IFI204 protects host defense against Staphylococcus aureus-induced pneumonia by promoting extracellular traps formation

Staphylococcus aureus (S. aureus) is a significant and ubiquitous opportunistic pathogen. It is a major cause of infection and morbidity in a large number of animal hosts, and therefore poses a serious threat to animal husbandry. It can cause a variety of infections, including skin or soft tissue infections, necrotizing pneumonia, bacteremia, endocarditis, and osteomyelitis [1,2]. Equally important, S. aureus is one of the main pathogens of nosocomial infections in the world, but effective treatment options against S. aureus infections are still limited [3]. Furthermore, S. aureus also can develop a variety of drug resistance, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus strains (VRSA) has become a severe threat to humans, animals, and environmental health [4]. The widespread drug resistance of S. aureus requires us to develop new strategies for the prevention and treatment of infections.

The immune responses of the innate immune system provide natural immunity against microorganisms via phagocytosis and intracellular killing, recruitment of other inflammatory cells, and presentation of antigens [5]. As part of the innate immunity, neutrophils protect the host through phagocytosis, release of cytotoxic molecules, and release of neutrophil extracellular traps (NETs) [6,7]. The extracellular traps(ETs)are a newly discovered way to defend against pathogenic infections [8]. ETs rely on their mesh structure to capture bacteria. Previous studies had demonstrated that ETs can capture S. aureus [9], Streptococcus pneumoniae, Mycobacterium tuberculosis, and other Gram-positive bacteria as well as Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, and other gram-negative bacteria [10,11]. These reticular structures are composed of DNA fibers and antimicrobial proteins, including histones, antimicrobial peptides, and proteases. These structures were first described as NETs in neutrophils by Brinkmann et al. [8,12]. Currently, the formation of ETs has been confirmed not only in neutrophils but also in immune cells such as macrophages [13], eosinophils [14,15], mast cells [16], and monocytes [17]. ETs are an indispensable process in the innate immune response. These structures contain a chromatin-DNA backbone with attached antimicrobial peptides and enzymes that can capture and kill microorganism [18]. ETs can immobilize and kill microorganisms, but is also associated with disease pathology, including sterile inflammation and autoimmune diseases [19].

Interferon-inducible protein 204 (IFI204) is an intracellular DNA receptor that can recognize DNA viruses and intracellular bacteria [20]. It plays an essential protective role in viral and bacterial infections [21,22]. In our study, we revealed that IFI204 attenuated S. aureus respiratory infections and contributed to the formation of ETs. IFI204 deficiency exhibited reduced cell-free DNA level, declined expression of citrullination histone H3 (CitH3), and lower ETs structure. IFI204 promoted the formation of S. aureus-induced ETs via a NOX non-dependent manner. Moreover, IFI204 contributed to the formation of ETs by promoting the expression of PAD4. In brief, these findings suggested the beneficial effects of IFI204 on S. aureus pneumonia and the regulatory mechanism in ET formation.

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