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

Manoranjan Sahoo, Laura del Barrio, Mark Miller, Fabio Re

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1004327
JournalPLoS Pathogens
Volume10
Issue number8
DOIs
StatePublished - Aug 28 2014

Fingerprint

Burkholderia Infections
Leukocyte Elastase
Pancreatic Elastase
Burkholderia pseudomallei
Lung
Melioidosis
Infection
Bradykinin
Interleukin-1
Inflammasomes
Interleukin-18
Neutrophil Infiltration
Capillary Permeability
Gram-Negative Bacteria
Inbred C57BL Mouse
Bacterial Infections
Blood Vessels
Macrophages
Inflammation
Health

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Neutrophil Elastase Causes Tissue Damage That Decreases Host Tolerance to Lung Infection with Burkholderia Species. / Sahoo, Manoranjan; del Barrio, Laura; Miller, Mark; Re, Fabio.

In: PLoS Pathogens, Vol. 10, No. 8, e1004327, 28.08.2014.

Research output: Contribution to journalArticle

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