Increased susceptibility to lethal Candida infections in burned mice preinfected with Pseudomonas aeruginosa or pretreated with proteolytic enzymes

Abstract

Lethal Candida infections in burn patients are frequently preceded by or occur concomitantly with bacterial infections, which are often due to Pseudomonas aeruginosa. In this study, we developed a burned, mixed-challenge mouse model, which was designed to determine whether and how a recent bacterial infection could influence the development of subsequent candidosis. In this model, burned mice that were preinfected with a sublethal challenge of elastase-producing P. aeruginosa strain WR-5 and then sublethally challenged with Candida albicans exhibited a mortality rate of 60%, while unburned mice challenged in the same way and burned mice that received only one challenge organism exhibited mortality rates of less than 10%. Quantitative microbial counts performed with the kidneys, livers, and eschars of burned mice challenged with both organisms indicated that the deaths were due to Candida infection. Substitution of an elastase-negative P. aeruginosa strain for strain WR-5 in the model resulted in significantly lower mortality rates and lower microbial numbers in the organs. When the Pseudomonas enzyme elastase was substituted for the elastase-positive bacteria in the model, both the mortality rates and the organ counts were comparable to the values found after preinfection with strain WR-5. Another protease, thermolysin, was substituted for the elastase and produced similar mortality results. When the protease inhibitor alpha 2-macroglobulin was given to burned mice infected with the two organisms, it prevented the deaths due to Candida infection. We concluded that this model is one way to study bacterial-fungal infections in burned mice, that recent Pseudomonas infections could predispose burned mice to fatal candidosis, and that the proteolytic activity generated by the bacteria was primarily responsible for the establishment of lethal fungal infections.