Synergistic Action of Nitric Oxide Release from Murine Macrophages Caused by Group B Streptococcal Cell Wall and β‐Hemolysin/Cytolysin (original) (raw)

2002, The Journal of Infectious Diseases

Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. It has been shown that GBS b-hemolysin/cytolysin (b-h/c) stimulates the transcription of inducible NO synthase (iNOS) in murine macrophages via intracellular pathways similar to those that mediate lipopolysaccharide-induced iNOS activation. Here, it is demonstrated that the GBS cell wall and b-h/c act synergistically to induce iNOS in interferon (IFN)-a-primed RAW 264.7 murine macrophages. In nonprimed macrophages, combined activation by the GBS cell wall plus bh/c is necessary to induce an NO response, which indicates that both virulence factors cooperate to substitute for the priming signal typically provided by IFN-a. Group B streptococcus (GBS) is the leading cause of pneumonia, meningitis, and septic shock in newborns, particularly those born prematurely. All clinical isolates are encapsulated, and 98%-99% are b-hemolytic [1]. GBS b-hemolytic activity is mediated by a pore-forming cytotoxin, the genetic basis of which has recently been elucidated [2]. In vitro, the GBS b-hemolysin/cytolysin (b-h/c) is associated with injury to lung epithelial, lung endothelial, and brain endothelial cells and is thus speculated to contribute to GBS penetration of host cellular barriers. Very recently, we reported that b-h/c is responsible for high mortality and liver injury in a rabbit model of GBS septic shock [3]. The hypotension of septic shock is thought to be due, in part, to an excess production of nitric oxide (NO), because elevated NO levels are found in patients with sepsis. Three isoforms of NO synthases (NOS) are present in mammals, the high-output inducible NOS (iNOS) and 2 constitutive isoforms, one originally identified in neurons and the other in endothelial cells. Activated macrophages constitute a major source of NO production. The inflammatory activation of macrophages is thought to involve 2 sequential steps, priming and triggering [4]. Priming is initiated by binding of interferon (IFN)-a to its specific receptor, which results in a number of biochemical and functional alterations that render the macrophages sensitive to triggering agents such as proinflammatory cytokines, lipopolysaccharide (LPS) [4],