled with an imbalance in host immune defenses. There are diverse pathogenic strategies for different pathogens in infection, including biofilm formation, secretion of multiple virulence factors, and modulation of host immune signaling pathways, thereby promoting their persistent survival and immune evasion within bone tissue. As infection progresses, the evolving interactions between pathogens and the host lead to prolonged local inflammation, exacerbated tissue destruction, and ultimately drive the transition from acute inflammation to chronic, refractory bone infections.

2.1 S. aureus in bone infections

The distribution of pathogens and pathogenesis in bone infections exhibit considerable diversity (Table 1). S. aureus has been verified to be the most prevalent pathogen, accounting for approximately 75% of osteomyelitis cases (Arciola et al., 2005; Masters et al., 2019; Alder et al., 2020; Urish and Cassat, 2020). Methicillin-resistant Staphylococcus aureus (MRSA) has been reported in over 50% of cases, especially in implant-associated or chronic infections (Kaplan, 2014; Dudareva et al., 2019). Staphylococcus aureus establishes persistent infection within bone tissue through multiple coordinated mechanisms, including intracellular persistence, invasion of bone microstructures, biofilm formation, and abscess development. The bacterium exploits surface adhesins, such as fibronectin-binding proteins, to invade host cells including osteoblasts via integrin-mediated uptake (Hoffmann et al., 2011; Josse et al., 2017; Speziale and Pietrocola, 2020). It achieves intracellular latency through low metabolic states by inhibiting lysosomal fusion and autophagy (Neumann et al., 2016; Wang et al., 2019; Tuchscherr et al., 2020). During this process, phenotypic switching frequently occurs, giving rise to small-colony variants (SCVs). SCVs are characterized by slow growth, reduced metabolic activity, and defects in the respiratory chain, which collectively confer pronounced tolerance to multiple classes of antimicrobial agents—including β-lactams and aminoglycosides—as well as to host antimicrobial mechanisms that depend on bacterial metabolic activity. This phenotype markedly enhances intracellular persistence and promotes the chronicity of infection (Proctor et al., 1995; Tuchscherr et al., 2010). Experimental and clinical studies further demonstrate that SCVs preferentially survive within osteoblasts and phagocytic cells and can revert to a highly virulent phenotype once antimicrobial pressure is relieved, thereby contributing to recurrent and refractory osteomyelitis (Valour et al., 2015; Tuchscherr et al., 2016). Furthermore, S. aureus can invade the osteocytic lacunar–canalicular network (OLCN) to disseminate, evade immune clearance, and form cryptic colonies within the bone matrix, damaging bone cell and disrupting tissue structure (Muthukrishnan et al., 2019; Rong et al., 2025). It also forms highly resistant biofilms on the bone surfaces (Sweeney et al., 2019; Gimza and Cassat, 2021). The abscesses it induces, as well as hypoxic and high-lactic acid environments, also favor long-term bacterial survival (Parimon et al., 2013; Zorzoli et al., 2016).

Table 1. Major pathogens involved in bone and joint infections, their pathogenic characteristics, typical infection settings, and affected populations.

PathogenPathogenic characteristicsTypical infection settingsAffected populationsReferences
Staphylococcus aureusStrong adhesion; biofilm formation; immune evasion; antimicrobial resistance; intracellular persistence.Hematogenous osteomyelitis; open fractures; postoperative infectionsChildren, elderly, immunocompromised(Proctor et al., 1995; Tuchscherr et al., 2010; Parimon et al., 2013; Valour et al., 2015; Tuchscherr et al., 2016; Zorzoli et al., 2016; Muthukrishnan et al., 2019; Sweeney et al., 2019; Gimza and Cassat, 2021; Rong et al., 2025; Song et al., 2025)
Staphylococcus epidermidisBiofilm formation; multidrug resistanceImplant-associated or prosthetic joint infectionsIndividuals with orthopedic implants(Sabaté Brescó et al., 2017; Martínez-García et al., 2018; Maucotel et al., 2025)
Streptococcus pyogenesHigh invasiveness; toxin productionHematogenous spread; post-soft-tissue infection; trauma-related infectionChildren and adolescents(Le Saux, 2018; Yi et al., 2019; Nori et al., 2020)
Streptococcus pneumoniaeAnti-phagocytic capsule; IgA proteaseSecondary hematogenous spread after respiratory infectionYoung children, elderly, splenectomized patients(Olarte et al., 2017; Weiser et al., 2018)
Pseudomonas aeruginosaBiofilm formation; multidrug resistance; toxin secretionBiofilm formation; multidrug resistance; toxin secretionDiabetic and trauma patients(Laghmouche et al., 2017; Cerioli et al., 2020; Garousi et al., 2023)
Enterobacteriaceae (E. coli, Klebsiella)Capsule; β-lactamase productionUTI-related hematogenous osteomyelitisElderly; immunosuppressed individuals(Kucisec-Tepes, 1996; Garazzino et al., 2005; Lavery et al., 2009)
Acinetobacter baumanniiMultidrug resistance (XDR/PDR) biofilm formationICU infections; severe traumaCritically ill patients(Wang et al., 2025)
Anaerobes (e.g., Bacteroides, fusobacteria and anaerobic cocci)Thrive in ischemic/necrotic tissue; polymicrobial infectionsDiabetic foot ulcers; pressure ulcers; necrotic woundsDiabetic or bedridden individuals(Lewis et al., 1978; Nakata and Lewis, 1984; Brook, 2008)
Mycobacterium tuberculosisGranulomatous inflammation; chronic infectionSpinal tuberculosisImmunocompromised; young adults(Pigrau-Serrallach and Rodríguez-Pardo, 2013; Leonard Michael and Blumberg Henry, 2017)
Salmonella spp.Intracellular survivalHematogenous osteomyelitisSickle cell disease patients(Ikejiri et al., 2020; Ochocinski et al., 2020; Williams and Towle, 2021)
Pasteurella multocidaHigh invasiveness; animal-origin pathogenCat/dog bite–related injuriesAnimal handlers; pet owners(Kloos et al., 2015; Mohan et al., 2023; Wei et al., 2025)
Fungi (e.g., Aspergillus, Candida, dimorphic fungi)Chronic infection; biofilm formationHematogenous spread; postoperative infectionImmunosuppressed; transplant recipients(Rammaert et al., 2014; Ganesh et al., 2015)

