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Open Access 01-12-2007 | Research

Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue

Authors: Sailesh C Harwani, Nell S Lurain, M Reza Zariffard, Gregory T Spear

Published in: Virology Journal | Issue 1/2007

Abstract

Human cytomegalovirus (HCMV) can be acquired sexually and is shed from the genital tract. Cross-sectional studies in women show that changes in genital tract microbial flora affect HCMV infection and/or shedding. Since genital microbial flora may affect HCMV infection or replication by stimulating cells through Toll-like receptors (TLR), we assessed the effects of defined TLR-ligands on HCMV replication in foreskin fibroblasts and ectocervical tissue. Poly I:C (a TLR3-ligand) and lipopolysaccharide (LPS, a TLR4-ligand) inhibited HCMV and induced secretion of IL-8 and Interferon-beta (IFNβ) in both foreskin fibroblasts and ectocervical tissue. The anti-HCMV effect was reversed by antibody to IFNβ. CpG (TLR9 ligand) and lipoteichoic acid (LTA, TLR2 ligand) also inhibited HCMV infection in ectocervical tissue and this anti-HCMV effect was also reversed by anti-IFNβ antibody. In contrast, LTA and CpG did not inhibit HCMV infection in foreskin fibroblasts. This study shows that TLR ligands induce an HCMV-antiviral effect that is mediated by IFNβ suggesting that changes in genital tract flora may affect HCMV infection or shedding by stimulating TLR. This study also contrasts the utility of two models that can be used for assessing the interaction of microbial flora with HCMV in the genital tract. Clear differences in the response to different TLR ligands suggests the explant model more closely reflects in vivo responses to genital infections.

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Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ: Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis 2006,43(9):1143-1151. 10.1086/508173PubMedCrossRef

Fishman JA, Rubin RH: Infection in organ-transplant recipients. N Engl J Med 1998,338(24):1741-1751. 10.1056/NEJM199806113382407PubMedCrossRef

Handsfield HH, Chandler SH, Caine VA, Meyers JD, Corey L, Medeiros E, McDougall JK: Cytomegalovirus infection in sex partners: evidence for sexual transmission. J Infect Dis 1985,151(2):344-348.PubMedCrossRef

Ross SA, Novak Z, Ashrith G, Rivera LB, Britt WJ, Hedges S, Schwebke JR, Boppana AS: Association between genital tract cytomegalovirus infection and bacterial vaginosis. J Infect Dis 2005,192(10):1727-1730. 10.1086/497150PubMedCrossRef

Sobel JD: Vaginitis. N Engl J Med 1997,337(26):1896-1903. 10.1056/NEJM199712253372607PubMedCrossRef

Clarke LM, Duerr A, Feldman J, Sierra MF, Daidone BJ, Landesman SH: Factors associated with cytomegalovirus infection among human immunodeficiency virus type 1-seronegative and -seropositive women from an urban minority community. J Infect Dis 1996,173(1):77-82.PubMedCrossRef

Fowler KB, Pass RF: Sexually transmitted diseases in mothers of neonates with congenital cytomegalovirus infection. J Infect Dis 1991,164(2):259-264.PubMedCrossRef

Fisette PL, Ram S, Andersen JM, Guo W, Ingalls RR: The Lip lipoprotein from Neisseria gonorrhoeae stimulates cytokine release and NF-kappaB activation in epithelial cells in a Toll-like receptor 2-dependent manner. The Journal of biological chemistry 2003,278(47):46252-46260. 10.1074/jbc.M306587200PubMedCrossRef

Zariffard MR, Harwani S, Novak RM, Graham PJ, Ji X, Spear GT: Trichomonas vaginalis infection activates cells through toll-like receptor 4. Clin Immunol 2004,111(1):103-107. 10.1016/j.clim.2003.12.008PubMedCrossRef

10.

Mares D, Simoes JA, Novak RM, Spear GT: TLR2-mediated cell stimulation in bacterial vaginosis. J Reprod Immunol 2007.

11.

Ishii KJ, Akira S: Innate immune recognition of nucleic acids: beyond toll-like receptors. Int J Cancer 2005,117(4):517-523. 10.1002/ijc.21402PubMedCrossRef

12.

