Mechanismof interferon- -mediated anti-chlamydia infection

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1 Journal of Microbes and Infection, June 2009, Vol. 4, No ,,, :,,, ; : ; ; ; Mechanismof interferon- -mediated anti-chlamydia infection TANG Guo-Fang, LI Zhong-Yu, WU Yi-Mou Institute of Pathogenic Biology Institute, School of Medicine, University of South China, Hengyang , China Abstract: Chlamydia is an intracellular bacterium that infects many vertebrates, including humans. Previous studies have shown that interferon- ( IFN- ) plays an important role in defense against Chlamydia infection. IFN- - mediated anti-chlamydia effector mechanisms may include the exhaustion of tryptophan, the induction of iron loss, and/ or the activation of inducible nitric oxide synthase ( inos). However, Chlamydia has evolved to develop mechanisms to escape IFN- functions. In this review, we will discuss IFN- -mediated effector mechanisms in the control of Chlamydia infection. Key words:chlamydia; Interferon- ; Immune response; Immune escape,,, ( Chlamydia trachomatic, Ct),,, 10% ( Chlamydia pneumoniae, Cpn), Cpn,,,, CD4 + : ( ) :, yimouwu@ sina. com. cn Th1 [ 1], Th1 ( interferon Corresponding author: WU Yi-Mou, yimouwu@ sina. com. cn, IFN- ) [ 2 ], IFN- 1 IFN- IFN-, ( Chlamydia muridarum),, IFN- IFN- / IFN- R / ( IFN- IFN- ),2 100% [ 3 ] IFN- ; IFN-,, ( reticulate body, RB), RB, IFN-, RB,, ( elementary body, EB)

2 Journal of Microbes and Infection, June 2009, Vol. 4, No. 2 IFN-, Ct IFN-, IFN- [ 4] IFN- 2 IFN- CD8 + T CD4 + T ( natural killer, NK) - IFN-, IFN-, 2. 1 IFN- 1,, NK,, [ 5] Toll ( Toll-like receptor, TLR) ( heat shock protein60, HSP 60), IFN-, [ 6, 7 ] ( severe combined immunodeficiency, SCID), IFN- RAG-1 / / IFN- R / SCID ; 1 ( recombination activating gene 1, RAG-1) T B, IFN- SCID < RAG-1 / SCID, [ 8 ], IFN- NK NK T IFN-, IFN- NK, NK [ 5, 7, 9], NK, RAG- 1 / NK,, ; RAG- 1 / cr / ( B T NK / ) Cpn IFN- RAG-1 IFN- [ 10 ] NK T, IFN- Cpn J 18 ( NK T CD1d ), NK T Cpn NK T Cpn,,, Cpn NK T, NK T1, IFN-,, Cpn ; NK T2, 4 ( interleukin4, IL-4),, [ 11] NK T [ 12 ] NK NK T, IFN- Cpn ( bone-marrowderived macrophages, BMM) IFN- mrna [ 13 ] RAG- 1 / / IFN- /, Cpn, IFN-, [ 14] 2. 2 IFN-,,, [ 15 ], CD8 + T CD4 + T [ 1], CD8 + CD4 + T,,, IFN-, Ct DNA T IFN-, Ct DNA IFN- R /, Cpn DNA [ 16, 17 ], IFN- CD4 + Th1 Ct, Ct IFN- ( major histocompatibility complex, MHC), CD4 + T, IFN- CD4 + T, CD4 + T IFN- Ct, [ 18] IFN- /,, T

3 Journal of Microbes and Infection, June 2009, Vol. 4, No [ 19], IFN-, Ct L2 ( Chlamydial protease-like activity factor, CPAF) Th1 CpG IFN- / IFN- R /, CPAF CD4 + T IFN- R /, IFN-, ;, CPAF CD4 + T IFN- /, IFN-,, CD4 + IFN- [ 20], MHC CD4 + T T, IFN- Ct DNA Ct, CD8 + T, CD8 + T, [ 21] CD8 + Cpn ; T ( major outer membrane protein, MOMP) <,, Fas/FasL Cpn [ 21 ] ; CD8 + T, CD8 + T,, IFN- [ 21], CD8 + T IFN- Cpn, CrpA ( cysteine-rich membrane protein A) OmcB ( 60 kd cysteine-rich outer membrane protein B) CD8 + T IFN-, Ct [ 22, 23 ], Ct Tvinnereim [ 24], MHCIb H2-M3 Cpn P1 P4, CD8 + T IFN-, Cpn CD8 + T Kb - / - /Db - / -, Cpn, CD8 + T IFN-, Cpn T IFN-, IFN- / T IFN-, IFN- ;,,,, 3 IFN- IFN-, IFN- IFN- 2,3 ( indoleamine 2, 3-dioxygenase, IDO) ( inducible nitric oxide synthase, inos) ; IFN- IDO, ( nitrogen monoxide, NO) ; NO, IDO [ 25 ] Ct, IFN- p47 GTPase ( GTPases IRGs, ), Ct [ 18, 26] 3. 1 IFN- IDO IDO, IFN- IDO, L- N-,,, IFN- trpa trpb trpr trpc Cpn Ct,,, ( lipopolysaccharide, LPS) IL-1 ( tumor necrosis factor, TNF) IFN-IDO 3. 2 IFN- inos IFN- inos, L- NO, inos /,, inos / IFN- R / ;, Roshick [ 25 ], IFN- ( McCoy L929 RAW J774) NO, NO Ct