In addition to S. aureus, Gram-negative bacteria (including Streptococcus spp., Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii) are common pathogens, particularly in implant-associated infections and following open fractures (Lew and Waldvogel, 2004; Depypere et al., 2022). Propionibacterium acnes are usually observed in upper limb osteomyelitis and some joint replacement-associated infections (Boisrenoult, 2018; Passerini et al., 2023). Staphylococcus epidermidis, as a skin commensal, is an important opportunistic pathogen in implant-associated infections (accounting for approximately 25% of cases) and forms biofilms which contribute to chronic, difficult-to-treat infections (Sabaté Brescó et al., 2017). Specific host susceptibilities exist toward certain pathogens, salmonella osteomyelitis is not restricted to specific high-risk populations and can also occur in immunocompetent adults, however, its incidence is markedly increased among patients with hemoglobinopathies (Anand and Glatt, 1994), the higher incidence in patients with hemoglobinopathies is thought to result from a combination of impaired splenic and reticuloendothelial function, altered complement-mediated immunity, intestinal ischemia with subsequent bacterial translocation, and ischemic bone marrow niches that predispose to Salmonella seeding. In addition, Salmonella osteomyelitis has been reported in individuals with diabetes mellitus, systemic lupus erythematosus, and various forms of immunodeficiency (Ochocinski et al., 2020; Huang et al., 2021), while Neisseria gonorrhoeae is a major causative agent of purulent arthritis in sexually active populations (Clerc et al., 2011). Most osteomyelitis cases involve single-pathogen infections, but polymicrobial infections are prevalent in key subgroups such as fracture-associated infections and diabetic foot (Rupp et al., 2024; Vicenti et al., 2024). These mixed infections (often involving staphylococci, enterococci, and Enterobacteriaceae) increase antimicrobial treatment complexity and recurrence risk, posing persistent challenges for clinically precise interventions (Masters et al., 2019).

2.2 Immune evasion mechanisms of S. aureus

The chronic progression of bone infections is closely associated with the successful evasion of host immune clearance by S. aureus. In fact, S. aureus constructs a complex immune evasion network through multi-layered and synergistic mechanisms.

S. aureus interferes with immune recognition and phagocytic clearance, and mediates adhesion that facilitates its intracellular persistence within phagocytes through microbial surface components (MSCRAMMs), such as ClfA and FnbA/B. Secreted proteins such as protein A (SpA), Efb, and Sbi effectively bind and inhibit complement activation, while molecules including SCIN, CHIPS, and coagulase (Coa) suppress neutrophil chemotaxis and phagocytosis, thereby blocking early immune recognition (Koymans et al., 2015; Koymans et al., 2017).

S. aureus can directly kill immune cells by secreting multiple pore-forming toxins (such as α-hemolysin, leukocidin LukAB/GH/ED, and PVL), which specifically lyse neutrophils and macrophages, leading to massive necrosis of immune cells (Seilie and Bubeck Wardenburg, 2017; Spaan et al., 2017). Furthermore, Phenol-soluble modulins (PSMs) are a family of amphipathic α-helical toxins secreted by Staphylococcus aureus. PSMs can insert into and disrupt phagosomal membranes, leading to phagosomal rupture or functional inactivation. This process interferes with phagolysosomal maturation and acidification, thereby markedly impairing host cell–mediated intracellular killing and promoting bacterial escape from phagosomes or prolonged intracellular persistence (Thammavongsa et al., 2015).

The physical and immunological barrier functions of S. aureus biofilms make biofilm formation a key defensive strategy. Biofilm matrix impedes the penetration of antibodies, complement, and immune cells. Concurrently, bacteria within the biofilm continuously express multiple immunosuppressive molecules such as Eap, SCIN, and SpA, synergistically suppressing local immune responses. This promotes the formation of immunosuppressive cells like M2 macrophages and myeloid-derived suppressor cells (MDSCs), thereby shaping an immunosuppressive microenvironment (De Vor et al., 2020). In this context, Staphylococcus aureus can actively induce the production of the anti-inflammatory cytokine IL-10, which represents a critical regulatory node within its immune evasion network. Accumulating evidence indicates that S. aureus activates macrophages and dendritic cells via pattern recognition receptors such as TLR2, thereby inducing IL-10 secretion and promoting the expansion of regulatory T cells and regulatory B cells (Kelly et al., 2022). In addition, S. aureus–derived superantigens (e.g., enterotoxins) and protein A can directly stimulate host regulatory T-cell or B-cell populations, resulting in robust IL-10 production (Björkander et al., 2016). IL-10 suppresses the expression of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6, downregulates Th1- and Th17-mediated immune responses, and impairs the bactericidal functions of neutrophils and effector T cells (Kelly et al., 2022). Concurrently, IL-10 drives macrophage polarization toward an M2 phenotype, thereby sustaining a local immunosuppressive milieu and facilitating the chronicity of infection (Chen et al., 2023).

S. aureus can modulate adaptive immunity and induces chronicity. Superantigens (SAgs) non-specifically activate T cells while interfering with the normal activation of antigen-specific T/B cells, thereby promoting abscess formation (Shepherd et al., 2023). The synergistic action of multiple mechanisms collectively enables S. aureus to establish an immunologically inert microenvironment within the host, ultimately resulting in chronic and recurrent infections.

3 IFNs-mediated immune regulation in bone infections

In bone infections, IFNs serve as pivotal factors in initiating anti-pathogen signaling and modulating immune cell function, in which IFN-I and IFN-II play particularly crucial roles. Under sustained stimulation by pathogens such as S. aureus, these IFNs orchestrate a complex immune network by regulating phagocyte activation, antigen presentation, and adaptive immunity.

