Surfactant protein A (SP-A)-mediated clearance of Staphylococcus aureus involves binding of SP-A to the staphylococcal adhesin Eap and the macrophage receptors SP-A receptor 210 and scavenger receptor class A

Staphylococcus aureus causes life-threatening pneumonia in hospitals and deadly superinfection during viral influenza. The current study investigated the role of surfactant protein A (SP-A) in opsonization and clearance of S. aureus. Previous studies showed that SP-A mediates phagocytosis via the SP-A receptor 210 (SP-R210). Here, we show that SP-R210 mediates binding and control of SP-A-opsonized S. aureus by macrophages. We determined that SP-A binds S. aureus through the extracellular adhesin Eap. Consequently, SP-A enhanced macrophage uptake of Eap-expressing (Eap⁺) but not Eap-deficient (Eap ^-) S. aureus. In a reciprocal fashion, SP-A failed to enhance uptake of Eap⁺ S. aureus in peritoneal Raw264.7 macrophages with a dominant negative mutation (SP-R210(DN)) blocking surface expression of SP-R210. Accordingly,WTmice cleared infection with Eap⁺ but succumbed to sublethal infection with Eap- S. aureus. However, SP-R210(DN) cells compensated by increasing non-opsonic phagocytosis of Eap⁺ S. aureus via the scavenger receptor scavenger receptor class A (SR-A), while non-opsonic uptake of Eap^- S. aureus was impaired. Macrophages express two isoforms: SP-R210_L and SP-R210_S. The results show that WT alveolar macrophages are distinguished by expression of SP-R210^L, whereas SR-A^-/- alveolar macrophages are deficient in SP-R210_L expressing only SP-R210_S. Accordingly, SR-A^-/- mice were highly susceptible to both Eap⁺ and Eap^- S. aureus. The lungs of susceptible mice generated abnormal inflammatory responses that were associated with impaired killing and persistence of S. aureus infection in the lung. In conclusion, alveolar macrophage SP-R210L mediates recognition and killing of SP-A-opsonized S. aureus in vivo, coordinating inflammatory responses and resolution of S. aureus pneumonia through interaction with SR-A.