In Staphylococcus aureus, the Particulate State of the Cell Envelope Is Required for the Efficient Induction of Host Defense Responses

Abstract

Upon microbial infection, host immune cells recognize bacterial cell envelope components through cognate receptors. Although bacterial cell envelope components function as innate immune molecules, the role of the physical state of the bacterial cell envelope (i.e., particulate versus soluble) in host immune activation has not been clearly defined. Here, using two different forms of the staphylococcal cell envelope of Staphylococcus aureus RN4220 and USA300 LAC strains, we provide biochemical and immunological evidence that the particulate state is required for the effective activation of host innate immune responses. In a murine model of peritoneal infection, the particulate form of the staphylococcal cell envelope (PCE) induced the production of chemokine (C-X-C motif) ligand 1 (CXCL1) and CC chemokine ligand 2 (CCL2), the chemotactic cytokines for neutrophils and monocytes, respectively, resulting in a strong influx of the phagocytes into the peritoneal cavity. In contrast, compared with PCE, the soluble form of cell envelope (SCE), which was derived from PCE by treatment with cell wall-hydrolyzing enzymes, showed minimal activity. PCE also induced the secretion of calprotectin (myeloid-related protein 8/14 [MRP8/14] complex), a phagocyte-derived antimicrobial protein, into the peritoneal cavity at a much higher level than did SCE. The injected PCE particles were phagocytosed by the infiltrated neutrophils and monocytes and then delivered to mediastinal draining lymph nodes. More importantly, intraperitoneally (i.p.) injected PCE efficiently protected mice from S. aureus infection, which was abolished by the depletion of either monocytes/macrophages or neutrophils. This study demonstrated that the physical state of bacterial cells is a critical factor for efficient host immune activation and the protection of hosts from staphylococcal infections.

The Role of Macrophages in Staphylococcus aureus Infection

“…Following S. aureus brain infection in mice, gene expression of multiple pro-inflammatory cytokines and chemokines are upregulated, leading to macrophage recruitment ( 82 ). In peritoneal infection, particulate S. aureus cell envelope promotes phagocyte recruitment by inducing chemotactic cytokine production ( 83 ). Of note, some macrophages subtypes, including Kupffer cells, are tissue-resident which may be recruited to local infection sites ( 84 ), whereas monocyte-derived macrophages are recruited to sites of infection from circulation in the blood ( 85 ).…”

“…Phagocytosis is receptor-mediated targeted uptake of particles larger than 0.5 µm, and represents the primary pathway used by macrophages to internalize S. aureus ( 88 ). The physical state of bacterial cells is important for S. aureus phagocytosis, with particulate rather than soluble cell wall required to stimulate an efficient phagocyte immune response ( 83 ). S. aureus phagocytosis events occur following engagement of multiple receptors on the macrophage surface, including scavenger receptors (SRs), complement receptors and Fc receptors ( Figure 2 ).…”

The Influence of Antibiotic Resistance on Innate Immune Responses to Staphylococcus aureus Infection

“…In macrophages, staphylococcal lipoproteins induce proinflammatory cytokines, NO, and reactive oxygen species (ROS) [94][95][96][97]. In a murine model of peritoneal infection, the particulate form of the staphylococcal cell envelope activated macrophages by inducing the production of chemotactic cytokines [98]. In S. aureus sepsis, increased microbial load and mortality was noticed in mice lacking macrophages [99].…”