title: Selectively reduced intracellular proliferation of Salmonella enterica serovar typhimurium within APCs limits antigen presentation and development of a rapid CD8 T cell response.
abstract: Ag presentation to CD8(+) T cells commences immediately after infection, which facilitates their rapid expansion and control of pathogen. This paradigm is not followed during infection with virulent Salmonella enterica serovar Typhimurium (ST), an intracellular bacterium that causes mortality in susceptible C57BL/6J mice within 7 days and a chronic infection in resistant mice (129 x 1SvJ). Infection of mice with OVA-expressing ST results in the development of a CD8(+) T cell response that is detectable only after the second week of infection despite the early detectable bacterial burden. The mechanism behind the delayed CD8(+) T cell activation was evaluated, and it was found that dendritic cells/macrophages or mice infected with ST-OVA failed to present Ag to OVA-specific CD8(+) T cells. Lack of early Ag presentation was not rescued when mice or dendritic cells/macrophages were infected with an attenuated aroA mutant of ST or with mutants having defective Salmonella pathogenicity island I/II genes. Although extracellular ST proliferated extensively, the replication of ST was highly muted once inside macrophages. This muted intracellular proliferation of ST resulted in the generation of poor levels of intracellular Ag and peptide-MHC complex on the surface of dendritic cells. Additional experiments revealed that ST did not actively inhibit Ag presentation, rather it inhibited the uptake of another intracellular pathogen, Listeria monocytogenes, thereby causing inhibition of Ag presentation against L. monocytogenes. Taken together, this study reveals a dichotomy in the proliferation of ST and indicates that selectively reduced intracellular proliferation of virulent pathogens may be an important mechanism of immune evasion.
authors.affiliation: National Research Council Institute for Biological Sciences, Ottawa, Ontario, Canada.
authors.forename: Homam
authors.initials: H
authors.lastname: Albaghdadi
authors.forename: Nirmal
authors.initials: N
authors.lastname: Robinson
authors.forename: Brett
authors.initials: B
authors.lastname: Finlay
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Krishnan
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D008089:Listeria monocytogenes; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D012486:Salmonella typhimurium / Q000276:immunology / Q000502:physiology*; D014779:Virus Replication
references.citation: Cell. 1993 Jun 4;73(5):903-20
references.pmid: 8500180
references.citation: Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11470-4
references.pmid: 1763061
references.citation: Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12013-7
references.pmid: 1465432
references.citation: J Immunol. 2002 Jun 1;168(11):5737-45
references.pmid: 12023374
references.citation: Science. 2001 Jul 13;293(5528):245-8
references.pmid: 11452113
references.citation: Proc Natl Acad Sci U S A. 1989 Sep;86(18):7077-81
references.pmid: 2674945
references.citation: Infect Immun. 2006 Nov;74(11):6438-48
references.pmid: 17057096
references.citation: Science. 2001 Mar 23;291(5512):2413-7
references.pmid: 11264538
references.citation: Annu Rev Cell Dev Biol. 2001;17:53-86
references.pmid: 11687484
references.citation: J Immunol. 1998 Apr 15;160(8):3971-7
references.pmid: 9558105
references.citation: J Exp Med. 1995 Sep 1;182(3):655-66
references.pmid: 7650477
references.citation: Nature. 2003 Sep 25;425(6956):402-6
references.pmid: 14508490
references.citation: Science. 1996 Apr 5;272(5258):54-60
references.pmid: 8600537
references.citation: J Immunol. 1999 May 1;162(9):5398-406
references.pmid: 10228017
references.citation: Cell Microbiol. 2005 Jul;7(7):901-9
references.pmid: 15953023
references.citation: J Immunol. 2007 Jul 1;179(1):211-20
references.pmid: 17579040
references.citation: Nature. 1999 Oct 14;401(6754):708-12
references.pmid: 10537110
references.citation: Cell. 1998 May 29;93(5):815-26
references.pmid: 9630225
references.citation: J Immunol. 2002 Feb 15;168(4):1528-32
references.pmid: 11823476
references.citation: Science. 1989 Feb 24;243(4894 Pt 1):1059-62
references.pmid: 2646710
references.citation: J Immunol. 2006 Sep 15;177(6):3983-93
