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

Abstract

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.

Macrophages inhibit Aspergillus fumigatus germination and neutrophil-mediated fungal killing

“…These macrophage-driven phagocyte clusters have never been observed before in an animal model of Aspergillus infection, but phagocyte clustering is a common phenomenon in infections, with the mycobacteria granuloma as the classic example [ 43 ]. We do find some neutrophils infiltrating into these clusters and neutrophil aggregates have been reported in response to both to Aspergillus [ 12 ] and Candida [ 44 ]. Zebrafish larvae have been an ideal model in which to detect phagocyte clusters, and they have been found in response to not just mycobacteria [ 45 ], but also Streptococcus iniaie [ 46 ] and Mucor circinelloides [ 47 ].…”

Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence

“…As the first line of defense, a high number of polymorphonuclear leukocytes (PMNs) infiltrate the tissue. PMN extravasation coupled with the proliferation of other immune cells and the activation of oxygen-consuming enzymes fuel the creation of environments with decreasing oxygen levels ( 16 ).…”

T-cell-specific mTOR deletion in mice ameliorated CD4+ T-cell survival in lethal sepsis induced by severe invasive candidiasis

“…Therefore, we chose a high concentration of 10 6 cfu to produce lethal Candida sepsis and collected relevant data 12 h after challenge. In addition, we use the Murine Sepsis Score (MSS) [30], which is a validated, reliable and independent scoring system for sepsis severity evaluation to further verify our model success [26]. As we expected, after infection, the mice showed typical disease symptoms, like ruffled coat caused by reduced grooming, increased/decreased movement, abnormal posture (hunched back), and trembling.…”

“…We constructed a mouse model of rapidly progressive lethal sepsis induced by C. albicans bloodstream infection to mimic the clinical characteristics of C. albicans septic shock. To this end, we upgraded the candida intravenous challenge model [25,26], which is one of the recognized models that can mimic clinical candidemia. The severity of this model is directly related to the variety and sex of the mice used, as well as the variety and dose of the strains of Candida used in the challenge [27,28].…”