title: Combined stimulation of Toll-like receptor 5 and NOD1 strongly potentiates activity of NF-κB, resulting in enhanced innate immune reactions and resistance to Salmonella enterica serovar Typhimurium infection.
abstract: Pathogen recognition receptors (PRRs) are essential components of host innate immune systems that detect specific conserved pathogen-associated molecular patterns (PAMPs) presented by microorganisms. Members of two families of PRRs, transmembrane Toll-like receptors (TLRs 1, 2, 4, 5, and 6) and cytosolic NOD receptors (NOD1 and NOD2), are stimulated upon recognition of various bacterial PAMPs. Such stimulation leads to induction of a number of immune defense reactions, mainly triggered via activation of the transcription factor NF-κB. While coordination of responses initiated via different PRRs sensing multiple PAMPS present during an infection makes clear biological sense for the host, such interactions have not been fully characterized. Here, we demonstrate that combined stimulation of NOD1 and TLR5 (as well as other NOD and TLR family members) strongly potentiates activity of NF-κB and induces enhanced levels of innate immune reactions (e.g., cytokine production) both in vitro and in vivo. Moreover, we show that an increased level of NF-κB activity plays a critical role in formation of downstream responses. In live mice, synergy between these receptors resulting in potentiation of NF-κB activity was organ specific, being most prominent in the gastrointestinal tract. Coordinated activity of NOD1 and TLR5 significantly increased protection of mice against enteroinvasive Salmonella infection. Obtained results suggest that cooperation of NOD and TLR receptors is important for effective responses to microbial infection in vivo.
authors.affiliation: N. F. Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia.
authors.forename: Amir I
authors.initials: AI
authors.lastname: Tukhvatulin
authors.forename: Ilya I
authors.initials: II
authors.lastname: Gitlin
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Shcheblyakov
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Artemicheva
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Burdelya
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Shmarov
authors.forename: Boris S
authors.initials: BS
authors.lastname: Naroditsky
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gintsburg
authors.forename: Denis Y
authors.initials: DY
authors.lastname: Logunov
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D051198:Toll-Like Receptor 5
references.citation: Nat Immunol. 2003 Jul;4(7):702-7
references.pmid: 12796777
references.citation: Nat Immunol. 2012 Nov;13(11):1063-71
references.pmid: 23001144
references.citation: J Dent Res. 2008 Jul;87(7):682-6
references.pmid: 18573991
references.citation: Proc Natl Acad Sci U S A. 2013 May 14;110(20):E1857-66
references.pmid: 23630282
references.citation: J Immunol. 2000 Nov 15;165(10):5392-6
references.pmid: 11067888
references.citation: Oncogene. 2006 Oct 30;25(51):6758-80
references.pmid: 17072327
references.citation: Eur J Immunol. 2005 Aug;35(8):2471-6
references.pmid: 16021603
references.citation: J Immunol. 2010 Feb 1;184(3):1148-52
references.pmid: 20042586
references.citation: Proc Soc Exp Biol Med. 1946 Mar;61:248-50
references.pmid: 21024160
references.citation: Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2683-8
references.pmid: 12766073
references.citation: Science. 2005 Feb 4;307(5710):731-4
references.pmid: 15692051
references.citation: Genes Dev. 2010 Dec 1;24(23):2666-77
references.pmid: 21123652
references.citation: Blood. 2007 Apr 1;109(7):2727-35
references.pmid: 17110449
references.citation: Infect Immun. 2005 Dec;73(12):7967-76
references.pmid: 16299289
references.citation: Immunity. 2008 Feb;28(2):246-57
references.pmid: 18261938
references.citation: Cell Microbiol. 2005 Jan;7(1):53-61
references.pmid: 15617523
references.citation: J Immunol. 2005 Oct 1;175(7):4490-8
references.pmid: 16177092
references.citation: Infect Immun. 1999 Jul;67(7):3542-7
references.pmid: 10377137
references.citation: Science. 2003 Jun 6;300(5625):1584-7
references.pmid: 12791997
references.citation: J Immunol. 2002 Oct 1;169(7):3480-4
references.pmid: 12244136
references.citation: J Leukoc Biol. 2006 Aug;80(2):267-77
references.pmid: 16731773
references.citation: Blood. 2010 Mar 11;115(10):1921-31
references.pmid: 20065289
references.citation: Int Immunol. 2009 Apr;21(4):317-37
references.pmid: 19246554
references.citation: Science. 2008 Apr 11;320(5873):226-30
references.pmid: 18403709
references.citation: J Biol Chem. 1999 May 7;274(19):13443-50
references.pmid: 10224109