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BMC Infectious Diseases
Published in: BMC Infectious Diseases 1/2019

Open Access 01-12-2019 | Chlamydia Trachomatis | Research article

High expression of IDO1 and TGF-β1 during recurrence and post infection clearance with Chlamydia trachomatis, are independent of host IFN-γ response

Authors: Noa Ziklo, Wilhelmina M. Huston, Kuong Taing, Peter Timms

Published in: BMC Infectious Diseases | Issue 1/2019

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Abstract

Background

Chlamydia trachomatis infections in women continue to be a major public health concern due to their high prevalence and consequent reproductive morbidities. While antibiotics are usually efficient to clear the Chlamydia, repeat infections are common and may contribute to pathological outcomes. Interferon-gamma (IFN-γ)-mediated immunity has been suggested to be protective against reinfection, and represent an important anti-chlamydial agent, primarily via the induction of indoleamine-2,3 dioxygenase 1 (IDO1) enzyme. IDO1 catalyzes the degradation of tryptophan, which can eliminate C. trachomatis infection in vitro. Here, we sought to measure IDO1 expression levels and related immune markers during different C. trachomatis infection statuses (repeated vs single infection vs post antibiotic treatment), in vitro and in vivo.

Methods

In this study, we measured the expression levels of IDO1 and immune regulatory markers, transforming growth factor β1 (TGF-β1) and forkhead box P3 (FoxP3), in vaginal swab samples of C. trachomatis-infected women, with either single or repeated infection. In addition, we used an in vitro co-culture model of endometrial carcinoma cell-line and peripheral blood mononuclear cells (PBMCs) to measure the same immune markers.

Results

We found that in women with repeated C. trachomatis infections vaginal IDO1 and TGF-β1 expression levels were significantly increased. Whereas, women who cleared their infection post antibiotic treatment, had increased levels of IDO1 and TGF-β1, as well as FoxP3. Similarly, using the in vitro model, we found significant upregulation of IDO1 and TGF-β1 levels in the co-culture infected with C. trachomatis. Furthermore, we found that in PBMCs infected with C. trachomatis there was a significant upregulation in IDO1 levels, which was independent of IFN-γ. In fact, C. trachomatis infection in PBMCs failed to induce IFN-γ levels in comparison to the uninfected culture.