Ashkar AA, Bauer S, Mitchell WJ, Vieira J, Rosenthal KL: Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2. J Virol 2003,77(16):8948-8956. 10.1128/JVI.77.16.8948-8956.2003PubMedPubMedCentralCrossRef

13.

Sato A, Iwasaki A: Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments. Proc Natl Acad Sci U S A 2004,101(46):16274-16279. 10.1073/pnas.0406268101PubMedPubMedCentralCrossRef

14.

Isogawa M, Robek MD, Furuichi Y, Chisari FV: Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol 2005,79(11):7269-7272. 10.1128/JVI.79.11.7269-7272.2005PubMedPubMedCentralCrossRef

15.

Gill N, Deacon PM, Lichty B, Mossman KL, Ashkar AA: Induction of innate immunity against herpes simplex virus type 2 infection via local delivery of Toll-like receptor ligands correlates with beta interferon production. J Virol 2006,80(20):9943-9950. 10.1128/JVI.01036-06PubMedPubMedCentralCrossRef

16.

Isomura H, Stinski MF: The human cytomegalovirus major immediate-early enhancer determines the efficiency of immediate-early gene transcription and viral replication in permissive cells at low multiplicity of infection. J Virol 2003,77(6):3602-3614. 10.1128/JVI.77.6.3602-3614.2003PubMedPubMedCentralCrossRef

17.

Caliendo AM, Yen-Lieberman B, Baptista J, Andersen J, Crumpacker C, Schuurman R, Spector SA, Bremer J, Lurain NS: Comparison of molecular tests for detection and quantification of cell-associated cytomegalovirus DNA. Journal of clinical microbiology 2003,41(8):3509-3513. 10.1128/JCM.41.8.3509-3513.2003PubMedPubMedCentralCrossRef

18.

Fox-Canale AM, Hope TJ, Martinson J, Lurain JR, Rademaker AW, Bremer JW, Landay A, Spear GT, Lurain NS: Human cytomegalovirus and human immunodeficiency virus type-1 co-infection in human cervical tissue. Virology 2007.

19.

Lurain NS, Kapell KS, Huang DD, Short JA, Paintsil J, Winkfield E, Benedict CA, Ware CF, Bremer JW: Human cytomegalovirus UL144 open reading frame: sequence hypervariability in low-passage clinical isolates. J Virol 1999,73(12):10040-10050.PubMedPubMedCentral

20.

Hu Q, Frank I, Williams V, Santos JJ, Watts P, Griffin GE, Moore JP, Pope M, Shattock RJ: Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med 2004,199(8):1065-1075. 10.1084/jem.20022212PubMedPubMedCentralCrossRef

21.

Harada A, Sekido N, Akahoshi T, Wada T, Mukaida N, Matsushima K: Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol 1994,56(5):559-564.PubMed

22.

Helfgott DC, May LT, Sthoeger Z, Tamm I, Sehgal PB: Bacterial lipopolysaccharide (endotoxin) enhances expression and secretion of beta 2 interferon by human fibroblasts. J Exp Med 1987,166(5):1300-1309. 10.1084/jem.166.5.1300PubMedCrossRef

23.

Van Damme J, Schaafsma MR, Fibbe WE, Falkenburg JH, Opdenakker G, Billiau A: Simultaneous production of interleukin 6, interferon-beta and colony-stimulating activity by fibroblasts after viral and bacterial infection. European journal of immunology 1989,19(1):163-168. 10.1002/eji.1830190126PubMedCrossRef

24.

Zariffard MR, Novak RM, Lurain N, Sha BE, Graham P, Spear GT: Induction of tumor necrosis factor- alpha secretion and toll-like receptor 2 and 4 mRNA expression by genital mucosal fluids from women with bacterial vaginosis. J Infect Dis 2005,191(11):1913-1921. 10.1086/429922PubMedCrossRef

25.

Sainz B Jr., LaMarca HL, Garry RF, Morris CA: Synergistic inhibition of human cytomegalovirus replication by interferon-alpha/beta and interferon-gamma. Virol J 2005, 2: 14. 10.1186/1743-422X-2-14PubMedPubMedCentralCrossRef

26.

