Interactions of Aspergillus fumigatus with endothelial cells: internalization, injury, and stimulation of tissue factor activity

Abstract

Invasive aspergillosis causes significant mortality among patients with hematologic malignancies. This infection is characterized by vascular invasion and thrombosis. To study the pathogenesis of invasive aspergillosis, we investigated the interactions of Aspergillus fumigatus conidia and hyphae with endothelial cells in vitro. We found that both forms of the organism induced endothelial cell microfilament rearrangement and subsequent endocytosis. Conidia were endocytosed 2-fold more avidly than hyphae, and endocytosis was independent of fungal viability. Endocytosed conidia and hyphae caused progressive endothelial cell injury after 4 hours of infection. Live conidia induced more endothelial cell injury than did live hyphae. However, endothelial cell injury caused by conidia was dependent on fungal viability, whereas injury caused by hyphae was not, indicating that conidia and hyphae injure endothelial cells by different mechanisms. Neither live nor killed conidia increased tissue factor activity of endothelial cells. In contrast, both live and killed hyphae stimulated significant endothelial cell tissue factor activity, as well as the expression of tissue factor antigen on the endothelial cell surface. These results suggest that angioinvasion and thrombosis caused by A fumigatus hyphae in vivo may be due in part to endothelial cell invasion, induction of injury, and stimulation of tissue factor activity. ( IntroductionInvasive aspergillosis has become one of the leading causes of death among bone marrow transplantation and leukemia patients. Even with current therapy, the mortality rate of invasive aspergillosis is 80% to 90% in immunocompromised patients. 1 Aspergillus fumigatus is responsible for 90% of invasive Aspergillus infections. 1 This ubiquitous mould releases numerous conidia into the atmosphere, which are small enough (2 to 3 m in diameter) to reach the pulmonary alveoli after they are inhaled. 2 Once the conidia reach the alveoli, they swell and germinate, producing hyphae that invade the pulmonary parenchyma. These hyphae have a marked tropism for blood vessels. A key finding in invasive aspergillosis is angioinvasion, which subsequently leads to thrombosis and tissue infarction. [3][4][5] In immunocompromised hosts, invasion of the pulmonary vasculature can result in widespread hematogenous dissemination to organs such the brain, kidneys, heart, and eyes. 1,3 During angioinvasion, A fumigatus hyphae interact with vascular endothelium. We hypothesize that this interaction plays an important role in the pathogenesis of invasive aspergillosis. Once the hyphae have entered the bloodstream, they must adhere to and penetrate the endothelial cell lining of the blood vessels to invade the deep tissues of the target organs.In addition, the prominent thrombosis at sites of A fumigatus angioinvasion suggests that the organism stimulates endothelial cells to become prothrombotic. A major mechanism by which endothelial cells can promote intravascular thrombus formation is by expressing tissue factor, also k...

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