Department of Microbiology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
Department of Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
mSphere. 2022 Apr 27;7(2):e0008122. doi: 10.1128/msphere.00081-22. Epub 2022 Apr 5.
Bartonella bacilliformis is a Gram-negative bacterial pathogen that provokes pathological angiogenesis and causes Carrion's disease, a neglected tropical disease restricted to South America. Little is known about how facilitates vasoproliferation resulting in hemangioma in the skin in verruga peruana, the chronic phase of Carrion's disease. Here, we demonstrate that extracellularly secrets a passenger domain of the autotransporter BafA exhibiting proangiogenic activity. The -derived BafA passenger domain (BafA) increased the number of human umbilical endothelial cells (HUVECs) and promoted tube-like morphogenesis. Neutralizing antibody against BafA detected the BafA derivatives from the culture supernatant of and inhibited the infection-mediated hyperproliferation of HUVECs. Moreover, stimulation with BafA promoted phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and extracellular-signal-regulated kinase 1/2 in HUVECs. Suppression of VEGFR2 by anti-VEGFR2 antibody or RNA interference reduced the sensitivity of cells to BafA. In addition, surface plasmon resonance analysis confirmed that BafA directly interacts with VEGFR2 with lower affinity than VEGF or Bartonella henselae-derived BafA. These findings indicate that BafA acts as a VEGFR2 agonist analogous to the previously identified B. henselae- and Bartonella quintana-derived BafA proteins despite the low sequence similarity. The identification of a proangiogenic factor produced by that directly stimulates endothelial cells provides an important insight into the pathophysiology of verruga peruana. Bartonella bacilliformis causes life-threatening bacteremia or dermal eruption known as Carrion's disease in South America. During infection, promotes endothelial cell proliferation and the angiogenic process, but the underlying molecular mechanism has not been well understood. We show that induces vasoproliferation and angiogenesis by producing the proangiogenic autotransporter BafA. As the cellular/molecular basis for angiogenesis, BafA stimulates the signaling pathway of vascular endothelial growth factor receptor 2 (VEGFR2). Identification of functional BafA protein from in addition to B. henselae and , the causes of cat scratch disease and trench fever, raises the possibility that BafA is a common virulence factor for human-pathogenic .
贝纳柯克斯体是一种革兰氏阴性细菌病原体，可引发病理性血管生成，并导致卡里翁病，这是一种局限于南美洲的被忽视的热带病。人们对贝纳柯克斯体如何促进秘鲁疣（卡里翁病的慢性期）中皮肤血管增生，导致血管内皮瘤的机制知之甚少。在这里，我们证明 细胞外分泌具有促血管生成活性的自转运蛋白 BafA 的过客结构域。源自 的 BafA 过客结构域（BafA）增加了人脐静脉内皮细胞（HUVEC）的数量，并促进了管状形态发生。针对 BafA 的中和抗体检测到 培养上清液中的 BafA 衍生物，并抑制了感染介导的 HUVEC 过度增殖。此外，BafA 刺激促进了 HUVEC 中血管内皮生长因子受体 2（VEGFR2）和细胞外信号调节激酶 1/2 的磷酸化。用抗 VEGFR2 抗体或 RNA 干扰抑制 VEGFR2 可降低细胞对 BafA 的敏感性。此外，表面等离子体共振分析证实 BafA 与 VEGFR2 的直接相互作用亲和力低于 VEGF 或贝纳柯克斯体衍生的 BafA。这些发现表明，尽管序列相似性较低，但 BafA 作为一种 VEGFR2 激动剂，类似于先前鉴定的贝纳柯克斯体和 Bartonella quintana 衍生的 BafA 蛋白。鉴定出由 产生的直接刺激内皮细胞的促血管生成因子，为秘鲁疣的病理生理学提供了重要的见解。贝纳柯克斯体在南美洲引起危及生命的菌血症或皮肤疹，称为卡里翁病。在感染过程中， 促进内皮细胞增殖和血管生成过程，但潜在的分子机制尚未得到很好的理解。我们表明， 通过产生促血管生成的自转运蛋白 BafA 诱导血管增生和血管生成。作为血管生成的细胞/分子基础，BafA 刺激血管内皮生长因子受体 2（VEGFR2）的信号通路。除了引起猫抓病和战壕热的原因——亨氏巴尔通体和 Bartonella quintana 之外，还从 中鉴定出功能性 BafA 蛋白，这增加了 BafA 是人类病原体的共同毒力因子的可能性。
