title: The B subunit of an AB5 toxin produced by Salmonella enterica serovar Typhi up-regulates chemokines, cytokines, and adhesion molecules in human macrophage, colonic epithelial, and brain microvascular endothelial cell lines.
abstract: The principal function of bacterial AB5 toxin B subunits is to interact with glycan receptors on the surfaces of target cells and mediate the internalization of holotoxin. However, B subunit-receptor interactions also have the potential to impact cell signaling pathways and, in so doing, contribute to pathogenesis independently of the catalytic (toxic) A subunits. Various Salmonella enterica serovars, including Salmonella enterica serovar Typhi, encode an AB5 toxin (ArtAB), the A subunit of which is an ADP-ribosyltransferase related to the S1 subunit of pertussis toxin. However, although the A subunit is able to catalyze ADP-ribosylation of host G proteins, a cytotoxic phenotype has yet to be identified for the holotoxin. We therefore examined the capacity of the purified B subunit (ArtB) from S. Typhi to elicit cytokine, chemokine, and adhesion molecule responses in human macrophage (U937), colonic epithelial (HCT-8) cell, and brain microvascular endothelial cell (HBMEC) lines. Secretion of the chemokines monocyte chemotactic protein 1 (MCP-1) and interleukin 8 (IL-8) was increased in all three tested cell lines, with macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and granulocyte colony-stimulating factor (G-CSF) also significantly increased in U937 cells. ArtB also upregulated the cytokines tumor necrosis factor alpha (TNF-α) and IL-6 in HBMECs and HCT-8 cells, but not in U937 cells, while intercellular adhesion molecule 1 (ICAM-1) was upregulated in HCT-8 and U937 cells and vascular cell adhesion molecule 1 (VCAM-1) was upregulated in HBMECs. Thus, ArtB may contribute to pathogenesis independently of the A subunit by promoting and maintaining a strong inflammatory response at the site of infection.
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Brock P
authors.initials: BP
authors.lastname: Herdman
authors.forename: Trisha J
authors.initials: TJ
authors.lastname: Rogers
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
mesh_terms: D001427:Bacterial Toxins / Q000737:chemistry / Q000633:toxicity*; D001921:Brain / Q000098:blood supply; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012485:Salmonella typhi / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D016207:Cytokines; D021122:Protein Subunits