Therapeutic Administration of Anti-PcrV F(ab′)2 in Sepsis Associated with Pseudomonas aeruginosa

Abstract

The effects of rabbit-derived polyclonal Ab against PcrV, a protein involved in the translocation of type III secreted toxins of Pseudomonas aeruginosa, was investigated in two animal models of P. aeruginosa sepsis. In a mouse survival study, the i.v. administration of anti-PcrV IgG after the airspace instillation of a lethal dose of P. aeruginosa resulted in the complete survival of the animals. In a rabbit model of septic shock associated with Pseudomonas-induced lung injury, animals treated with anti-PcrV IgG intratracheally or i.v. had significant decreases in lung injury, bacteremia, and plasma TNF-α and significant improvement in the hemodynamic parameters associated with shock compared with animals treated in a similar manner with nonspecific control IgG. The administration of anti-PcrV F(ab′)2 showed protective effects comparable to those of whole anti-PcrV IgG. These results document that the therapeutic administration of anti-PcrV IgG blocks the type III secretion system-mediated virulence of P. aeruginosa and prevents septic shock and death, and that these protective effects are largely Fc independent. We conclude that Ab therapy neutralizing the type III secretion system has significant potential against lethal P. aeruginosa infections.

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

“…Most strains of P. aeruginosa secrete virulence factors by the type III secretion system [6,7]. The role of proteins secreted and translocated across eukaryotic cell plasma membranes by the type III secretion system has been highlighted both in vitro [8,9] and in animal models in recent years [10]. Neutralization of the type III secretion proteins have shown to prevent septic shock and an improved survival in a mouse model of P. aeruginosa infection [10].…”

“…The role of proteins secreted and translocated across eukaryotic cell plasma membranes by the type III secretion system has been highlighted both in vitro [8,9] and in animal models in recent years [10]. Neutralization of the type III secretion proteins have shown to prevent septic shock and an improved survival in a mouse model of P. aeruginosa infection [10]. In addition, type III secretion has been associated with more severe clinical disease in human studies [11].…”

Effect of anti-PcrV antibody in a murine chronic airway Pseudomonas aeruginosa infection model

“…Expression of PcrV in clinical isolates of P. aeruginosa is associated with morbidity and mortality in infected patients [12]. Previous studies have shown that anti-PcrV IgG protects animals from acute P. aeruginosa infection [7,8]. In these studies, anti-PcrV was given to animals at the same time, or soon after, inoculation.…”

“…The polyclonal rabbit-derived anti-PcrV Ab and pre-immune serum-derived control Ab used in the present study were prepared and stored at -80uC, as previously reported [8]. The mice were separated into three groups; each group received i.p.…”

“…In a previous study, it was shown that administration of anti-PcrV antibody (Ab) was able to block the translocation of P. aeruginosa type III-secreted toxins [7]. Anti-PcrV immunoglobulin (Ig)G also exerted therapeutic effects, reducing septic shock and mortality in an animal model of acute P. aeruginosa infection [7,8]. However, the efficacy of anti-PcrV IgG in chronic P. aeruginosa infection has not yet been clarified.…”