Human vascular endothelial cells express epithelial growth factor in response to infection by Bartonella bacilliformis

• Published in: PLoS neglected tropical diseases 2020-04, Vol.14 (4), p.e0008236-e0008236
• Main Authors: Hicks, Linda D, Minnick, Michael F
• Format: Article
• Language: English
• Subjects: Anemia; Angiogenesis; Apoptosis; Bacteria; Bartonella bacilliformis; Bartonella bacilliformis - growth & development; Bartonella Infections - pathology; Bartonellosis; Biology and Life Sciences; Capillary tubes; Cell culture; Cell growth; Cell migration; Cell Proliferation; Cells; Deoxyribonucleic acid; Development and progression; DNA; ELISA; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - microbiology; Endothelial Cells - pathology; Enzyme-linked immunosorbent assay; Epidermal growth factor; Epidermal Growth Factor - metabolism; Epidermal growth factor receptors; Fibroblast growth factor 2; Gram-negative bacteria; Growth factors; Health aspects; Hicks, Michael; Host-Pathogen Interactions; Human Umbilical Vein Endothelial Cells; Humans; Infections; Lysates; Mammals; Medicine and Health Sciences; Microbiological strains; Models, Biological; Mutagenesis; Pathogens; Physiological aspects; Proteins; Receptors; Recombinants; Secretion; Skin; Strains; Strains (organisms); Tropical climate; Tropical diseases; Umbilical vein; Vascular endothelial growth factor; Virulence; Warts
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0008236

Bartonella are Gram-negative bacterial pathogens that trigger pathological angiogenesis during infection of humans. Bartonella bacilliformis (Bb) is a neglected tropical agent endemic to South America, where it causes Carrión's disease. Little is known about Bb's virulence determinants or how the pathogen elicits hyperproliferation of the vasculature, culminating in Peruvian warts (verruga peruana) of the skin. In this study, we determined that active infection of human umbilical vein endothelial cells (HUVECs) by live Bb induced host cell secretion of epidermal growth factor (EGF) using ELISA. Killed bacteria or lysates of various Bb strains did not cause EGF production, suggesting that an active infection was necessary for the response. Bb also caused hyperproliferation of infected HUVECs, and the mitogenic response could be inhibited by the EGF-receptor (EGFR) inhibitor, AG1478. Bb strains engineered to overexpress recombinant GroEL, evoked greater EGF production and hyperproliferation of HUVECs compared to control strains. Conditioned (spent) media from cultured HUVECs that had been previously infected by Bb were found to be mitogenic for naïve HUVECs, and the response could be inhibited by EGFR blocking with AG1478. Bb cells and cell lysates stimulated HUVEC migration and capillary-like tube formation in transmigration and Matrigel assays, respectively. To our knowledge, this is the first demonstration of EGF production by Bb-infected endothelial cells; an association that could contribute to hyperproliferation of the vascular bed during bartonellosis.