Pyocyanin Production byPseudomonas aeruginosaInduces Neutrophil Apoptosis and Impairs Neutrophil-Mediated Host Defenses In Vivo

Abstract

Clearance of neutrophils from inflamed sites is critical for resolution of inflammation, but pathogen-driven neutrophil apoptosis can impair host defenses. We previously showed that pyocyanin, a phenazine toxic metabolite produced by Pseudomonas aeruginosa, accelerates neutrophil apoptosis in vitro. We compared wild-type and pyocyanin-deficient strains of P. aeruginosa in a murine model of acute pneumonia. Intratracheal instillation of either strain of P. aeruginosa caused a rapid increase in bronchoalveolar lavage neutrophil counts up to 18 h after infection. In wild-type infection, neutrophil numbers then declined steadily, whereas neutrophil numbers increased up to 48 h in mice infected with pyocyanin-deficient P. aeruginosa. In keeping with these differences, pyocyanin production was associated with reduced bacterial clearance from the lungs. Neutrophil apoptosis was increased in mice infected with wild-type compared with the phenazine-deficient strain or two further strains that lack pyocyanin production, but produce other phenazines. Concentrations of potent neutrophil chemokines (MIP-2, KC) and cytokines (IL-6, IL-1β) were significantly lower in wild-type compared with phenazine-deficient strain-infected mice at 18 h. We conclude that pyocyanin production by P. aeruginosa suppresses the acute inflammatory response by pathogen-driven acceleration of neutrophil apoptosis and by reducing local inflammation, and that this is advantageous for bacterial survival.

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

“…As expected, very few neutrophils were detected in the lungs of unchallenged mice. Similar to previously published data from other laboratories using the same model, [16][17][18][19] the number of neutrophils in the WT BALF reached nearly 10 6 cells/lung 8 hours after bacteria instillation and nearly 2 ϫ 10 6 cells/lung 24 hours after bacteria instillation. Myeloid-specific PTEN Ϫ/Ϫ mice showed a dramatic increase in bacteria-induced neutrophil recruitment.…”

Evaluation of the effect of α-defensin human neutrophil peptides on neutrophil apoptosis

“…The inappropriate or premature apoptosis of neutrophils could deplete cell numbers and functions, impairing host defense and favoring bacterial persistence in infections. In this context, it has been reported that neutrophil apoptosis is accelerated and neutrophil-mediated host defense is impaired in vivo during infection with Pseudomonas aeruginosa by the action of pyocyanin, a predominant phenazine exotoxin (14). Considering their anti-apoptotic action, antimicrobial peptides (LL-37, hBD-3 and HNP-1) exert an advantageous effect on host defense against bacterial infections by prolonging the lifespan of neutrophils, major phagocytes engaged in the killing of invading bacteria.…”

“…However, the prolonged survival of activated neutrophils in patients with the above disorders, can cause the uncontrolled release of cytotoxic metabolites and pro-inflammatory substances (i.e., reactive oxygen species and proteases), which leads to the amplification of systemic inflammation, tissue injury and organ failure (9,10). In contrast, neutrophil apoptosis can be accelerated by the Fas ligand, reactive oxygen species, immune complexes and bacterial toxins (such as Pseudomonas aeruginosa exotoxin, pyocyanin) produced at the sites of inflammation and infection (11)(12)(13)(14). The inappropriate induction of neutrophil apoptosis likely depletes neutrophil numbers and functions, thereby impairing host defense and favoring bacterial invasion and persistence.…”

Virulence profiles of clinical and environmental Pseudomonas aeruginosa isolates from Central Morocco

“…Pyocyanin, a representative pigment produced by P. aeruginosa, targets multiple cellular functions and contributes to acute as well as chronic infections, as it has several effects such as stimulating IL-8 release (Look et al, 2005), depressing host-response and inducing apoptosis in neutrophils (Allen et al, 2005). Pyoverdin is also a virulence marker in this pathogen, it was found that pyoverdin regulates its own secretion and the secretion of other P. aeruginosa virulence factors, such as exotoxin A (Lamont et al, 2002).…”