Vilcek J, Kohase M, Henriksen-DeStefano D: Mitogenic effect of double-stranded RNA in human fibroblasts: role of autogenous interferon. J Cell Physiol 1987,130(1):37-43. 10.1002/jcp.1041300107PubMedCrossRef

27.

Servant MJ, Grandvaux N, tenOever BR, Duguay D, Lin R, Hiscott J: Identification of the minimal phosphoacceptor site required for in vivo activation of interferon regulatory factor 3 in response to virus and double-stranded RNA. The Journal of biological chemistry 2003,278(11):9441-9447. 10.1074/jbc.M209851200PubMedCrossRef

28.

Matsumoto M, Kikkawa S, Kohase M, Miyake K, Seya T: Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem Biophys Res Commun 2002,293(5):1364-1369. 10.1016/S0006-291X(02)00380-7PubMedCrossRef

29.

Szomolanyi-Tsuda E, Liang X, Welsh RM, Kurt-Jones EA, Finberg RW: Role for TLR2 in NK cell-mediated control of murine cytomegalovirus in vivo. J Virol 2006,80(9):4286-4291. 10.1128/JVI.80.9.4286-4291.2006PubMedPubMedCentralCrossRef

30.

Compton T, Kurt-Jones EA, Boehme KW, Belko J, Latz E, Golenbock DT, Finberg RW: Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol 2003,77(8):4588-4596. 10.1128/JVI.77.8.4588-4596.2003PubMedPubMedCentralCrossRef

31.

Boehme KW, Guerrero M, Compton T: Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J Immunol 2006,177(10):7094-7102.PubMedCrossRef

32.

Iversen AC, Norris PS, Ware CF, Benedict CA: Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta. J Immunol 2005,175(11):7568-7574.PubMedCrossRef

33.

Lauzon NM, Mian F, Mackenzie R, Ashkar AA: The direct effects of Toll-like receptor ligands on human NK cell cytokine production and cytotoxicity. Cell Immunol 2006.

34.

Krug A, French AR, Barchet W, Fischer JA, Dzionek A, Pingel JT, Orihuela MM, Akira S, Yokoyama WM, Colonna M: TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 2004,21(1):107-119. 10.1016/j.immuni.2004.06.007PubMedCrossRef

35.

Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Alexopoulou L, Flavell RA, Beutler B: Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci U S A 2004,101(10):3516-3521. 10.1073/pnas.0400525101PubMedPubMedCentralCrossRef

36.

Doyle S, Vaidya S, O'Connell R, Dadgostar H, Dempsey P, Wu T, Rao G, Sun R, Haberland M, Modlin R, Cheng G: IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002,17(3):251-263. 10.1016/S1074-7613(02)00390-4PubMedCrossRef

37.

Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S, Williams BR, Major J, Hamilton TA, Fenton MJ, Vogel SN: TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol 2002,3(4):392-398. 10.1038/ni774PubMedCrossRef

38.

Youn HS, Lee JY, Fitzgerald KA, Young HA, Akira S, Hwang DH: Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: molecular targets are TBK1 and RIP1 in TRIF complex. J Immunol 2005,175(5):3339-3346.PubMedCrossRef

39.

Fichorova RN, Cronin AO, Lien E, Anderson DJ, Ingalls RR: Response to Neisseria gonorrhoeae by cervicovaginal epithelial cells occurs in the absence of toll-like receptor 4-mediated signaling. J Immunol 2002,168(5):2424-2432.PubMedCrossRef

40.

van Duin D, Medzhitov R, Shaw AC: Triggering TLR signaling in vaccination. Trends Immunol 2006,27(1):49-55. 10.1016/j.it.2005.11.005PubMedCrossRef

41.

Hardy MP, Mc GGAF, O'Neill LA: Transcriptional regulation of the human TRIF (TIR domain-containing adaptor protein inducing interferon beta) gene. Biochem J 2004,380(Pt 1):83-93. 10.1042/BJ20040030PubMedPubMedCentralCrossRef

Title: Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue
Authors: Sailesh C Harwani
Nell S Lurain
M Reza Zariffard
Gregory T Spear
Publication date: 01-12-2007
Publisher: BioMed Central
Published in: Virology Journal / Issue 1/2007
Electronic ISSN: 1743-422X
DOI: https://doi.org/10.1186/1743-422X-4-133

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