Limited role for ASC and NLRP3 during in vivo Salmonella Typhimurium infection

BMC Immunology

W Joost Wiersinga³  Tom van der Poll³  Jaap T van Dissel⁴  Joris JTH Roelofs¹  Miriam HP van Lieshout²  Gavin CKW Koh⁵  Hanna K De Jong² 

[1] Department of Pathology, Academic Medical Center, Meibergdreef 9, Room G2-132, Amsterdam, 1105, AZ, the Netherlands;Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Meibergdreef 9, Room G2-132, Amsterdam, 1105, AZ, the Netherlands;Department of Medicine, Division of Infectious Diseases, Academic Medical Center, Meibergdreef 9, Room G2-132, Amsterdam, 1105, AZ, the Netherlands;Department of Infectious Diseases, Leiden University Medical Center, Leiden, 2300, RC, the Netherlands;Department of Infection and Tropical Medicine, Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK

关键词: Host-pathogen interactions;    Salmonella Typhimurium;    Inflammasomes;   

Others  :  1077712
DOI  :  10.1186/s12865-014-0030-7

 received in 2014-01-04, accepted in 2014-07-18,  发布年份 2014

【 摘 要 】

Background

The inflammasome is an intracellular protein complex triggered by exposure to intracellular pathogens, its components or other endogenous proteins. It leads to the activation of and subsequent release of proinflammatory cytokines such as IL-1β and IL-18. S. Typhimurium is a Gram-negative intracellular bacterium, which is known to trigger inflammasome assembly via recognition by the cytosolic receptors, NLRP3 and NLRC4 (which act via the adaptor protein, ASC) to induce cell death and cytokine release. We sought to characterize the role of ASC and NLRP3 in two different murine models (typhoid and colitis) of systemic Salmonella infection.

Results

Release of the inflammasome cytokine IL-18 was hampered in Asc^−/− but not Nlrp3^−/− mice (background C57BL/6) during S. Typhimurium infection. Unexpectedly, neither ASC nor NLRP3 played a significant role in host defense against S. Typhimurium infection, as reflected by equal bacterial counts in WT, Asc^−/− and Nlrp3^−/− mice at all time points, in both the typhoid and colitis models. Proinflammatory cytokine levels (TNF-α, IL-6) and the extent of hepatic and splenic pathology did not differ between groups in the typhoid model. In the colitis model small differences were seen with regard to splenic and hepatic inflammation, although this was IL-18 independent.

Conclusions

IL-18 release was reduced in Asc^−/− but not Nlrp3^−/− mice during S. Typhimurium infection. Despite this reduction, bacterial counts, cytokine levels and histological inflammation did not differ between wild-type and knockout mice in either model. Our results reveal a limited role for ASC and NLRP3 during in vivo S. Typhimurium infection despite its role in cytokine maturation.