4 Journal of Microbes and Infection, June 2009, Vol. 4, No. 2, IFN- inos, IFN- IFN- NADPHgp IFN-,,, [ 27] IFN-, : IFN- ( transferrin receptor, TFR), [ 28] ; IFN- - ( ferroportin),, [ 28] ; IFN- - 1( divalent metal transporter 1, DMT1), -, [ 28 ], IFN- ( hepcidin), Paradkar [ 29], Ct ( Chlamydia psittaci, Cps), -,, IFN- 4 IFN- IFN-, IFN-, Ct > 99%,, IFN- Ct,, Ct IFN-p47 GTPases, Irgm1( Lrg47) Irgm3( Igtp) Irgb10 Irga6, GTPases Irgb10, IFN- [ 30], ( plasticity zone, PZ) IFN-, PZ IFN- PZ 3 ( TC437 TC439), clcts cyopt : clcts UDP-, GTPases ; cyopt GTPases, IFN- p47 GTPase [ 3 1] IFN- IDO,,, IFN-, -1 ( upstream stimulatory factor-1, USF-1), IFN-, IFN- MHC, CD4 + T [ 3 2] 5,,,, ;, IFN-, CD4 + T CD8 + T IFN-, CD4 + T CD8 + T IFN- [ 1] Roan NR, Starnbach MN. Immune-mediated control of Chlamydia infection[ J]. Cell Microbiol, 2008, 10( 1) : 9-19 [ 2] Brunham RC, Rey-Ladino J. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine[ J]. Nat Rev Immunol, 2005, 5( 2) : [ 3] Jupelli M, Guentzel MN, Meier PA, et al. Endogenous IFN-gamma production is induced and required for protective immunity against pulmonary chlamydial infection in neonatal mice[ J]. J Immunol, 2008, 180 ( 6) : [ 4] Morrison RP, Caldwell HD. Immunity to murine chlamydial genital infection[ J]. Infect Immun, 2002, 70 ( 6) : [ 5] Wira CR, Fahey JV, Sentman CL, et al. Innate and adaptive immunity in female genital tract: cellular responses and interactions [ J]. Immunol Rev, 2005, 206:

