Neutrophil Elastase Causes Tissue Damage That Decreases Host Tolerance to Lung Infection with Burkholderia Species

Abstract

Two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and causes melioidosis. We have recently shown that inflammasome-triggered pyroptosis and IL-18 are equally important for resistance to B. pseudomallei, whereas IL-1β is deleterious. Here we show that the detrimental role of IL-1β during infection with B. pseudomallei (and closely related B. thailandensis) is due to excessive recruitment of neutrophils to the lung and consequent tissue damage. Mice deficient in the potentially damaging enzyme neutrophil elastase were less susceptible than the wild type C57BL/6J mice to infection, although the bacterial burdens in organs and the extent of inflammation were comparable between C57BL/6J and elastase-deficient mice. In contrast, lung tissue damage and vascular leakage were drastically reduced in elastase-deficient mice compared to controls. Bradykinin levels were higher in C57BL/6 than in elastase-deficient mice; administration of a bradykinin antagonist protected mice from infection, suggesting that increased vascular permeability mediated by bradykinin is one of the mechanisms through which elastase decreases host tolerance to melioidosis. Collectively, these results demonstrate that absence of neutrophil elastase increases host tolerance, rather than resistance, to infection by minimizing host tissue damage.

Author Summary

Two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. Burkholderia pseudomallei, the causative agent of melioidosis, is a Gram-negative intracellular bacteria that is categorized as a potential bioterrorism agent. Using murine models, we previously demonstrated that during B. pseudomallei infection, production of IL-1β is deleterious as it recruited excessive neutrophils to the site of infection. In the present work, we focused on the detrimental role of neutrophils during infection with B. pseudomallei and B. thailandensis. Here, we demonstrate that the excessive recruitment of neutrophils to the site of infection causes tissue damage because of release of the protease elastase. Mice lacking neutrophil elastase have increased survival even though they carry an equal amount of bacteria in their organs as compared to the wild-type C57BL/6J. Thus, neutrophil elastase is a host defense mechanism that causes tissue damage and reduces host tolerance to infection.