Leukotriene B4-Mediated Neutrophil Recruitment Causes Pulmonary Capillaritis during Lethal Fungal Sepsis

Cell Host Microbe. 2018 Jan 10;23(1):121-133.e4. doi: 10.1016/j.chom.2017.11.009. Epub 2017 Dec 28.


Candida albicans bloodstream infection causes fungal septicaemia and death in over half of afflicted patients. Polymorphonuclear leukocytes (PMN) mediate defense against invasive candidiasis, but their role in protection versus tissue injury and sepsis is unclear. We observe PMN intravascular swarming and subsequent clustering in response to C. albicans yeast in a lethal septic mouse and human pulmonary circulation model. Live C. albicans sequester to the endothelium and are immediately captured by complement-dependent PMN chemotaxis, which is required for host survival. However, complement activation also leads to Leukotriene B4 (LTB4)-mediated intravascular PMN clustering and occlusion, resulting in capillaritis with pulmonary hemorrhage and hypoxemia. This clustering is unique to fungi and triggered by fungal cell wall components. PMN clustering is absent in mice lacking LTB4-receptor, and capillaritis is attenuated upon pharmacological LTB4 blockade without affecting phagocytosis. Therefore, therapeutically disrupting infection-induced capillaritis may limit organ injury without impairing host defense during fungal sepsis.

Keywords: Candida albicans; capillaritis; fungal infection; host defense; innate immunity; leukotriene; neutrophils; pulmonary inflammation; sepsis; swarming.

MeSH terms

  • Animals
  • Arterial Occlusive Diseases / immunology
  • Arterial Occlusive Diseases / microbiology*
  • Candida albicans / immunology*
  • Candidiasis / immunology*
  • Candidiasis / microbiology
  • Candidiasis / pathology
  • Cells, Cultured
  • Female
  • Humans
  • Leukotriene B4 / immunology*
  • Lung / blood supply
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration / immunology*
  • Neutrophils / immunology*
  • Sepsis / immunology*
  • Sepsis / microbiology
  • Sepsis / pathology


  • Leukotriene B4

Supplementary concepts

  • Systemic candidiasis