3.1 IFN-I

IFN-I constitute a crucial cytokine family produced by the innate immune system upon recognition of bacterial and damage-associated molecular patterns (PAMPs), IFN-I mainly include IFN-α, IFN-β, and several tissue-specific subtypes, such as IFN-ϵ, IFN-κ, and IFN-ω. Notably, IFN-α itself comprises at least 13 distinct subtypes, which exhibit substantial differences in signaling potency, immune cell targeting, and regulatory effects on inflammation and bone remodeling (Schreiber, 2017; Lazear et al., 2019). The classical pathway involves: PRRs recognizing pathogen components activate IRF3/IRF7, inducing IFN-I secretion; and Secreted IFN-I binds to the IFNAR receptor, activating the JAK-STAT signaling pathway to drive extensive expression of interferon-stimulated genes (ISGs), ultimately exerting antimicrobial and immunoregulatory effects (Platanias, 2005; Ivashkiv and Donlin, 2014; Mcnab et al., 2015).

Staphylococcus aureus effectively induces IFN-I production by activating host pattern recognition receptors through multiple PAMPs (Figure 1) (Parker and Prince, 2012; Lentini et al., 2021). Extracellular components such as lipoteichoic acid and peptidoglycan are recognized by TLR2, whereas bacterial nucleic acids are sensed within endosomal compartments by nucleic acid–sensing TLRs, including TLR3, TLR7, TLR8, and TLR9. These signals are transduced predominantly through adaptor proteins such as MyD88 (and TRIF in the case of TLR3), leading to activation of interferon regulatory factors IRF1 and IRF7 and subsequent transcription of IFN-α/β (Parker and Prince, 2012; Schäffler et al., 2014; Askarian et al., 2018; Rodriguez and Kuehn, 2020; Lentini et al., 2021). In addition, the Xr domain of SpA, a cell wall-anchored virulence factor, has been identified as a potent inducer of IFN-β (Martin et al., 2009; Foster et al., 2014). Following bacterial invasion into non-professional phagocytic cells such as osteoblasts, bacterial DNA released into the cytosol is detected by cGAS, which catalyzes the production of the second messenger cGAMP and activates the STING–TBK1–IRF3 signaling axis, constituting the core intracellular pathway for IFN-I induction (Zhou et al., 2021; Johnson et al., 2022; Collet et al., 2025; Xu and Zhu, 2025). Moreover, S. aureus–derived cyclic dinucleotides such as c-di-AMP can directly activate STING, providing an additional mechanism for sensing metabolically active bacteria (Burdette et al., 2011; Corrigan et al., 2011). In dendritic cells, IFN-I induction is predominantly mediated through the TLR9–MyD88–IRF1 pathway (Parker and Prince, 2012). Functionally, IFN-I exerts a stage-dependent dual role in bone infection: during the early phase, it enhances pathogen clearance by promoting phagocyte activation and antigen presentation, thereby bridging innate and adaptive immunity (Nakamura et al., 2007; Nguyen-Pham et al., 2011; Hayashida et al., 2014), in contrast, during sustained infection, dysregulated IFN-I signaling suppresses inflammatory responses and promotes osteoclast activation, leading to bone destruction and tissue damage, as demonstrated in S. aureus osteomyelitis models (Takayanagi et al., 2002; Woeckel et al., 2012; Wilson et al., 2013; Teijaro, 2016; Lukhele et al., 2019; Place et al., 2021; Johnson et al., 2022; Zhang et al., 2025).

Innate immune recognition pathways triggered by *Staphylococcus aureus* in the bone microenvironment. *Staphylococcus aureus*–derived pathogen-associated molecular patterns (PAMPs) are sensed by multiple pattern recognition receptors (PRRs) across distinct cellular compartments in bone-resident and bone marrow–derived cells, including osteoblasts, macrophages, and dendritic cells. At the plasma membrane, triacylated and diacylated lipoproteins are detected by TLR2 heterodimers (TLR2/TLR1 and TLR2/TLR6), leading to recruitment of TIRAP and MyD88, activation of IRAK family kinases and TRAF6, and downstream signaling through NF-κB and interferon regulatory factors (IRFs). Following bacterial internalization, bacterial nucleic acids, including single-stranded RNA (ssRNA) and CpG-rich DNA, are recognized by endosomal TLRs (TLR3, TLR7, TLR8, and TLR9), predominantly via MyD88-dependent pathways, thereby amplifying inflammatory and interferon responses in bone marrow–derived antigen-presenting cells. In the cytosol, bacterial double-stranded DNA is sensed by cyclic GMP–AMP synthase (cGAS), resulting in cGAMP production, activation of endoplasmic reticulum–associated STING, and engagement of the TBK1–IRF3 signaling axis. Collectively, these pathways converge on IRF3/IRF7 activation and drive the transcriptional induction of and interferon-stimulated genes, shaping innate immune activation and downstream adaptive immune responses during *S. aureus* bone infection.
Figure 1. Innate immune recognition pathways triggered by Staphylococcus aureus in the bone microenvironment. Staphylococcus aureus–derived pathogen-associated molecular patterns (PAMPs) are sensed by multiple pattern recognition receptors (PRRs) across distinct cellular compartments in bone-resident and bone marrow–derived cells, including osteoblasts, macrophages, and dendritic cells. At the plasma membrane, triacylated and diacylated lipoproteins are detected by TLR2 heterodimers (TLR2/TLR1 and TLR2/TLR6), leading to recruitment of TIRAP and MyD88, activation of IRAK family kinases and TRAF6, and downstream signaling through NF-κB and interferon regulatory factors (IRFs). Following bacterial internalization, bacterial nucleic acids, including single-stranded RNA (ssRNA) and CpG-rich DNA, are recognized by endosomal TLRs (TLR3, TLR7, TLR8, and TLR9), predominantly via MyD88-dependent pathways, thereby amplifying inflammatory and interferon responses in bone marrow–derived antigen-presenting cells. In the cytosol, bacterial double-stranded DNA is sensed by cyclic GMP–AMP synthase (cGAS), resulting in cGAMP production, activation of endoplasmic reticulum–associated STING, and engagement of the TBK1–IRF3 signaling axis. Collectively, these pathways converge on IRF3/IRF7 activation and drive the transcriptional induction of and interferon-stimulated genes, shaping innate immune activation and downstream adaptive immune responses during S. aureus bone infection.

