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

Abstract

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 beta-hemolysin/cytolysin (beta-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 beta-h/c act synergistically to induce iNOS in interferon (IFN)-gamma-primed [corrected] RAW 264.7 murine macrophages. In nonprimed macrophages, combined activation by the GBS cell wall plus beta-h/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-gamma [corrected].

Inhibition of Nitric Oxide Synthase Exacerbates Group BStreptococcusSepsis and Arthritis in Mice

“…There is evidence that GBS are able to induce NO production in murine macrophages (8) and that cell wall and ␤-hemolysin cooperate to substitute for the priming signal typically provided by gamma interferon (19). In contrast to what was observed in a rat model of group A streptococcal sepsis (20), our data account for NO as an essential protective mechanism during GBS infection.…”

Virulence Role of Group BStreptococcusβ‐Hemolysin/Cytolysin in a Neonatal Rabbit Model of Early‐Onset Pulmonary Infection

“…The phospholipid dipalmotyl phosphatidylcholine (DPPC), a major component of human surfactant, inhibits GBS bh/c-mediated cytotoxicity, invasion, and IL-8 activation, providing a potential link to the increased susceptibility of premature, surfactant-deficient neonates to lung damage and sepsis from GBS infection [4,5]. GBS bh/c production has been clearly associated with increased virulence in intravenous challenge of mice and rabbits [6,7], but these experiments have bypassed the lung and, thereby, the natural route of neonatal infection.…”

“…Rabbit pups in their first day of life were infected intratracheally with an equivalent inoculum ( cfu/kg) of 7 3 ϫ 10 wt GBS ( ), the isogenic Dbh/c mutant ( ), or saline n p 23 n p 15 alone (control, ). Within 6 h of injection, several rabbits n p 4 infected with wt GBS showed tachypnea and labored breathing, clinical findings that were absent in the Dbh/c mutant-infected rabbits and controls.…”

Role of Pore-Forming Toxins in Neonatal Sepsis

“…Interestingly, Rubens and colleagues initially proposed that β -hemolysin/cytolysin was no longer needed for systemic disease manifestation once the epithelial barriers have been breached [44]. However, pro- and anti-inflammatory activity of β -hemolysin/cytolysin in macrophages was demonstrated, indicating more profound immunomodulatory functions of the cytolysin [45, 46]. One direct or indirect molecular β -hemolysin/cytolysin target with important implications for mononuclear phagocyte activation is the NLPRP3 inflammasome.…”