references.pmid: 16951361
references.citation: J Immunol. 1998 Nov 15;161(10):5338-46
references.pmid: 9820507
references.citation: Infect Immun. 1991 Jul;59(7):2232-8
references.pmid: 2050395
references.citation: J Immunol. 1990 Dec 1;145(11):3540-6
references.pmid: 2147195
references.citation: J Microbiol Methods. 2004 Jan;56(1):83-91
references.pmid: 14706753
references.citation: J Immunol. 2005 May 1;174(9):5341-50
references.pmid: 15843531
references.citation: Annu Rev Immunol. 2003;21:29-70
references.pmid: 12414723
references.citation: Nat Med. 2003 Aug;9(8):1039-46
references.pmid: 12872166
references.citation: Infect Immun. 2000 Oct;68(10):5702-9
references.pmid: 10992474
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2593-7
references.pmid: 8637919
references.citation: Immunity. 1997 Jun;6(6):715-26
references.pmid: 9208844
references.citation: J Immunol. 2007 Nov 1;179(9):6088-96
references.pmid: 17947683
references.citation: J Immunol. 2008 May 1;180(9):5853-61
references.pmid: 18424704
references.citation: Infect Immun. 2008 Nov;76(11):4924-33
references.pmid: 18765734
references.citation: J Leukoc Biol. 2000 Apr;67(4):457-63
references.pmid: 10770276
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4197-201
references.pmid: 8633040
references.citation: J Exp Med. 1995 Sep 1;182(3):639-41
references.pmid: 7650475
references.citation: Gene. 1995 Aug 19;161(2):211-6
references.pmid: 7665081
references.citation: J Immunol. 1987 Apr 1;138(7):2266-71
references.pmid: 3104455
references.citation: J Exp Med. 2000 Feb 21;191(4):613-24
references.pmid: 10684853
references.citation: Immunity. 1998 Feb;8(2):177-87
references.pmid: 9491999
references.citation: Annu Rev Immunol. 1996;14:533-61
references.pmid: 8717524
references.citation: Nature. 1998 Mar 5;392(6671):86-9
references.pmid: 9510252
references.citation: Science. 1995 Jul 21;269(5222):400-3
references.pmid: 7618105
references.citation: J Virol. 1999 Sep;73(9):7278-86
references.pmid: 10438816
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14650-5
references.pmid: 11121065
references.citation: J Immunol. 2004 Mar 15;172(6):3491-500
references.pmid: 15004149
references.citation: Annu Rev Immunol. 1998;16:201-23
references.pmid: 9597129
references.citation: J Immunol. 2006 Aug 1;177(3):1516-25
references.pmid: 16849458
references.citation: Cell Microbiol. 2001 Nov;3(11):731-44
references.pmid: 11696033
references.citation: J Immunol. 1998 Jan 15;160(2):898-905
references.pmid: 9551927
references.citation: Cell Microbiol. 1999 Jul;1(1):33-49
references.pmid: 11207539
references.citation: Nature. 2001 Mar 1;410(6824):101-5
references.pmid: 11242050
references.citation: Infect Immun. 2002 Jun;70(6):3264-70
references.pmid: 12011022
references.citation: J Exp Med. 1992 Jun 1;175(6):1531-8
references.pmid: 1375265
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13477-82
references.pmid: 14595029
references.citation: Infect Immun. 1993 Mar;61(3):1113-6
references.pmid: 8432593
references.citation: Curr Opin Microbiol. 2008 Feb;11(1):46-52
references.pmid: 18282735
references.citation: J Immunol. 2000 Dec 15;165(12):6833-9
references.pmid: 11120806
references.citation: Nat Immunol. 2001 May;2(5):423-9
references.pmid: 11323696
references.citation: J Immunol. 2004 Sep 15;173(6):4091-9
references.pmid: 15356159
references.citation: Nat Immunol. 2003 Mar;4(3):225-34
references.pmid: 12563257
references.citation: Proc Natl Acad Sci U S A. 1989 Aug;86(16):6383-7
references.pmid: 2548211
references.citation: Cell Microbiol. 2003 Dec;5(12):933-45
references.pmid: 14641178
references.citation: Nat Rev Immunol. 2002 Apr;2(4):251-62
references.pmid: 12001996
references.citation: Microbes Infect. 2001 Nov-Dec;3(14-15):1305-11
references.pmid: 11755419
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2396-401
references.pmid: 10051653
references.citation: J Immunol. 2005 Mar 1;174(5):2892-9
references.pmid: 15728500
references.citation: Proc Natl Acad Sci U S A. 1989 Jul;86(13):5054-8
references.pmid: 2544889
references.citation: Microbes Infect. 2001 Nov-Dec;3(14-15):1321-6
references.pmid: 11755421
references.citation: Microbes Infect. 2001 Nov-Dec;3(14-15):1293-8
references.pmid: 11755417
references.citation: Nat Immunol. 2001 May;2(5):415-22
references.pmid: 11323695