Type I interferons (IFN-I) display a pronounced stage- and context-dependent dual role in bone infection, in which the magnitude and duration of signaling determine whether the outcome is protective or pathological (Josse et al., 2015; Chen et al., 2023; Qiu et al., 2025). During the early phase of infection, IFN-I generally exerts beneficial effects. Basal “tonic” IFN-I signaling is essential for skeletal homeostasis, as mice deficient in IFNAR1, IFN-β, or downstream mediators such as STAT1 or IRF1 exhibit increased osteoclastogenesis and reduced bone mineral density even in the absence of infection, indicating that IFN-I negatively regulates osteoclast differentiation through suppression of c-Fos and NFATc1 (Gimza and Cassat, 2021). In the infectious setting, these protective effects are amplified. In vitro studies show that recombinant IFN-β treatment significantly and time-dependently reduces intracellular Staphylococcus aureus burden in infected osteoblasts, an effect mediated by interferon-stimulated genes such as IFIT1 and IFIT3 with direct antibacterial activity (Qiu et al., 2025). Consistently, murine bone infection models demonstrate markedly elevated local IFN-β expression during the early stage of infection, supporting its physiological relevance in early containment of bacterial spread (Johnson et al., 2022). In addition, IFN-I promotes dendritic cell maturation and enhances MHC class II–dependent antigen presentation, facilitating efficient priming of T cell–mediated adaptive immunity during bone infection (Parker and Prince, 2012; Darisipudi et al., 2018). In contrast, sustained or dysregulated IFN-I signaling shifts its role toward immune pathology and tissue damage. The detrimental potential of excessive IFN-I signaling has been clearly demonstrated in S. aureus infection models, where aberrant IFN-I responses suppress neutrophil recruitment and bactericidal activity while exacerbating inflammatory cytokine production, ultimately promoting bacterial expansion (Martin et al., 2009; Peignier and Parker, 2021; Chaudhary et al., 2023). In chronic bone infection and osteomyelitis, persistent inflammation activates IFN-I–dependent osteoclastogenic pathways, tipping physiological bone remodeling toward pathological bone loss (Josse et al., 2015). Although MyD88 and IL-1R dependent inflammatory signaling constitutes a major driver of infection-induced osteoclastogenesis, sustained interaction with IFN-I signaling is required to maintain osteoclast activation and progressive bone resorption (Putnam et al., 2019). Furthermore, acute IFN-α–mediated inflammation can disrupt the bone marrow niche by targeting endothelial cells and altering vascular integrity, thereby further contributing to bone pathology during chronic infection (Wang et al., 2025).

To persist within the host, S. aureus has evolved multiple strategies to evade or suppress IFN-I–mediated immunity. One of the most effective mechanisms involves modification of its cell wall structure: the bacterial enzyme O-acetyltransferase A (OatA) catalyzes O-acetylation of peptidoglycan, rendering it resistant to degradation by host lysosomal enzymes and allowing the bacterium to remain structurally intact within phagosomes (Kaplan et al., 2012). This limits the release of bacterial DNA and other ligands required for activation of the cGAS–STING or TLR9 pathways, thereby suppressing IFN-β production as well as downstream chemokines such as CXCL10 and CCL5, which are critical for efficient neutrophil recruitment (Zhu et al., 2015). At the signaling level, S. aureus infection induces host expression of endogenous negative regulators of the JAK–STAT pathway, including SOCS-1 and IFI44, resulting in feedback inhibition of interferon signaling (Klopfenstein et al., 2021; Zheng et al., 2022). In chronic infections such as osteomyelitis, biofilm formation further creates a hypoxic and nutrient-depleted microenvironment that drives metabolic reprogramming of infiltrating immune cells from glycolysis toward oxidative phosphorylation (Horn and Kielian, 2020). This milieu favors polarization of macrophages toward an M2-like anti-inflammatory phenotype, characterized by attenuated interferon responsiveness and preferential activation of STAT3/STAT6 rather than STAT1 signaling, ultimately compromising IFN-I-dependent host clearance mechanisms (Chen et al., 2023).

3.2 IFN-II

IFN-γ is a key pro-inflammatory effector cytokine in bacterial infections and is primarily produced by activated Th1 cells, CD8+ T cells, and natural killer (NK) cells. Upon binding to its receptor complex (IFNGR1/IFNGR2), IFN-γ activates the JAK1/2–STAT1 signaling pathway, leading to STAT1 homodimerization and nuclear translocation as the γ-activated factor (GAF), which regulates the transcription of downstream target genes (Bach et al., 1997; Schroder et al., 2004; Platanias, 2005; Bhat et al., 2017; Chen et al., 2024). In bacterial infection, IFN-γ serves as a critical bridge between innate and adaptive immunity by enhancing macrophage and dendritic cell functions, upregulating MHC class II expression, and promoting the production of pro-inflammatory cytokines, thereby facilitating effective T-cell responses (Johnson, 2014; Cordeiro et al., 2022).

Staphylococcus aureus can induce IFN-γ production through multiple complementary mechanisms. A canonical pathway involves activation of macrophages and dendritic cells, leading to the secretion of IL-12 and IL-18, which cooperatively drive IFN-γ production by NK cells and Th1 cells; the synergistic action of IL-12 and IL-18 is particularly critical in this process (Wei et al., 1999; Horowitz et al., 2011). In addition, S. aureus–derived lipid antigens can be presented via CD1d to activate type II NKT cells, resulting in robust IFN-γ secretion in the presence of IL-12 (Genardi et al., 2020). γδ T cells and conventional CD4+ T cells also contribute to IFN-γ production, while NK cells represent the dominant early source during acute infection (Horowitz et al., 2011). Notably, S. aureus virulence factors can aberrantly amplify IFN-γ responses: superantigens induce non-specific activation of large numbers of T cells and massive IFN-γ release (Tuffs et al., 2022), whereas β-hemolysin enhances IFN-γ production in CD56^bright NK cells through its sphingomyelinase activity (Greenlee-Wacker and Nauseef, 2017; Guan et al., 2021). Furthermore, S. aureus cell-free supernatants and staphylococcal enterotoxin A (SEA) can induce IFN-γ expression in FOXP3+ T cells in a monocyte-dependent manner, while intact bacteria broadly activate NK cells; the SaeR/S two-component system additionally promotes IFN-γ production by neutrophils during invasive infection (Watkins et al., 2013; Björkander et al., 2016).

