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The Bartonella autotransporter BafA activates the host VEGF pathway to drive angiogenesis.

ABSTRACT: Pathogenic bacteria of the genus Bartonella can induce vasoproliferative lesions during infection. The underlying mechanisms are unclear, but involve secretion of an unidentified mitogenic factor. Here, we use functional transposon-mutant screening in Bartonella henselae to identify such factor as a pro-angiogenic autotransporter, called BafA. The passenger domain of BafA induces cell proliferation, tube formation and sprouting of microvessels, and drives angiogenesis in mice. BafA interacts with vascular endothelial growth factor (VEGF) receptor-2 and activates the downstream signaling pathway, suggesting that BafA functions as a VEGF analog. A BafA homolog from a related pathogen, Bartonella quintana, is also functional. Our work unveils the mechanistic basis of vasoproliferative lesions observed in bartonellosis, and we propose BafA as a key pathogenic factor contributing to bacterial spread and host adaptation.

SUBMITTER: Tsukamoto K

PROVIDER: S-EPMC7366657 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The Bartonella autotransporter BafA activates the host VEGF pathway to drive angiogenesis.

Tsukamoto Kentaro K Shinzawa Naoaki N Kawai Akito A Suzuki Masahiro M Kidoya Hiroyasu H Takakura Nobuyuki N Yamaguchi Hisateru H Kameyama Toshiki T Inagaki Hidehito H Kurahashi Hiroki H Horiguchi Yasuhiko Y Doi Yohei Y

Nature communications 20200716 1

Pathogenic bacteria of the genus Bartonella can induce vasoproliferative lesions during infection. The underlying mechanisms are unclear, but involve secretion of an unidentified mitogenic factor. Here, we use functional transposon-mutant screening in Bartonella henselae to identify such factor as a pro-angiogenic autotransporter, called BafA. The passenger domain of BafA induces cell proliferation, tube formation and sprouting of microvessels, and drives angiogenesis in mice. BafA interacts wit ...[more]

PMID: 32678094

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Project description: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 B. bacilliformis facilitates vasoproliferation resulting in hemangioma in the skin in verruga peruana, the chronic phase of Carrion's disease. Here, we demonstrate that B. bacilliformis extracellularly secrets a passenger domain of the autotransporter BafA exhibiting proangiogenic activity. The B. bacilliformis-derived BafA passenger domain (BafABba) increased the number of human umbilical endothelial cells (HUVECs) and promoted tube-like morphogenesis. Neutralizing antibody against BafABba detected the BafA derivatives from the culture supernatant of B. bacilliformis and inhibited the infection-mediated hyperproliferation of HUVECs. Moreover, stimulation with BafABba 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 BafABba. In addition, surface plasmon resonance analysis confirmed that BafABba directly interacts with VEGFR2 with lower affinity than VEGF or Bartonella henselae-derived BafA. These findings indicate that BafABba 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 B. bacilliformis that directly stimulates endothelial cells provides an important insight into the pathophysiology of verruga peruana. IMPORTANCE Bartonella bacilliformis causes life-threatening bacteremia or dermal eruption known as Carrion's disease in South America. During infection, B. bacilliformis promotes endothelial cell proliferation and the angiogenic process, but the underlying molecular mechanism has not been well understood. We show that B. bacilliformis 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 B. bacilliformis in addition to B. henselae and B. quintana, the causes of cat scratch disease and trench fever, raises the possibility that BafA is a common virulence factor for human-pathogenic Bartonella.

