Passive protection by antitoxin in experimental Pseudomonas aeruginosa burn infections

Abstract

The protective effect of intravenously administred rabbit antitoxin serum was studied in lethal Pseudomonas aeruginosa bum infections in mice. Survival after infection with 2 median lethal doses of a toxigenic, low-protease-producing strain (PA103) was enhanced in antitoxin-treated mice, as compared with controls that had received anti-bovine serum albumin serum (P = 0.0004). Survival time was prolonged in other antitoxin-treated mice infected with toxigenic, highprotease-producing strains (PA86 and PA220, P = 0.0003 and P = 0.01, respectively). In contrast, antitoxin had no protective effect in mice challenged with a nontoxigenic strain (WR 5, P = 0.57). There were fewer viable bacteria in blood and liver of antitoxin-treated mice than in those of anti-bovine serum albumintreated controls after infection with toxigenic organisms, whereas there were no significant differences between the two groups after challenge with the nontoxigenic strain. These data suggest that P. aeruginosa exotoxin A contributes to lethality in this burn infection model, and this effect is diminished by passive immunization with antitoxin.

Analysis of immunization with DNA encoding Pseudomonas aeruginosa exotoxin A

“…Speci¢cally, the current model of native PE processing in non-lymphoid cells speci¢es entry by receptor-mediated endocytosis via the K-2-macroglobulin/low density lipoprotein receptor [12], cleavage at the Arg 279 -Gly 280 bond by a furin-like protease within the endosome, resulting in a 28-kDa N-terminal fragment and a C-terminal enzymatically active 37-kDa fragment which translocates to the cytosol [13,14] and ultimately causes cell death. PE has been well-studied as a virulence factor associated with the morbidity due to Pseudomonas infections [15,16]. Previous studies have reported a correlation between anti-PE titers and survival in cases of Pseudomonas infection [17].…”

Generation and characterization of murine antiflagellum monoclonal antibodies that are protective against lethal challenge with Pseudomonas aeruginosa

“…In particular, immunotherapeutic strategies focusing on the abrogation of one or more virulence factors associated with the pathogenesis of P. aeruginosa have been studied in animal models and have been investigated in human clinical trials as well (24). While active or passive immunization targeting extracellular products, e.g., elastase, protease, and exotoxin A, has had limited success in prevention and treatment of P. aeruginosa infections in animal models (10,39,40), similar therapies to stimulate or augment an antilipopolysaccharide (anti-LPS) immune response have been more effective (10,11,42,46). A significant drawback to anti-LPS immunotherapy, however, is the necessity to develop a multicomponent vaccine, immunoglobulin preparation, or monoclonal antibody (MAb) cocktail to provide protection against P. aeruginosa strains that characteristically express any one of at least 17 different serotypes of LPS (34).…”

Locus of the Pseudomonas aeruginosa toxin A gene

“…Suitably activated preparations of toxin A catalyze the transfer of the ADPribosyl moiety of NAD+ onto eucaryotic elongation factor 2, thereby inhibiting protein synthesis (15,31). Toxin A is associated with virulence of P. aeruginosa in some animal models (17,18,20,21,35) and in some human infections (4,22). Our laboratory has recently characterized a mutant strain, PAO-PR1, of P. aeruginosa PAO which produces an altered form of toxin A (5).…”