During the early phase of bone infection, IFN-γ generally exerts protective antibacterial effects. It is a key inducer of inducible nitric oxide synthase (iNOS) in macrophages, driving nitric oxide (NO) production that synergizes with reactive oxygen species (ROS) to kill intracellular pathogens and destabilize bacterial biofilms (Sasaki et al., 1998; Greenlee-Wacker and Nauseef, 2017; Pidwill et al., 2021). IFN-γ also promotes dendritic cell maturation and antigen presentation, thereby enhancing Th1-polarized adaptive immune responses and restricting bacterial expansion (Lacasse et al., 2011; Furuta et al., 2023). These protective roles are supported by animal studies: in a cranial implant–associated S. aureus biofilm infection model, Ifngr1<sup>-/-</sup> mice exhibit significantly higher bacterial burdens and impaired innate and T-cell responses compared with wild-type controls, demonstrating that intact IFN-γ signaling is essential for effective clearance of biofilm-fassociated infection (Van Roy et al., 2025).

In contrast, during chronic or persistent bone infection, IFN-γ can shift toward an immunopathological role. Under sustained inflammatory conditions, IFN-γ cooperates with cytokines such as IL-1β and TNF-α to promote osteoclast differentiation and bone resorption, ultimately leading to bone destruction (Kim and Chung, 2012; Chenery et al., 2016). Its effects on osteoclastogenesis are highly context dependent: in the absence of inflammatory priming, IFN-γ can directly inhibit osteoclast precursor responsiveness to RANKL by blocking NFATc1 and NF-κB/JNK signaling, thereby suppressing osteoclast formation (Cheng et al., 2012). However, during sustained immune activation in vivo, IFN-γ indirectly promotes bone loss by enhancing antigen-dependent T-cell activation and stimulating the production of osteoclastogenic factors such as RANKL and TNF-α, resulting in increased osteoclast activity and pathological bone resorption (Gao et al., 2007). Moreover, during S. aureus bloodstream infection, excessive IFN-γ induced by superantigens can distort macrophage responses and facilitate intracellular bacterial replication, further highlighting the pathogenic potential of dysregulated IFN-γ signaling in chronic infection (Tuffs et al., 2022). Collectively, IFN-γ exhibits complex, stage-dependent effects on bone metabolism by influencing both osteogenesis and osteoclast activity, making it a critical contributor to bone pathology across diverse infectious and inflammatory conditions (Tang et al., 2018).

4 IFN-mediated regulation of immune cells in bone infection

In the immunological landscape of bone infection, interferons exert their protective roles primarily through the coordinated regulation of diverse immune cell populations. Type I and type II interferons integrate cooperative and antagonistic signalling cues to modulate the activation, differentiation and effector programs of neutrophils, macrophages, dendritic cells, NK cells, and adaptive lymphocytes, thereby forming a multilayered antimicrobial network against Staphylococcus aureus. However, S. aureus deploys a suite of virulence factors that selectively disrupt these IFN-driven responses—dampening phagocyte function, skewing cellular polarization, impairing antigen presentation and distorting lymphocyte activation.

4.1 Neutrophils

Neutrophils serve as the first line of defense against pathogen invasion. In bone infections, they are rapidly recruited to the lesion site, where they eliminate pathogens through phagocytosis, degranulation, and the formation of neutrophil extracellular traps (NETs) (Sadik et al., 2011; Sollberger et al., 2018; Gierlikowska et al., 2021; Sipprell et al., 2023). Impaired neutrophil numbers or function—due to bone marrow suppression, drug effects, or chronic infection—significantly increases susceptibility to bacterial infections, including osteomyelitis (Amulic et al., 2012; Lehman and Segal, 2020). Persistent infection or inflammation can lead to neutrophil overactivation without timely apoptosis or clearance, resulting in massive release of inflammatory mediators and tissue-degrading enzymes that cause bone tissue damage (Soehnlein et al., 2017; Dömer et al., 2021). This exemplifies the classic double-edged sword characteristic of neutrophils.

IFN signaling exerts multi-level, precise regulation over neutrophil function. IFN-I enhance bactericidal capacity by activating the p38 MAPK pathway to increase reactive oxygen species (ROS) production and promote apoptosis (Spolski et al., 2019; Glennon-Alty et al., 2021). IFN-II enhances phagocytosis, ROS bursts, and phagosome acidification via JAK-STAT1 signaling, effectively combating intracellular bacteria and biofilm infections. They also reverse the suppression of neutrophil function by S. aureus enterotoxin A (SEA) (Hodny et al., 2016; Ferreira-Duarte et al., 2017).

However, IFN regulation involves a complex equilibrium. S. aureus can induce IFN-γ production, but excessive endogenous IFN-γ conversely weakens the overall innate immune response (Kelly et al., 2022). However, the regulation of IFNs involves a complex equilibrium. Staphylococcus aureus itself can induce IFN-γ production, but excessive endogenous IFN-γ conversely weakens the overall innate immune response (Björkander et al., 2016; Chen et al., 2023; Shepherd et al., 2023). Meanwhile, Staphylococcus aureus has evolved multilayered immune evasion strategies targeting neutrophil extracellular traps (NETs). On the one hand, the bacterium secretes nucleases such as Nuc that directly degrade the DNA scaffold of NETs, disrupting their structural integrity and thereby releasing entrapped bacteria while reducing the capacity of NETs to restrict and kill pathogens. On the other hand, S. aureus–derived leukotoxin LukGH and PSMα can induce rapid neutrophil lysis or aberrant, non-programmed NET release, resulting in the formation of “dysfunctional NETs” that lack effective antimicrobial granule proteins and enzymatic activity. These NETs are not only ineffective in bacterial clearance but may also exacerbate local tissue damage. By simultaneously compromising NET structural integrity and manipulating the mode of NET release, S. aureus effectively weakens neutrophil-mediated innate immune defense (Thammavongsa et al., 2013; Janesch et al., 2017; Speziale and Pietrocola, 2021).

