title: Peptidoglycan deacetylation in Helicobacter pylori contributes to bacterial survival by mitigating host immune responses.
abstract: An oxidative stress-induced enzyme, peptidoglycan deacetylase (PgdA), in the human gastric pathogen Helicobacter pylori was previously identified and characterized. In this study, we constructed H. pylori pgdA mutants in two mouse-adapted strains, X47 and B128, to investigate the role of PgdA in vivo (to determine the mutants' abilities to colonize mice and to induce an immune response). H. pylori pgdA mutant cells showed increased sensitivity to lysozyme compared to the sensitivities of the parent strains. We demonstrated that the expression of PgdA was significantly induced (3.5-fold) when H. pylori cells were in contact with macrophages, similar to the effect observed with oxidative stress as the environmental inducer. Using a mouse infection model, we first examined the mouse colonization ability of an H. pylori pgdA mutant in X47, a strain deficient in the major pathway (cag pathogenicity island [PAI] encoded) for delivery of peptidoglycan into host cells. No animal colonization difference between the wild type and the mutant was observed 3 weeks after inoculation. However, the pgdA mutant showed a significantly attenuated ability to colonize mouse stomachs (9-fold-lower bacterial load) at 9 weeks postinoculation. With the cag PAI-positive strain B128, a significant colonization difference between the wild type and the pgdA mutant was observed at 3 weeks postinoculation (1.32 × 10(4) versus 1.85 × 10(3) CFU/gram of stomach). To monitor the immune responses elicited by H. pylori in the mouse infection model, we determined the concentrations of cytokines present in mouse sera. In the mice infected with the pgdA mutant strain, we observed a highly significant increase in the level of MIP-2. In addition, significant increases in interleukin-10 and tumor necrosis factor alpha in the pgdA mutant-infected mice compared to the levels in the wild-type H. pylori-infected mice were also observed. These results indicated that H. pylori peptidoglycan deacetylation is an important mechanism for mitigating host immune detection; this likely contributes to pathogen persistence.
authors.affiliation: Department of Microbiology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Wang
authors.forename: Susan E
authors.initials: SE
authors.lastname: Maier
authors.forename: Leja F
authors.initials: LF
authors.lastname: Lo
authors.forename: George
authors.initials: G
authors.lastname: Maier
authors.forename: Shruti
authors.initials: S
authors.lastname: Dosi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Maier
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054426:Chemokine CXCL2 / Q000378:metabolism; D015169:Colony Count, Microbial; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018922:HL-60 Cells; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000201:enzymology / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D009154:Mutation; D010457:Peptidoglycan / Q000378:metabolism*; D013270:Stomach / Q000276:immunology / Q000382:microbiology
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D010457:Peptidoglycan; D000581:Amidohydrolases
references.citation: Gastroenterology. 1996 Dec;111(6):1524-33
references.pmid: 8942731
references.citation: J Clin Invest. 2007 Jan;117(1):60-9
references.pmid: 17200707
references.citation: Infect Immun. 2006 Dec;74(12):6839-46
references.pmid: 17030577
references.citation: Am J Pathol. 2001 Sep;159(3):1149-57
references.pmid: 11549608
references.citation: Gastroenterology. 2007 Jul;133(1):288-308
references.pmid: 17631150
references.citation: Helicobacter. 2002 Apr;7(2):139-40; author reply 140-1
references.pmid: 11966874
references.citation: Gut. 2001 Oct;49(4):526-33
references.pmid: 11559650
references.citation: Gastroenterology. 1994 Feb;106(2):533-9
references.pmid: 8299918
references.citation: Infect Immun. 2009 Jan;77(1):286-91
references.pmid: 18981252
references.citation: Infect Immun. 2001 Jun;69(6):4034-40
references.pmid: 11349073
references.citation: Infect Immun. 2002 Dec;70(12):7176-8
references.pmid: 12438406
references.citation: J Biol Chem. 2009 Mar 13;284(11):6790-800
references.pmid: 19147492
references.citation: Mol Microbiol. 2000 Oct;38(1):103-13
references.pmid: 11029693
references.citation: J Biol Chem. 2003 Oct 24;278(43):41702-8
references.pmid: 12871942
references.citation: Mol Microbiol. 2008 Dec;70(5):1120-35
references.pmid: 18990186
references.citation: PLoS Pathog. 2006 Oct;2(10):e110
references.pmid: 17121461
references.citation: Cell Microbiol. 2002 May;4(5):285-96
references.pmid: 12064285
references.citation: J Clin Invest. 2001 Mar;107(5):611-20
references.pmid: 11238562
references.citation: Scand J Immunol. 1993 Jan;37(1):65-70
references.pmid: 8418474
references.citation: Infect Immun. 2005 Jan;73(1):378-84
references.pmid: 15618175
references.citation: Nature. 2006 Jul 6;442(7098):39-44
references.pmid: 16823444
references.citation: Annu Rev Pathol. 2006;1:63-96
references.pmid: 18039108
references.citation: Biochem Soc Trans. 2007 Dec;35(Pt 6):1479-84
references.pmid: 18031249
references.citation: Gut. 1997 Oct;41(4):442-51
references.pmid: 9391240
references.citation: Science. 2003 Jun 6;300(5625):1584-7
references.pmid: 12791997
references.citation: Clin Microbiol Rev. 2006 Oct;19(4):597-613
references.pmid: 17041136
references.citation: Clin Microbiol Rev. 1997 Oct;10(4):720-41
references.pmid: 9336670
references.citation: Microbiology (Reading). 2003 Jul;149(Pt 7):1901-1909
references.pmid: 12855741
references.citation: Infect Immun. 2007 Feb;75(2):810-9
references.pmid: 17101659
references.citation: J Clin Pathol. 1995 Jan;48(1):41-5
references.pmid: 7706517
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):997-1002
references.pmid: 17215377
references.citation: Scand J Gastroenterol. 1994 May;29(5):425-9
references.pmid: 8036458
references.citation: Infect Immun. 2008 Feb;76(2):551-61
references.pmid: 18070899
references.citation: N Engl J Med. 2002 Oct 10;347(15):1175-86
references.pmid: 12374879
references.citation: Gastroenterology. 2007 Mar;132(3):1009-23
references.pmid: 17383424
references.citation: Hum Immunol. 2009 Nov;70(11):935-45
references.pmid: 19664671
references.citation: Cell Microbiol. 2010 Mar;12(3):372-85
references.pmid: 19888989
references.citation: Nat Rev Immunol. 2006 Jan;6(1):9-20
references.pmid: 16493424
references.citation: Mol Microbiol. 2006 Aug;61(4):847-60
references.pmid: 16879643
references.citation: Nat Immunol. 2004 Nov;5(11):1166-74
references.pmid: 15489856