title: The Human Antimicrobial Protein Calgranulin C Participates in Control of Helicobacter pylori Growth and Regulation of Virulence.
abstract: During infectious processes, antimicrobial proteins are produced by both epithelial cells and innate immune cells. Some of these antimicrobial molecules function by targeting transition metals and sequestering these metals in a process referred to as "nutritional immunity." This chelation strategy ultimately starves invading pathogens, limiting their growth within the vertebrate host. Recent evidence suggests that these metal-binding antimicrobial molecules have the capacity to affect bacterial virulence, including toxin secretion systems. Our previous work showed that the S100A8/S100A9 heterodimer (calprotectin, or calgranulin A/B) binds zinc and represses the elaboration of the H. pylori cag type IV secretion system (T4SS). However, there are several other S100 proteins that are produced in response to infection. We hypothesized that the zinc-binding protein S100A12 (calgranulin C) is induced in response to H. pylori infection and also plays a role in controlling H. pylori growth and virulence. To test this, we analyzed gastric biopsy specimens from H. pylori-positive and -negative patients for S100A12 expression. These assays showed that S100A12 is induced in response to H. pylori infection and inhibits bacterial growth and viability in vitro by binding nutrient zinc. Furthermore, the data establish that the zinc-binding activity of the S100A12 protein represses the activity of the cag T4SS, as evidenced by the gastric cell "hummingbird" phenotype, interleukin 8 (IL-8) secretion, and CagA translocation assays. In addition, high-resolution field emission gun scanning electron microscopy (FEG-SEM) was used to demonstrate that S100A12 represses biogenesis of the cag T4SS. Together with our previous work, these data reveal that multiple S100 proteins can repress the elaboration of an oncogenic bacterial surface organelle.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Haley
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Alberto G
authors.initials: AG
authors.lastname: Delgado
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Mortensen
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
authors.affiliation: Departments of Biochemistry and Chemistry, Vanderbilt University, Nashville, Tennessee, USA Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA Department of Life and Physical Sciences, Fisk University, Nashville, Tennessee, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Damo
authors.affiliation: Departments of Biochemistry and Chemistry, Vanderbilt University, Nashville, Tennessee, USA Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.affiliation: Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, USA Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.affiliation: Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, USA Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA jennifer.a.gaddy@vanderbilt.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Gaddy
mesh_terms: D000328:Adult; D001706:Biopsy; D005753:Gastric Mucosa / Q000473:pathology; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D016480:Helicobacter pylori / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D050296:Microbial Viability; D008855:Microscopy, Electron, Scanning; D009418:S100 Proteins / Q000378:metabolism*; D000067616:S100A12 Protein; D014774:Virulence; D015032:Zinc / Q000378:metabolism
chemical_list: D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D015032:Zinc