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

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. [Display omitted] •The PMN-rich lung vasculature is a site for host defense against C. albicans•Complement is essential for PMN-mediated host defense in the lung vasculature•Zymosan drives LTB4-mediated PMN capillaritis and vessel occlusion in the lung•Blocking LTB4 during C. albicans sepsis is a therapeutic option Fungal sepsis has a high mortality rate. Using live imaging, Lee, et al. discovered that the lung bloodstream is an important site of host defense; however, fungi caused extensive vessel occlusions due to leukotriene-meditated neutrophil capillaritis. Inhibiting occlusion improved lung function and outcomes, thus revealing a therapeutic target.