Collaborative Interferon-γ and Interleukin-17 Signaling Protects the Oral Mucosa from Staphylococcus aureus

Area of Science:

• Immunology
• Microbiology
• Infectious Diseases

Background:

• Staphylococcus aureus infections pose a significant public health challenge in both community and hospital settings.
• Current preclinical models for S. aureus often involve experimental infections with inherent limitations.
• Understanding innate host defense mechanisms against S. aureus is crucial for developing effective treatments.

Purpose of the Study:

• To establish and characterize a novel spontaneous model of oral Staphylococcus aureus infection.
• To elucidate the distinct and collaborative roles of Interleukin-17 (IL-17) and Interferon-gamma (IFN-γ) in host defense against S. aureus.
• To investigate the contribution of neutrophils and macrophages in the context of IL-17 and IFN-γ signaling during S. aureus infection.

Main Methods:

• Generation of double knockout mice lacking IL-17 receptor A (IL-17RA) and IFN-γ receptor I (IFNγRI) (GRAKO mice).
• Induction of oral staphylococcal infection in GRAKO mice and assessment of disease progression.
• Flow cytometry analysis of immune cell infiltration in oral tissues and draining lymph nodes.
• Depletion of macrophages and monocytes in vivo using clodronate-loaded liposomes to assess their role.

Main Results:

• GRAKO mice spontaneously developed progressive oral abscesses upon S. aureus infection.
• Extensive neutrophilic infiltration was observed in the oral tissues of GRAKO mice, with IL-17 signaling playing a predominant role in neutrophil function.
• Perturbations in monocyte recruitment and macrophage differentiation were noted in GRAKO mice, suggesting a role for IFN-γ signaling.
• Depletion of monocytes and macrophages in IL17RA(-/-) mice recapitulated the oral abscess phenotype observed in GRAKO mice.

Conclusions:

• IL-17 and IFN-γ signaling pathways exhibit collaborative functions in innate mucocutaneous host defense against Staphylococcus aureus.
• IL-17 primarily influences neutrophil responses, while IFN-γ signaling impacts monocyte recruitment and macrophage differentiation.
• This novel GRAKO mouse model provides a valuable platform for studying S. aureus pathogenesis and host immunity.