【 授权许可】

   
2014 de Jong et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Crump JA, Mintz ED: Global trends in typhoid and paratyphoid Fever. Clin Infect Dis 2010, 50(2):241-246.
• [2]Feasey NA, Dougan G, Kingsley RA, Heyderman RS, Gordon MA: Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet 2012, 379(9835):2489-2499.
• [3]de Jong HK, Parry CM, van der Poll T, Wiersinga WJ: Host-pathogen interaction in invasive salmonellosis. PLoS Pathog 2012, 8(10):e1002933.
• [4]Dougan G, John V, Palmer S, Mastroeni P: Immunity to salmonellosis. Immunol Rev 2011, 240(1):196-210.
• [5]Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ: Typhoid fever. N Engl J Med 2002, 347(22):1770-1782.
• [6]Parry CM, Threlfall EJ: Antimicrobial resistance in typhoidal and nontyphoidal salmonellae. Curr Opin Infect Dis 2008, 21(5):531-538.
• [7]Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11(5):373-384.
• [8]Schroder K, Tschopp J: The inflammasomes. Cell 2010, 140(6):821-832.
• [9]Broz P, Monack DM: Molecular mechanisms of inflammasome activation during microbial infections. Immunol Rev 2011, 243(1):174-190.
• [10]Butler T, Ho M, Acharya G, Tiwari M, Gallati H: Interleukin-6, gamma interferon, and tumor necrosis factor receptors in typhoid fever related to outcome of antimicrobial therapy. Antimicrob Agents Chemother 1993, 37(11):2418-2421.
• [11]Keuter M, Dharmana E, Gasem MH, van der Ven-Jongekrijg J, Djokomoeljanto R, Dolmans WM, Demacker P, Sauerwein R, Gallati H, van der Meer JW: Patterns of proinflammatory cytokines and inhibitors during typhoid fever. J Infect Dis 1994, 169(6):1306-1311.
• [12]Raffatellu M, Chessa D, Wilson RP, Tukel C, Akcelik M, Baumler AJ: Capsule-mediated immune evasion: a new hypothesis explaining aspects of typhoid fever pathogenesis. Infect Immun 2006, 74(1):19-27.
• [13]Thompson LJ, Dunstan SJ, Dolecek C, Perkins T, House D, Dougan G, Nguyen TH, Tran TP, Doan CD, Le TP, Nguyen TD, Tran TH, Farrar JJ, Monack D, Lynn DJ, Popper SJ, Falkow S: Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi. Proc Natl Acad Sci U S A 2009, 106(52):22433-22438.
• [14]Monack DM, Bouley DM, Falkow S: Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+mice and can be reactivated by IFNgamma neutralization. J Exp Med 2004, 199(2):231-241.
• [15]Kupz A, Guarda G, Gebhardt T, Sander LE, Short KR, Diavatopoulos DA, Wijburg OL, Cao H, Waithman JC, Chen W, Fernandez-Ruiz D, Whitney PG, Heath WR, Curtiss R, Tschopp J, Strugnell RA, Bedoui S: NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8(+) T cells. Nat Immunol 2012, 13(2):162-169.
• [16]Mastroeni P, Clare S, Khan S, Harrison JA, Hormaeche CE, Okamura H, Kurimoto M, Dougan G: Interleukin 18 contributes to host resistance and gamma interferon production in mice infected with virulent Salmonella typhimurium. Infect Immun 1999, 67(2):478-483.
• [17]Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, Warren SE, Wewers MD, Aderem A: Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 2010, 11(12):1136-1142.
• [18]Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM: Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med 2010, 207(8):1745-1755.
• [19]Raupach B, Peuschel SK, Monack DM, Zychlinsky A: Caspase-1-mediated activation of interleukin-1beta (IL-1beta) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection. Infect Immun 2006, 74(8):4922-4926.
• [20]Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N, Dixit VM, Monack DM: Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 2012, 490:288-291.
• [21]Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, Coyle AJ, Flavell RA, Galan JE: Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J Exp Med 2006, 203(6):1407-1412.
• [22]Broz P, von Moltke J, Jones JW, Vance RE, Monack DM: Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe 2010, 8(6):471-483.
• [23]Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galan JE, Askenase PW, Flavell RA: Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 2006, 24(3):317-327.
• [24]Carter PB, Collins FM: The route of enteric infection in normal mice. J Exp Med 1974, 139(5):1189-1203.
• [25]Barthel M, Hapfelmeier S, Quintanilla-Martinez L, Kremer M, Rohde M, Hogardt M, Pfeffer K, Russmann H, Hardt WD: Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect Immun 2003, 71(5):2839-2858.
• [26]Hapfelmeier S, Hardt WD: A mouse model for S. typhimurium-induced enterocolitis. Trends Microbiol 2005, 13(10):497-503.
• [27]Santos RL, Zhang S, Tsolis RM, Kingsley RA, Adams LG, Baumler AJ: Animal models of Salmonella infections: enteritis versus typhoid fever. Microbes Infect 2001, 3(14–15):1335-1344.
• [28]Kufer TA, Sansonetti PJ: NLR functions beyond pathogen recognition. Nat Immunol 2011, 12(2):121-128.
• [29]Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Muller M, Blander JM: Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 2011, 474(7351):385-389.
• [30]Martinon F, Mayor A, Tschopp J: The inflammasomes: guardians of the body. Annu Rev Immunol 2009, 27:229-265.
• [31]Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A, Kugler D, Hieny S, Caspar P, Nunez G, Schlueter D, Flavell RA, Sutterwala FS, Sher A: Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol 2010, 184(7):3326-3330.
• [32]Ceballos-Olvera I, Sahoo M, Miller MA, Del Barrio L, Re F: Inflammasome-dependent pyroptosis and IL-18 protect against Burkholderia pseudomallei lung infection while IL-1beta is deleterious. PLoS Pathog 2011, 7(12):e1002452.
• [33]Kaiser P, Diard M, Stecher B, Hardt WD: The streptomycin mouse model for Salmonella diarrhea: functional analysis of the microbiota, the pathogen’s virulence factors, and the host’s mucosal immune response. Immunol Rev 2012, 245(1):56-83.
• [34]Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM: Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004, 430(6996):213-218.
• [35]Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA, Hoffman HM, Hugot JP, Inohara N, Mackenzie A, Maltais LJ, Nunez G, Ogura Y, Otten LA, Philpott D, Reed JC, Reith W, Schreiber S, Steimle V, Ward PA: The NLR gene family: a standard nomenclature. Immunity 2008, 28(3):285-287.