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

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.