Neutrophil elastase causes tissue damage that decreases host tolerance to lung infection with burkholderia species.

Manoranjan Sahoo,Laura Del Barrio,Mark A Miller,Fabio Re,David Weiss

doi:10.1371/journal.ppat.1004327

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.

Highlights

The inflammatory response elicited by infection is highly effective against microbes, it is greatly pathogenic and, in extreme cases, the damage caused to host tissues becomes the main source of morbidity and mortality associated with the disease [1]
Confirming what we observed during infection with B. pseudomallei [6], production of IL-1b following infection with B. thailandensis was dependent on NLRP3, ASC, and caspase-1 while pyropotosis was dependent on NLRC4
The increased survival and lower bacterial burden observed in Il1-r12/2 mice correlated with reduced neutrophil influx in the alveolar spaces, reduced levels of myeloperoxidase and elastase in lung homogenates, and lower inflammation in the lung, suggesting that neutrophil recruitment to the lungs is as deleterious in this infection model as it is during B. pseudomallei infection [6]

Summary

Introduction

The inflammatory response elicited by infection is highly effective against microbes, it is greatly pathogenic and, in extreme cases, the damage caused to host tissues becomes the main source of morbidity and mortality associated with the disease [1]. The host can protect itself using mainly two distinct strategies: resistance or tolerance Tolerance does not directly affect pathogen burden, but rather it is a measure of the host’s ability to withstand the presence of the infectious agent by minimizing the negative impact it has on the host’s health. Much of what is known about the protective response to infection concerns resistance mechanisms and clearly falls in the realm of immunology. The phenomenon of tolerance to infection in animals has remained largely unexplored, and only recently has begun to attract the attention of immunologists and microbiologists

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Conclusion