4.2 Macrophages

Macrophages originate from bone marrow monocytes and serve as key immune effector cells in defending against pathogen infections and maintaining tissue homeostasis. As the first line of defense in the innate immune system, macrophages are central cells of the innate immune response. They not only phagocytose and eliminate pathogens but also bridge innate and adaptive immunity through antigen presentation (Plüddemann et al., 2011; Hirayama et al., 2017; Acharya et al., 2019), playing vital roles in inflammation regulation and tissue repair (Saha et al., 2017; Watanabe et al., 2019; Rodríguez-Morales and Franklin, 2023). Depending on microenvironmental signals, macrophages can polarize into classically activated pro-inflammatory M1 or alternatively activated anti-inflammatory/reparative M2 types. The dynamic balance between these two states profoundly influences infection outcomes (Mulder et al., 2014; Soldano et al., 2016; Shapouri-Moghaddam et al., 2018).

In the early stages of osteomyelitis from S. aureus, monocytes infiltrating bone tissue are exposed to high levels of proinflammatory cytokines, thereby activating them into a classical proinflammatory state (Gordon and Martinez, 2010). Infiltrating macrophages are polarized toward the M1 phenotype under the drive of signals such as IFNs Among these, INF-I and INF-II serve as key inducers in this process. They promote macrophage expression of inducible nitric oxide synthase (iNOS), which catalyzes the production of antibacterial NO and enhances ROS generation. This boosts the phagocytic and bactericidal capabilities of macrophages (Weinberg et al., 1995; Bogdan et al., 2000; Lim et al., 2020; Yu et al., 2020). They also promote the expression of inflammatory cytokines and facilitate MHC-II-mediated antigen presentation (Ma et al., 2012), thereby effectively controlling infection.

However, in the late stages of infection, S. aureus exploits the plasticity of macrophages to manipulate them to shift from the bactericidal M1 phenotype to the anti-inflammatory/reparative M2 phenotype. This polarization inhibits effective immune clearance and creates a microenvironment conducive to bacterial long-term survival and latency, thereby serving as a key mechanism for infection chronicity (De Vor et al., 2020; Lathram and Radka, 2025).

4.3 Dendritic cells

DCs serve as a critical bridge linking innate and adaptive immunity. In bone infections, DCs recognize pathogens such as S. aureus via pattern recognition receptors (PRRs), initiating antigen presentation and secreting cytokines (e.g., IL-12, IL-18) to induce Th1 cell polarization and IFN production (Stoll et al., 1998; Jin et al., 2014; Fischer, 2018). This activates T cells and NK cells and amplifies the anti-infective immune response (Lichtenegger et al., 2012; Lim et al., 2012). Plasma cell-like DCs (pDCs) can perceive nucleic acid signals via TLR7/9 and massively produce IFN-I, forming a complementary immunoregulatory axis with type II interferons (IFN-γ) (Gilliet et al., 2008; Tang et al., 2010).

There is bidirectional regulatory circuit between IFNs and DCs. On one hand, IFN-γ promotes DC maturation and IL-12 secretion via the JAK-STAT1 pathway, and further enhances the IFN-II response through an NK-DC positive feedback loop, thereby driving effective Th1/Th17 immunity (Lexberg et al., 2010; Jiao et al., 2011; Schindler et al., 2012). On the other hand, during chronic infection, sustained high-level IFN-I signaling induces DCs to differentiate toward an immunosuppressive phenotype, attenuating Th1 responses and upregulating IL-10 to promote local immune tolerance (Cunningham et al., 2016; Murira and Lamarre, 2016). Prolonged IFN-γ stimulation may also lead to DC functional exhaustion, characterized by downregulation of co-stimulatory molecules and diminished T cell activation capacity (Svajger et al., 2014).

S. aureus further disrupts DC function through multiple mechanisms, such as secreting PSMs to alter cytokine profiles and suppress T cell activation (Armbruster et al., 2016), or directly damaging DCs via the leukotoxin LukAB to inhibit T cell activation and evade immune clearance (Berends et al., 2019). Collectively, DCs play a central regulatory role in balancing bone infection immunity by precisely integrating IFN-I and IFN-II signaling.

4.4 Natural killer cells

NK cells belong to the innate lymphoid cell (ILC1) family and play a crucial role in the host defense against S. aureus infection (Nilsson et al., 1999; Elemam et al., 2021). They can be rapidly activated during early infection, directly killing target cells by releasing perforin and granzyme, while secreting key cytokines such as IFN-γ to coordinate the immune response (Lopez et al., 2013). In bone infections, NK cells residing in the bone marrow and periosteal regions serve as major early sources of IFN-γ. The IFN-γ they secrete can effectively enhance the phagocytic and bactericidal functions of macrophages and neutrophils, promotes Th1 immune differentiation, and establishes a critical defense against S. aureus infection (Casbon et al., 2012; Goldszmid et al., 2012; Askenase et al., 2015; Baruah et al., 2019).

IFN-I exert a positive regulatory role in this process: IFN-I significantly promotes NK cell proliferation, survival, and effector functions by binding to the IFNAR receptor on NK cell surfaces and activating the JAK-STAT pathway (Madera et al., 2016; Huang et al., 2021). This includes the generation of enhanced IFN-γ, which further activates other immune cells such as Kupffer cells, thereby synergistically boosting overall antimicrobial capacity (Miyazaki et al., 2011). NK cell-derived IFN-γ enhances macrophage phagocytic function and cytokine secretion, thereby improving the host’s ability to control S. aureus infections (Greenlee-Wacker and Nauseef, 2017).

