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Zusammenfassung:
Bartonella henselae is a facultative intracellular bacterium and the causative agent of bacillary angiomatosis, a vascular-proliferative disease characterized by the tumorous growth of capillary sized vessels in immune suppressed patients. In recent years there has been a growing interest in the contribution of myeloid cells to cancer progression through microenvironmental control of tumor invasion and angiogenesis. In particular, a pro-angiogenic subset of circulating progenitor cells (Myeloid Angiogenic Cells; MACs) have been implicated as important accessory cells in both regenerative and pathological angiogenic conditions. To date, however, knowledge about how B. henselae interacts with myeloid cells and how they might contribute to B. henselae related pathological angiogenesis is still limited. Our investigations revealed that MACs are readily infected with B. henselae and that infection inhibits apoptosis, increases migratory capacity and activates the hypoxia inducible factor 1 (HIF-1) dependent pro-angiogenic program. Infected MACs developed a vascular mimicry phenotype over long term culture and in a 3D spheroid assay of sprouting angiogenesis they incorporated into growing endothelium and increased the rate of sprouting angiogenesis in a paracrine manner. Phenotypic analysis of infected cells (FACS, gene microarray) revealed that this increase in angiogenic activity was associated with the development of a distinct macrophage phenotype including upregulation of angiogenic and matrix remodeling genetic programs and a predominantly M2 anti-inflammatory activation profile. Finally, analysis of cytokine secretion profiles from infected cells revealed that B. henselae infected MACs release a diverse array of inflammatory-angiogenic cytokines and matrix remodeling compounds creating a tumor-like paracrine microenvironment with a high potential to promote pathological tissue growth. These results provide new nsights into the interaction of B. henselae with myeloid cells and highlight their role as paracrine mediators of B. henselae induced vascular tumor formation. Furthermore, these findings establish a connection between the manipulation of myeloid cell responses by intracellular bacteria and the creation of stimulatory microenvironments that promote pathological tissue growth in conditions such as cancer.
