Staphylococcal phosphatidylinositol‐specific phospholipase C potentiates lung injury via complement sensitisation

Abstract

Staphylococcus aureus is frequently isolated from patients with community-acquired pneumonia and acute respiratory distress syndrome (ARDS). ARDS is associated with staphylococcal phosphatidylinositol-specific phospholipase C (PI-PLC); however, the role of PI-PLC in the pathogenesis and progression of ARDS remains unknown. Here, we showed that recombinant staphylococcal PI-PLC possesses enzyme activity that causes shedding of glycosylphosphatidylinositol-anchored CD55 and CD59 from human umbilical vein endothelial cell surfaces and triggers cell lysis via complement activity. Intranasal infection with PI-PLC-positive S. aureus resulted in greater neutrophil infiltration and increased pulmonary oedema compared with a plc-isogenic mutant. Although indistinguishable proinflammatory genes were induced, the wildtype strain activated higher levels of C5a in lung tissue accompanied by elevated albumin instillation and increased lactate dehydrogenase release in bronchoalveolar lavage fluid compared with the plc − mutant. Following treatment with cobra venom factor to deplete complement, the wild-type strain with PI-PLC showed a reduced ability to trigger pulmonary permeability and tissue damage. PI-PLC-positive S. aureus induced the formation of membrane attack complex, mainly on type II pneumocytes, and reduced the level of CD55/CD59, indicating the importance of complement regulation in pulmonary injury. In conclusion, S. aureus PI-PLC sensitised tissue to complement activation leading to more severe tissue damage, increased pulmonary oedema, and ARDS progression.

Phosphatidylinositol-specific phospholipase C enhances epidermal penetration by Staphylococcus aureus

“…In addition to the Δ plc strain, the complemented strain was generated by reintroducing the plc gene into the Δ plc strain (designated as Δ plc :: plc ). Since a previous study demonstrated the necessity of His-80 in the activity of S. aureus PI-PLC 25 , another strain was constructed for the complemented strain with mutated plc gene that encoded His-80-mutated catalytically inactive mutants of PI-PLC (designated as Δ plc :: plc-MT ). This would help determine the role of PI-PLC activity.…”

“…The GPI-anchored proteins CD55 and CD59 present on keratinocytes are suggested to play a role in the alleviation of AD 39 . Since S. aureus PI-PLC was observed to cleave CD55 and CD59 from the surface of human umbilical vein endothelial cells and mouse pneumocytes 25 , the PI-PLC-mediated shedding of CD55 and CD59 from keratinocytes might enhance epidermal penetration by S. aureus, epidermal hyperplasia, and immune cell infiltration in S. aureus-infected skin in AD model mice. www.nature.com/scientificreports/ www.nature.com/scientificreports/ Although keratinocyte-derived AMPs kill extracellular S. aureus in the epidermis and inhibit epidermal penetration by S. aureus, AMPs are less effective in combating intracellular S. aureus.…”

“…The GPI-anchored proteins CD55 and CD59 present on keratinocytes are suggested to play a role in the alleviation of AD 39 . Since S. aureus PI-PLC was observed to cleave CD55 and CD59 from the surface of human umbilical vein endothelial cells and mouse pneumocytes 25 , the PI-PLC-mediated shedding of CD55 and CD59 from keratinocytes might enhance epidermal penetration by S . aureus , epidermal hyperplasia, and immune cell infiltration in S. aureus -infected skin in AD model mice.…”

“…PI-PLC was observed to promote the survival of ingested S. aureus in human polymorphonuclear neutrophils (PMNs) and enhance the survival of S. aureus against host defense mechanisms 24 . S. aureus PI‐PLC induces severe tissue damage, promotes pulmonary edema, and induces the progression of acute respiratory distress syndrome through the sensitization of tissues to complement activation 25 . However, the role of S. aureus PI-PLC in the pathogenesis of skin diseases, including AD, remains unknown.…”

cjrABC-senB hinders survival of extraintestinal pathogenic E. coli in the bloodstream through triggering complement-mediated killing

“…Complement depletion in mice with cobra venom factor CVF) was performed as describe previously [25]. Briefly, CVF (Quidel) was diluted in PBS at a concentration of 2.5 U/100 μl.…”