The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling Pathway
ABSTRACT 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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2022-04-01
|
| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/msphere.00081-22 |
| _version_ | 1817979223709581312 |
|---|---|
| author | Kentaro Tsukamoto Kayo Kumadaki Kaoru Tatematsu Natsumi Suzuki Yohei Doi |
| author_facet | Kentaro Tsukamoto Kayo Kumadaki Kaoru Tatematsu Natsumi Suzuki Yohei Doi |
| author_sort | Kentaro Tsukamoto |
| collection | DOAJ |
| description | ABSTRACT 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. |
| first_indexed | 2024-04-13T22:40:11Z |
| format | Article |
| id | doaj.art-a9cd29de7eee4522a96ff189e7690234 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-04-13T22:40:11Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-a9cd29de7eee4522a96ff189e76902342022-12-22T02:26:38ZengAmerican Society for MicrobiologymSphere2379-50422022-04-017210.1128/msphere.00081-22The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling PathwayKentaro Tsukamoto0Kayo Kumadaki1Kaoru Tatematsu2Natsumi Suzuki3Yohei Doi4Department of Microbiology, Fujita Health University School of Medicine, Toyoake, Aichi, JapanDepartment of Microbiology, Fujita Health University School of Medicine, Toyoake, Aichi, JapanDepartment of Microbiology, Fujita Health University School of Medicine, Toyoake, Aichi, JapanDepartment of Microbiology, Fujita Health University School of Medicine, Toyoake, Aichi, JapanDepartment of Microbiology, Fujita Health University School of Medicine, Toyoake, Aichi, JapanABSTRACT 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.https://journals.asm.org/doi/10.1128/msphere.00081-22Bartonellaautotransporterangiogenesisendothelial cellVEGF receptorBafA |
| spellingShingle | Kentaro Tsukamoto Kayo Kumadaki Kaoru Tatematsu Natsumi Suzuki Yohei Doi The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling Pathway mSphere Bartonella autotransporter angiogenesis endothelial cell VEGF receptor BafA |
| title | The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling Pathway |
| title_full | The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling Pathway |
| title_fullStr | The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling Pathway |
| title_full_unstemmed | The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling Pathway |
| title_short | The Passenger Domain of Bartonella bacilliformis BafA Promotes Endothelial Cell Angiogenesis via the VEGF Receptor Signaling Pathway |
| title_sort | passenger domain of bartonella bacilliformis bafa promotes endothelial cell angiogenesis via the vegf receptor signaling pathway |
| topic | Bartonella autotransporter angiogenesis endothelial cell VEGF receptor BafA |
| url | https://journals.asm.org/doi/10.1128/msphere.00081-22 |
| work_keys_str_mv | AT kentarotsukamoto thepassengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT kayokumadaki thepassengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT kaorutatematsu thepassengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT natsumisuzuki thepassengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT yoheidoi thepassengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT kentarotsukamoto passengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT kayokumadaki passengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT kaorutatematsu passengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT natsumisuzuki passengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway AT yoheidoi passengerdomainofbartonellabacilliformisbafapromotesendothelialcellangiogenesisviathevegfreceptorsignalingpathway |