However, S. aureus has evolved evasion mechanisms to interfere with NK cell function. For instance, its secreted β-hemolysin (Hlb) can abnormally activate CD56bright NK cells through the sphingolipase-Ca²+-ERK1/2 signaling pathway, leading to excessive IFN-γ release. This subsequently triggers local inflammation and immune imbalance, thereby aiding bacterial immune evasion (Guan et al., 2021).

4.5 T cells

T cells are the core component of adaptive immunity and initiate specific immune responses by recognizing antigen-peptide-MHC complexes on antigen-presenting cells (APCs) (Zareie et al., 2021). Based on functional differences, T cells are primarily divided into subpopulations including CD4+ helper T cells (Th), CD8+ cytotoxic T cells (CTL), and regulatory T cells (Treg). CD4+ T cells can be differentiated into Th1, Th2, and Th17 subsets, which dominate cellular immunity, humoral immunity, and inflammatory responses by secreting cytokines such as IFN-γ, IL-4, and IL-17, respectively (Liew, 2002; Raphael et al., 2015; Mills, 2023). CD8+ T cells directly kill infected cells and enhance local immunity by secreting cytokines like IFN-γ (Mittrücker et al., 2014; Koh et al., 2023). Regulatory T cells (Tregs) maintain immune tolerance by secreting inhibitory factors, jointly coordinating immune responses and homeostasis (Vignali et al., 2008).

In bone infections of S. aureus, IFN-γ serves as the core mediator of T cell immunity. It promotes Th1 differentiation and enhances antigen presentation, forming a positive feedback loop to effectively strengthen antimicrobial immunity (Bradley et al., 1996). Synergistic Th1 and Th17 responses aid infection control, but excessive IFN-γ expression may exacerbate osteoclast activation and bone destruction by upregulating pathways like RANKL (Gao et al., 2007; Van Roy et al., 2025). Furthermore, IFN-I exhibit complex roles in regulating T cell responses: they promote Th1 differentiation and enhance CD8+ T cell cytotoxicity and memory functions (Curtsinger et al., 2005; Huber and Farrar, 2011; Lu et al., 2019), while suppressing Tregs during the acute phase to amplify immune responses (Srivastava et al., 2014).

To evade from T cell immunity, S. aureus has evolved various mechanisms, including the use of superantigens to induce T cell hyperactivation followed by functional exhaustion (Stach et al., 2014; Kunkl et al., 2023; Shepherd et al., 2023); and the downregulation of antigen presentation-related molecules (such as HLA-DR) alongside the upregulation of inhibitory signals like PD-L1, thereby promoting chronic infection (Wang et al., 2012). As a result, the intricate interplay between T cells and the IFN network also determines the outcome of S. aureus bone infections.

4.6 B Cells

B cells are central members of the adaptive immune system and play multiple roles in anti-infective immunity. Their core function is to produce specific antibodies that directly eliminate pathogens through neutralization, phagocytosis regulation, and complement activation, while establishing long-term immune memory (Chi et al., 2024). Furthermore, B cells serve as crucial antigen-presenting cells that effectively activate T cell responses. Certain subsets, such as regulatory B cells (Bregs), negatively regulate immune inflammation by secreting inhibitory cytokines like IL-10 and TGF-β, making them indispensable for maintaining immune homeostasis (Gjertsson et al., 2000; Nygaard et al., 2016; Lo et al., 2021).

In bone infection immunity, IFN-I significantly enhances B cell-mediated humoral immunity. IFN-I signaling not only directly promotes B cell activation, proliferation, and differentiation into plasma cells, but also enhances their response to TLR7/9 signaling. Meanwhile, it induces dendritic cells and other cells to produce key survival factors such as BAFF, significantly increasing B cell survival rates and thereby synergistically strengthening the anti-infective humoral immune response (Kiefer et al., 2012; Higuchi et al., 2024).

In response to the host’s humoral immune assault, S. aureus has evolved sophisticated evasion mechanisms. Its secreted protein A acts as a B-cell “superantigen”, and non-specifically binds and activates large numbers of B cells, to induce their apoptosis. This effectively disrupts the generation of long-lived plasma cells and protective memory B cells, thereby weakening the host’s specific antibody response—a key strategy for evading humoral immune attacks (Shi et al., 2021) (Figure 2).

Interferon-mediated regulation of immune cells and Staphylococcus aureus immune evasion in osteomyelitis. Type I and type II interferons enhance antimicrobial immunity during Staphylococcus aureus osteomyelitis by increasing neutrophil ROS production, phagocytosis, and NET formation; promoting macrophage M1 polarization, NO/ROS generation, and bactericidal activity; driving dendritic cell (DC) maturation and Th1 priming; boosting NK-cell cytotoxicity, granzyme B release, and IFN-γ production; and supporting B-cell activation and antibody responses as well as CD8<sup>+</sup> T-cell differentiation. To evade these IFN-driven defenses, *S. aureus* deploys virulence factors including nucleases and LukGH/PSMα, which degrade or dysregulate NETs; α-toxin and biofilm components that impair macrophages; PSMs and LukAB that disrupt DC function; β-hemolysin (Hlb), which aberrantly activates NK cells; superantigens that dysregulate T cells; and Protein A (SpA), which interferes with B-cell responses—collectively fostering immune evasion and persistent infection.
Figure 2. Interferon-mediated regulation of immune cells and Staphylococcus aureus immune evasion in osteomyelitis. Type I and type II interferons enhance antimicrobial immunity during Staphylococcus aureus osteomyelitis by increasing neutrophil ROS production, phagocytosis, and NET formation; promoting macrophage M1 polarization, NO/ROS generation, and bactericidal activity; driving dendritic cell (DC) maturation and Th1 priming; boosting NK-cell cytotoxicity, granzyme B release, and IFN-γ production; and supporting B-cell activation and antibody responses as well as CD8+ T-cell differentiation. To evade these IFN-driven defenses, S. aureus deploys virulence factors including nucleases and LukGH/PSMα, which degrade or dysregulate NETs; α-toxin and biofilm components that impair macrophages; PSMs and LukAB that disrupt DC function; β-hemolysin (Hlb), which aberrantly activates NK cells; superantigens that dysregulate T cells; and Protein A (SpA), which interferes with B-cell responses—collectively fostering immune evasion and persistent infection.