Project description:Bartonella henselae, a Gram-negative facultative intracellular bacterium, is the etiological agent of cat-scratch disease and also causes bacillary angiomatosis in immunocompromised individuals. Although the ability to promote vascular endothelial cell proliferation differs among Bartonella species, variations among strains within B. henselae remain unclear. Bartonella angiogenic factor A (BafA) and Bartonella adhesin A (BadA) have been identified as autotransporters of B. henselae that are involved in endothelial cell proliferation. Although strain-specific differences in the expression of BadA and the VirB/D4 type IV secretion system have been reported, BafA expression among B. henselae strains has yet to be examined. Therefore, the present study investigated the proliferation-promoting ability of 13 B. henselae strains from several sources in human umbilical vein endothelial cells (HUVECs). We identified BafA variants 1 and 2 based on the deduced amino acid sequences of its passenger domain. The recombinant proteins of both variants exhibited similar proliferation activity against HUVECs. However, BafA variant 2 strains showed cytotoxicity at a high bacterial inoculum in a direct coculture with HUVECs, which was attenuated in an indirect coculture. These strains, in contrast to BafA variant 1 strains, highly expressed BadA and exhibited bacterial aggregation. Based on a core genome SNP analysis of 50 B. henselae strains, the BafA variant types corresponded to clades 1-4. These results indicate that vasoproliferative traits differ among B. henselae clades based on the variant types. Therefore, this study provides a new conceptual framework in which the clades of B. henselae may predict their pathogenicity in humans.IMPORTANCEBartonella species including Bartonella henselae, Bartonella quintana, and Bartonella bacilliformis cause vasoproliferative lesions. Their proliferation-promoting ability in vascular endothelial cells differs among Bartonella species; however, it is unclear whether these differences exist among B. henselae strains. We herein showed that B. henselae strains exhibited variable proliferation-promoting ability and cytotoxicity in vascular endothelial cells, which corresponded to the bafA gene variants possessed by the strains. The expression levels of Bartonella angiogenic factor A (BafA) and Bartonella adhesin A, as well as the degree of proliferation-promoting ability and cytotoxicity in endothelial cells, varied among the strains. A core genome SNP analysis of strains using whole genome sequencing data divided B. henselae strains into four clades, with each clade corresponding to BafA variants 1-4. These results suggest the differential vasoproliferative potency of B. henselae, with potential implications in clinical management, including risk stratification and predictions of the clinical course.

Project description:Background: Rheumatoid arthritis (RA) is a chronic disabling inflammatory disease that causes synovial angiogenesis in an invasive manner and leads to joint destruction. Currently available pharmacotherapy for RA has unwanted side effects and limitations. Although anti-angiogenic therapy is regarded as a new potential treatment for RA, only a few anti-angiogenic drugs are available. An increasing number of studies have shown that β-sitosterol (BSS) may exert inhibitory effects against angiogenesis. However, the mechanisms involved are still unclear. Methods: Based on the results of the gene set enrichment analysis (GSEA) of the transcriptome data of endothelial cells from RA patients, we evaluated the pharmacological effects of BSS on the tube formation, cell proliferation, and migration of human umbilical vein endothelial cells (HUVECs). Furthermore, the effects of BSS treatment on vascular endothelial growth factor receptor 2 (VEGFR2) were determined using molecular docking and Western blotting. Additionally, in the presence or absence of BSS, synovial angiogenesis and joint destruction of the ankle were investigated in collagen-induced arthritis (CIA) mice. The effect of BSS treatment on VEGFR2/p-VEGFR2 expression was verified through immunohistochemical staining. Results: The immunohistochemistry results revealed that BSS treatment inhibited angiogenesis both in vitro and in vivo. In addition, the results of 5-ethynyl-2'-deoxyuridine and cell cycle analysis showed that BSS treatment suppressed the proliferation of HUVECs, while the Transwell migration and stress fiber assays demonstrated that BSS treatment inhibited the migration of HUVECs. Notably, the inhibitory effect of BSS treatment on VEGFR2/p-VEGFR2 was similar to that of axitinib. In CIA mice, BSS also exerted therapeutic effects on the ankles by reducing the degree of swelling, ameliorating bone and cartilage damage, preventing synovial angiogenesis, and inhibiting VEGFR2 and p-VEGFR2 expression. Conclusion: Therefore, our findings demonstrate that BSS exerts an inhibitory effect on synovial angiogenesis by suppressing the proliferation and migration of endothelial cells, thereby alleviating joint swelling and bone destruction in CIA mice. Furthermore, the underlying therapeutic mechanisms may involve the inhibition of VEGF signaling pathway activation.

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The Bartonella autotransporter BafA activates the host VEGF pathway to drive angiogenesis.

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The Bartonella autotransporter BafA activates the host VEGF pathway to drive angiogenesis.

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