title: Epithelial innate immune response to Acinetobacter baumannii challenge.
abstract: Currently, Acinetobacter baumannii is recognized as one of the major pathogens seriously threatening our health care delivery system. Aspects of the innate immune response to A. baumannii infection are not yet well understood. Human β-defensins (hBDs) are epithelial cell-derived cationic antimicrobial peptides (AMPs) that also function to bridge the innate and adaptive immune system. We tested the induction of hBD-2 and -3 by A. baumannii on primary oral and skin epithelial cells and found that A. baumannii induces hBD-3 transcripts to a greater extent than it induces hBD-2 transcripts on both types of cells. In addition, we found that A. baumannii is susceptible to hBD-2 and -3 killing at submicromolar concentrations. Moreover, hBD-3 induction by A. baumannii was found to be dependent on epidermal growth factor receptor (EGFR) signaling. Inhibition of mitogen-activated protein kinase resulted in reduced expression of both hBD-2 and -3. Lastly, a disintegrin and metalloprotease 17 (ADAM17; also known as TACE) was found to be critical for hBD-3 induction, while ADAM10 and dual oxidase 1 (Duox1) were not required for hBD-3 induction. Induction of AMPs is an important component of innate sensing of pathogens and may play an important role in triggering systemic immune responses to A. baumannii infection. Further studies on the interactions between epithelial cells and A. baumannii will help us understand early stages of infection and may shed light on why some individuals are more vulnerable to A. baumannii infection.
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Jia
authors.affiliation: J. Craig Venter Institute, San Diego, California, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Ghosh
authors.affiliation: Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA aaron.weinberg@case.edu.
authors.forename: Aaron
authors.initials: A
authors.lastname: Weinberg
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D040981:Acinetobacter baumannii / Q000502:physiology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D018920:Coculture Techniques; D004151:Dipeptides / Q000494:pharmacology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007113:Immunity, Innate / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D023083:beta-Defensins / Q000378:metabolism
chemical_list: C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; D004151:Dipeptides; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D023083:beta-Defensins; D066246:ErbB Receptors; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
references.citation: Curr Pharm Des. 2009;15(21):2377-92
references.pmid: 19601838
references.citation: Infect Immun. 2007 Dec;75(12):5597-608
references.pmid: 17908807
references.citation: N Engl J Med. 2002 Oct 10;347(15):1199-200
references.pmid: 12374882
references.citation: Microbes Infect. 2004 Dec;6(15):1382-7
references.pmid: 15596124
references.citation: Curr Opin Infect Dis. 2005 Dec;18(6):502-6
references.pmid: 16258323
references.citation: PLoS One. 2010 Apr 07;5(4):e10033
references.pmid: 20383325
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):767-72
references.pmid: 15640347
references.citation: Microbes Infect. 2009 Oct;11(12):946-55
references.pmid: 19573619
references.citation: Res Microbiol. 2006 May;157(4):360-6
references.pmid: 16326077
references.citation: Antimicrob Agents Chemother. 2006 Dec;50(12):4114-23
references.pmid: 17000742
references.citation: Genes Dev. 2007 Mar 1;21(5):601-14
references.pmid: 17344419
references.citation: Oral Microbiol Immunol. 2008 Apr;23(2):119-26
references.pmid: 18279179
references.citation: J Immunol. 2006 Jul 15;177(2):782-6
references.pmid: 16818731
references.citation: J Immunol. 2006 Dec 15;177(12):8693-700
references.pmid: 17142770
references.citation: J Clin Microbiol. 2007 Oct;45(10):3352-9
references.pmid: 17715376
references.citation: Exp Cell Res. 2003 Mar 10;284(1):2-13
references.pmid: 12648462
references.citation: FEMS Immunol Med Microbiol. 2008 Oct;54(1):45-52
references.pmid: 18625015
references.citation: Blood. 2003 Aug 15;102(4):1186-95
references.pmid: 12714508
references.citation: Eur J Oral Sci. 2002 Apr;110(2):121-4
references.pmid: 12013554
references.citation: Science. 1999 Oct 15;286(5439):525-8
references.pmid: 10521347
references.citation: J Immunol. 2003 Jun 1;170(11):5583-9
references.pmid: 12759437
references.citation: Infect Immun. 2014 Mar;82(3):1112-22
references.pmid: 24366254
references.citation: BMC Immunol. 2009 Jun 12;10:36
references.pmid: 19523197
references.citation: Am J Physiol Gastrointest Liver Physiol. 2011 Apr;300(4):G547-53
references.pmid: 21233274
references.citation: Clin Chem. 2007 Apr;53(4):757-65
references.pmid: 17317882
references.citation: AIDS. 2003 Nov 7;17(16):F39-48
references.pmid: 14571200
references.citation: J Invest Dermatol. 2002 Feb;118(2):275-81
references.pmid: 11841544
references.citation: J Cell Biol. 2004 Mar 1;164(5):769-79
references.pmid: 14993236
references.citation: J Immunol. 2002 Jan 1;168(1):316-24
references.pmid: 11751976
references.citation: Nat Rev Mol Cell Biol. 2005 Jan;6(1):32-43
references.pmid: 15688065
references.citation: Infect Immun. 2000 May;68(5):2907-15
references.pmid: 10768988
references.citation: Oral Microbiol Immunol. 2003 Dec;18(6):359-63
references.pmid: 14622341
references.citation: Int Immunol. 2005 Jan;17(1):1-14
references.pmid: 15585605
references.citation: J Bacteriol. 2008 Dec;190(24):8053-64
references.pmid: 18931120
references.citation: J Biol Chem. 2001 Feb 23;276(8):5707-13
references.pmid: 11085990
references.citation: Crit Rev Oral Biol Med. 1998;9(4):399-414
references.pmid: 9825219
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18631-5
references.pmid: 18006661
references.citation: Am J Hum Genet. 2003 Sep;73(3):591-600
references.pmid: 12916016
references.citation: J Dent Res. 2005 May;84(5):445-50
references.pmid: 15840781
references.citation: J Biol Chem. 2010 Nov 19;285(47):36523-31
references.pmid: 20847052
references.citation: J Biol Chem. 2006 Apr 28;281(17):11637-48
references.pmid: 16513653
references.citation: Nat Rev Immunol. 2003 Sep;3(9):710-20
references.pmid: 12949495