title: Cholinergic stimulation of the immune system protects against lethal infection by Salmonella enterica serovar Typhimurium.
abstract: The cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival.
authors.affiliation: Department of Biochemistry, Faculty of Medicine & Health Sciences, UAE University, Al Ain, United Arab Emirates. mariac@uaeu.ac.ae
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Fernandez-Cabezudo
authors.forename: Dietrich E
authors.initials: DE
authors.lastname: Lorke
authors.forename: Sheikh
authors.initials: S
authors.lastname: Azimullah
authors.forename: Milena
authors.initials: M
authors.lastname: Mechkarska
authors.forename: Mohammed Y
authors.initials: MY
authors.lastname: Hasan
authors.forename: Georg A
authors.initials: GA
authors.lastname: Petroianu
authors.forename: Basel K
authors.initials: BK
authors.lastname: al-Ramadi
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D002452:Cell Count; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D058851:GPI-Linked Proteins; D007107:Immune System / Q000187:drug effects* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000382:microbiology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D010261:Paraoxon / Q000494:pharmacology / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000494:pharmacology; D012480:Salmonella Infections / Q000097:blood / Q000188:drug therapy / Q000382:microbiology* / Q000517:prevention & control*; D012486:Salmonella typhimurium / Q000472:pathogenicity; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects
chemical_list: C513728:4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D016207:Cytokines; D058851:GPI-Linked Proteins; D008070:Lipopolysaccharides; D010091:Oximes; D011726:Pyridinium Compounds; D003208:Concanavalin A; D009569:Nitric Oxide; D000110:Acetylcholinesterase; C548245:Ache protein, mouse; D010261:Paraoxon
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11008-13
references.pmid: 18669662
references.citation: J Immunol. 1995 May 15;154(10):5320-30
references.pmid: 7730635
references.citation: Toxicol Appl Pharmacol. 2007 Feb 1;218(3):215-26
references.pmid: 17196234
references.citation: J Exp Med. 2005 Apr 4;201(7):1113-23
references.pmid: 15809354
references.citation: Nature. 2003 Jan 23;421(6921):384-8
references.pmid: 12508119
references.citation: Life Sci. 2007 May 30;80(24-25):2314-9
references.pmid: 17383684
references.citation: Infect Immun. 2000 Jun;68(6):3344-8
references.pmid: 10816483
references.citation: Bioorg Med Chem Lett. 2003 Oct 20;13(20):3545-7
references.pmid: 14505667
references.citation: J Immunol. 2001 Nov 1;167(9):5304-15
references.pmid: 11673546
references.citation: Infect Immun. 1998 Oct;66(10):4767-76
references.pmid: 9746577
references.citation: Cell Mol Life Sci. 2004 Sep;61(18):2322-31
references.pmid: 15378203
references.citation: Clin Immunol. 2009 Jan;130(1):51-60
references.pmid: 18835224
references.citation: Infect Immun. 2001 Jun;69(6):3980-8
references.pmid: 11349067
references.citation: J Exp Med. 2006 Jul 10;203(7):1623-8
references.pmid: 16785311
references.citation: Nat Immunol. 2005 Aug;6(8):844-51
references.pmid: 16025117
references.citation: Infect Immun. 2000 Jan;68(1):46-53
references.pmid: 10603367
references.citation: Infect Immun. 1993 Sep;61(9):3981-4
references.pmid: 8359920
references.citation: Neurogastroenterol Motil. 2009 Jan;21(1):6-17
references.pmid: 19140954
references.citation: Mol Med. 2003 May-Aug;9(5-8):125-34
references.pmid: 14571320
references.citation: Mini Rev Med Chem. 2008 Nov;8(13):1328-42
references.pmid: 18991751
references.citation: J Appl Toxicol. 2006 May-Jun;26(3):262-8
references.pmid: 16583462
references.citation: J Appl Toxicol. 2007 Sep-Oct;27(5):482-90
references.pmid: 17309042
references.citation: Nat Med. 2004 Nov;10(11):1216-21
references.pmid: 15502843
references.citation: Gastroenterology. 2006 May;130(6):1822-30
references.pmid: 16697744
references.citation: Crit Care Med. 2008 Feb;36(2):404-8
references.pmid: 18091537
references.citation: J Immunol. 2006 Jan 1;176(1):496-506
references.pmid: 16365443
references.citation: Eur J Pharmacol. 2007 Jan 26;555(2-3):122-8
references.pmid: 17113068
references.citation: Curr Med Chem. 2008;15(8):743-53
references.pmid: 18393843
references.citation: Life Sci. 2007 May 30;80(24-25):2325-9
references.pmid: 17289087
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(14):5189-93
references.pmid: 3523484
references.citation: Int J Immunopathol Pharmacol. 2008 Oct-Dec;21(4):891-901
references.pmid: 19144274
references.citation: Semin Immunol. 2006 Dec;18(6):347-61
references.pmid: 16997570
references.citation: Drug Metab Dispos. 1983 Jul-Aug;11(4):366-70
references.pmid: 6137345
references.citation: J Clin Invest. 2007 Feb;117(2):289-96
references.pmid: 17273548
references.citation: Nature. 2002 Dec 19-26;420(6917):853-9
references.pmid: 12490958
references.citation: J Infect Dis. 1984 Sep;150(3):425-35
references.pmid: 6207248
references.citation: J Infect Dis. 2005 Jun 15;191(12):2138-48
references.pmid: 15898001
references.citation: J Appl Toxicol. 2005 Jan-Feb;25(1):68-73
references.pmid: 15669039
references.citation: J Endotoxin Res. 2005;11(6):395-9
references.pmid: 16303097
references.citation: Cochrane Database Syst Rev. 2005 Jan 25;(1):CD005085
references.pmid: 15654704
references.citation: Eur J Immunol. 1995 Aug;25(8):2220-7
references.pmid: 7664785
references.citation: J Exp Med. 1997 Aug 18;186(4):569-80
references.pmid: 9254655
references.citation: Langenbecks Arch Surg. 2006 Apr;391(2):83-7
references.pmid: 16568325
references.citation: Mol Immunol. 2003 Mar;39(13):763-70
references.pmid: 12617991
references.citation: World J Surg. 2005 Nov;29(11):1483-9
references.pmid: 16222449
references.citation: Infect Immun. 2007 Dec;75(12):5753-62
references.pmid: 17875635
references.citation: J Appl Toxicol. 1998 Jul-Aug;18(4):293-8
references.pmid: 9719430
references.citation: Microbes Infect. 2004 Apr;6(4):398-405
references.pmid: 15101397
references.citation: Crit Care Med. 2006 Feb;34(2):502-10
references.pmid: 16424734
references.citation: Infect Immun. 1992 Mar;60(3):791-7
references.pmid: 1541553
references.citation: Gastroenterology. 2006 Oct;131(4):1122-30
references.pmid: 17030182
references.citation: Nature. 2000 May 25;405(6785):458-62
references.pmid: 10839541
references.citation: Clin Chim Acta. 1961 Jul;6:538-44
references.pmid: 14453500