5 Journal of Microbes and Infection, June 2009, Vol. 4, No [ 6] Puolakkainen M. Innate immunity and vaccines in chlamydial infection with special emphasis on Chlamydia pneumoniae[ J]. FEMS Immunol Med Microbiol, 2009, 55( 2) : [ 7] Hafner L, Beagley K, Timms P. Chlamydia trachomatis infection: host immune responses and potential vaccines [ J]. Mucosal Immunol, 2008, 1( 2) : [ 8] Rottenberg ME, Gigliotti-Rothfuchs A, Gigliotti D, et al. Regulation and role of IFN-gamma in the innate resistance to infection with Chlamydia pneumoniae[ J]. J Immunol, 2000, 164( 9) : [ 9] Tseng CT, Rank RG. Role of NK cells in early host response to chlamydial genital infection [ J]. Infect Immun, 1998, 66( 12) : [ 10] Rottenberg ME, Gigliotti-Rothfuchs A, Wigzell H. The role of IFN-gamma in the outcome of chlamydial infection [ J]. Curr Opin Immunol, 2002, 14( 4) : [ 11] Joyee AG, Qiu H, Wang S, et al. Distinct NKT cell subsets are induced by different Chlamydia species leading to differential adaptive immunity and host resistance to the infections[ J]. J Immunol, 2007, 178 ( 2) : [ 12] Bilenki L, Wang S, Yang J, et al. NKT cell activation promotes Chlamydia trachomatis infection in vivo[ J]. J Immunol, 2005, 175( 5) : [ 13] Rothfuchs AG, Gigliotti D, Palmblad K, et al. IFN-alpha beta-dependent, IFN-gamma secretion by bone marrowderived macrophages controls an intracellular bacterial infection[ J]. J Immunol, 2001, 167( 11) : [ 14] Rothfuchs AG, Kreuger MR, Wigzell H, et al. Macrophages, CD4 + or CD8 + cells are each sufficient for protection against Chlamydia pneumoniae infection through their ability to secrete IFN-gamma [ J]. J Immunol, 2004, 172( 4) : [ 15] Roan NR, Gierahn TM, Higgins DE, et al. Monitoring the T cell response to genital tract infection[ J]. Proc Natl Acad Sci USA, 2006, 103( 32) : [ 16] Dong-Ji Z, Yang X, Shen C, et al. Priming with Chlamydia trachomatis major outer membrane protein ( MOMP) DNA followed by MOMP ISCOM boosting enhances protection and is associated with increased immunoglobulin A and Th1 cellular immune responses [ J]. Infect Immun, 2000,68( 6) : [ 17] Svanholm C, Bandholtz L, Castanos-Velez E, et al. Protective DNA immunization against Chlamydia pneumoniae[ J]. Scand J Immunol, 2000, 51( 4) : [ 18] Nelson DE, Virok DP, Wood H, et al. Chlamydial IFNgamma immune evasion is linked to host infection tropism[ J]. Proc Natl Acad Sci USA, 2005, 102( 30) : [ 19] Murthy AK, Chambers JP, Meier PA, et al. Intranasal vaccination with a secreted chlamydial protein enhances resolution of genital Chlamydia muridarum infection, protects against oviduct pathology, and is highly dependent upon endogenous gamma interferon production [ J]. Infect Immun, 2007,75( 2) : [ 20] Li W, Murthy AK, Guentzel MN, et al. Antigen-specific CD4 + T cells produce sufficient IFN-gamma to mediate robust protective immunity against genital Chlamydia muridarum infection[ J]. J Immunol, 2008, 180 ( 5) : [ 21] Wizel B, Nystr m-asklin J, Cortes C, et al. Role of CD8 + T cells in the host response to Chlamydia[ J]. Microbes Infect, 2008, 10( 14-15) : [ 22] Starnbach MN, Loomis WP, Ovendale P, et al. An inclusion membrane protein from Chlamydia trachomatis enters the MHCclass pathway and stimulates a CD8 + T cell response[ J]. J Immunol, 2003, 171( 9) : [ 23] Gervassi AL, Grabstein KH, Probst P, et al. Human CD8 + T cells recognize the 60-kDa cysteine-rich outer membrane protein from Chlamydia trachomatis[ J]. Immunol, 2004, 173( 11) : [ 24] Tvinnereim A, Wizel B. CD8 + T cell protective immunity against Chlamydia pneumoniae includes an H2- M3-restricted response that is largely CD4 + J T cellindependent[ J]. J Immunol, 2007, 179( 6) : [ 25] Roshick C, Wood H, Caldwell HD, et al. Comparison of gamma interferon-mediated antichlamydial defense mechanisms in human and mouse cells [ J]. Immun, 2006,74( 1) : Infect [ 26] Taylor GA. IRG proteins: key mediators of interferonregulated host resistance to intracellular pathogens[ J]. Cell Microbiol, 2007, 9( 5) : [ 27] Ong ST, Ho JZ, Ho B, et al. Iron-withholding strategy in innate immunity[ J]. Immunobiology, 2006, 211 ( 4) : [ 28] Ludwiczek S, Aigner E, Theurl I, et al. Cytokinemediated regulation of iron transport in human monocytic cells[ J]. Blood, 2003, 101( 10) : [ 29] Paradkar PN, De Domenico I, Durchfort N, et al. Iron depletion limits intracellular bacterial growth in macrophages[ J]. Blood, 2008, 112( 3) : ( 111 )

6 ( 107 ) [ 30] Coers J, Bernstein-Hanley I, Grotsky D, et al. Chlamydia muridarum evades growth restriction by the IFN-gammainducible host resistance factor Irgb10[ J]. J Immunol, 2008, 180( 9) : [ 31] Bernstein-Hanley I, Coers J, Balsara ZR, et al. The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq - 3 and mediate cellular resistance in mice [ J]. Proc Natl Acad Sci USA, 2006, 103( 38) : [ 32] Zhong G, Fan T, Liu L. Chlamydia inhibits interferon gamma-inducible major histocompatibility complex class expression by degradation of upstream stimulatory factor 1[ J]. J Exp Med, 1999,189( 12) : ( : )

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