5 Summary and outlook

Chronic osteomyelitis caused by S. aureus epitomizes the intricate interplay between pathogen immune evasion and host immune defense. This review systematically outlines core advances in the field and reveals how S. aureus successfully shapes an inhibitory microenvironment through multiple mechanisms including biofilm formation, toxin secretion, and immune disruption. The host primarily relies on IFN-I and IFN-II signaling to coordinate nearly all key immune cells—including neutrophils, macrophages, and lymphocytes—through pathways such as JAK-STAT, thereby constructing a multi-layered defense system. However, IFN signaling exhibits a classic double-edged sword characteristic: its timely activation is crucial for controlling infection, while persistent dysregulation directly leads to immune exhaustion and bone tissue destruction.

Despite deepening understanding, there are some critical scientific questions. Future research should focus on: 1), the spatiotemporal dynamics of IFN signaling within the bone microenvironment and its pivotal role in transitioning between acute and chronic infection; 2), the cross-talk between IFN and emerging pathways like cellular metabolism and programmed cell death, where novel mechanisms of immune imbalance may lie; and 3), the systemic impact of complex clinical factors such as diabetes and implanted devices on local immune responses.

At the therapeutic level, strategies for chronic bone infection are gradually shifting from a purely antimicrobial approach toward a precision framework that integrates antimicrobial therapy with modulation of the local immune microenvironment. Central to this concept is the stage-dependent regulation of interferon signaling: during the acute phase, short-term enhancement of protective IFN responses may improve phagocyte-mediated bacterial killing and antigen presentation, whereas during prolonged or chronic infection, suppression of sustained IFN-driven immunopathology—including immune suppression and bone destruction—may limit tissue damage and improve clinical outcomes.

Several clinically established drug classes provide feasible tools for targeting the IFN–JAK–STAT axis. JAK inhibitors such as ruxolitinib, baricitinib, and tofacitinib directly suppress IFN receptor–proximal JAK1/2–STAT1 signaling, thereby attenuating persistent ISG programs. These agents have well-characterized pharmacological and safety profiles in immune-mediated diseases and have been successfully applied to human interferonopathies as proof-of-concept for controlling pathological IFN activation (Schwartz et al., 2017; Hu et al., 2021; Bonelli et al., 2024), In parallel, upstream neutralizing monoclonal antibodies demonstrate clear translational relevance: the anti-IFNAR1 antibody anifrolumab has been approved for systemic lupus erythematosus (Cheng et al., 2025), while the IFN-γ–neutralizing antibody emapalumab is approved for primary hemophagocytic lymphohistiocytosis. Together, these agents highlight the feasibility of directly targeting IFN ligand–receptor interactions and provide pharmacological precedents for mitigating IFN-mediated immunopathology in chronic bone infection. In addition, modulation of upstream innate immune pathways, including the cGAS–STING axis, has attracted growing attention, as multiple animal studies indicate that STING inhibition can alleviate inflammation-driven bone resorption, suggesting a potential strategy to disrupt the IFN–inflammation–bone destruction amplification loop in chronic infection (Gao et al., 2022; Mao et al., 2024).

Concurrently, advances in multi-omics technologies are transforming the question of when to enhance or suppress IFN signaling from a conceptual hypothesis into a testable biological framework. In Staphylococcus aureus bone infection models, osteoblast infection has been shown to induce robust IFN-I/ISG transcriptional programs, providing direct evidence for early IFN responses at the bone cellular level (Johnson et al., 2022; Nicolas et al., 2022). Transcriptomic analyses in murine implant-associated osteomyelitis further reveal dynamic changes in immune and inflammatory pathways over the course of infection, supporting temporally stratified intervention strategies (Lin et al., 2021). Single-cell RNA sequencing has begun to resolve the functional heterogeneity of immune cells within biofilm-associated infections, including metabolic and hypoxia-adaptive states linked to altered IFN responsiveness, thereby enabling high-resolution identification of immunosuppressive or exhausted cell populations (Saito et al., 2024; Van Roy et al., 2024). With the rapid development of spatial transcriptomics in bone research, the spatial integration of immune cell states, bacterial niches, and bone-destructive lesions is becoming feasible, paving the way toward immune atlas–guided patient stratification and precision therapy (Wang et al., 2025; Giger and Wehrle, 2026). Collectively, the convergence of IFN-targeted pharmacological tools and multi-omics–based immune mapping supports a rational trajectory toward stage-specific, combination therapies that integrate interferon modulation with antimicrobial treatment in chronic bone infection.

In summary, deepening our understanding of the immune mechanisms underlying bone infections—particularly the interplay between the IFN network and pathogen evasion—is forging new pathways to overcome this clinical challenge. By multidisciplinary integration, innovative therapies capable of reshaping the infectious microenvironment and restoring immune balance are expected to emerge, ultimately improving patient outcomes.

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Footnotes

Edited by: Stanimir S. Ivanov, Louisiana State University Health Shreveport, United States

Reviewed by: Shameer Khader, Sanofi, France

Emilio G. Vozza, University of Cambridge, United Kingdom

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Author contributions

JQ: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft. WQ: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft. XT: Investigation, Writing – original draft. YY: Conceptualization, Project administration, Validation, Writing – review & editing.

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Citation

Qian, J., et al. (2026). Offense-defense in bone infection: interferon regulation and the immune evasion of Staphylococcus aureus. Frontiers in Bacteriology, Volume 5. https://doi.org/
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5 - 2026

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Copyright © 2026 Qian, Qian, Tang and Yang.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Yin Yang

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