Conclusions

Our data provide evidence for a regulatory immune response comprised of IDO1, TGF-β1 and FoxP3 in women post antibiotic treatment. In this study, we demonstrated a significant increase in IDO1 expression levels in response to C. trachomatis infection, both in vivo and in vitro, without elevated IFN-γ levels. This study implicates IDO1 and TGF-β1 as part of the immune response to repeated C. trachomatis infections, independently of IFN-γ.
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Literature
1.
Darville T, Thomas HJ. Pathogenesis of genital tract disease due to Chlamydia trachomatis. J Infect Di. 2010;201:S114–25.
2.
Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10:e0143304.PubMedPubMedCentral
3.
Geisler WM, Uniyal A, Lee JY, Lensing SY, Johnson S, Perry RCW, et al. Azithromycin versus doxycycline for urogenital Chlamydia trachomatis infection. N Engl J Med. 2015;373:2512–21.PubMedPubMedCentral
4.
Kong FYS, Hocking JS. Treatment challenges for urogenital and anorectal Chlamydia trachomatis. BMC Infect Dis. 2015;15:293.PubMedPubMedCentral
5.
Barral R, Desai R, Zheng X, Frazer LC, Sucato GS, Haggerty CL, et al. Frequency of Chlamydia trachomatis-specific T cell interferon-γ and interleukin-17 responses in CD4-enriched peripheral blood mononuclear cells of sexually active adolescent females. J Reprod Immunol. 2014;103:29–37.PubMedPubMedCentral
6.
Batteiger BE, Xu F, Johnson RE, Rekart ML. Protective immunity to Chlamydia trachomatis genital infection: evidence from human studies. J Infect Dis. 2010;201:178–89.
7.
Debattista J, Timms P, Allan J, Allan J. Reduced levels of gamma-interferon secretion in response to chlamydial 60 kDa heat shock protein amongst women with pel v ic inflammatory disease and a history of repeated Chlamydia trachomatis infections. Immunol Lett. 2002;81:205–10.PubMed
8.
Beaty WL, Belanger TA, Desai AA, Morrison RP, Byrne GI. Tryptophan depletion as a mechanism of gamma interferon- mediated chlamydial persistence. Infect Immun. 1994;62:3705–11.
9.
Caldwell HD, Wood H, Crane D, Bailey R, Jones RB, Mabey D, et al. Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates. J Clin Invest. 2003;111:1757–69.PubMedPubMedCentral
10.
Byrne GI, Lehmann LK, Landry GJ. Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells. Infect Immun. 1986;53:347–51.PubMedPubMedCentral
11.
Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 1991;5:2516–22.PubMed
12.
Takao S, Sumitsugu N, Hirata F, Hayaishi O. Indoleamine 2,3-dioxygenase. J Biol Chem. 1978;253:4700–6.
13.
14.
Lewis ME, Belland RJ, AbdelRahman YM, Beatty WL, Aiyar AA, Zea AH, et al. Morphologic and molecular evaluation of Chlamydia trachomatis growth in human endocervix reveals distinct growth patterns. Front Cell Infect Microbiol. 2014;4:71.PubMedPubMedCentral
15.
Jordan SJ, Olson KM, Barnes S, Wilson LS, Berryhill TF, Bakshi R, et al. Lower levels of Cervicovaginal tryptophan are associated with natural clearance of Chlamydia in women. J Infect Dis. 2017;215:1888–92.PubMedPubMedCentral
16.
Faal N, Bailey RL, Jeffries D, Joof H, Sarr I, Laye M, et al. Conjunctival FOXP3 expression in trachoma: do regulatory T cells have a role in human ocular Chlamydia trachomatis infection? PLoS Med. 2006;3:1292–301.
17.
Ziklo N, Vidgen ME, Taing K, Huston WM, Timms P. Dysbiosis of the vaginal microbiota and higher vaginal kynurenine/tryptophan ratio reveals an association with Chlamydia trachomatis genital infections. Front Cell Infect Microbiol. 2018;8:1–11.PubMedPubMedCentral
18.
Schroten H, Spors B, Hucke C, Stins M, Kim KS, Adam R, et al. Potential role of human brain microvascular endothelial cells in the pathogenesis of brain Abscess : inhibition of Staphylococcus aureus by activation of Indoleamine 2 , 3-dioxygenase. Neuropediatrics. 2001;32:206–10.PubMed
19.
Mackenzie CR, Heseler K, Müller A, Däubener W. Role of Indoleamine 2 , 3-dioxygenase in antimicrobial Defence and Immuno- Regulation : tryptophan depletion versus production of toxic kynurenines. Curr Drug Metab. 2007;8:237–44.PubMed
20.
Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185:3190–8.PubMedPubMedCentral
21.
Fallarino F, Grohmann U, You S, Mcgrath BC, Cavener DR, Vacca C, et al. The combined effects of Trypptophan starvation and tryptophan catabolites Down-regulate T cell receptor -chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176:6752–61.PubMed
22.
Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9:1069–77.PubMed
23.
Metz R, Rust S, DuHadaway JB, Mautino MR, Munn DH, Vahanian NN, et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology. 2012;1:1460–8.PubMedPubMedCentral
24.
Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633–42.PubMed
25.
Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189:1363–72.PubMedPubMedCentral
26.
Mbongue J, Nicholas D, Torrez T, Kim N-S, Firek A, Langridge W. The role of Indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity. Vaccines. 2015;3:703–29.PubMedPubMedCentral
27.
Fallarino F, Grohmann U, Vacca C, Orabona C, Spreca A, Fioretti MC, et al. T cell apoptosis by kynurenines. Dev tryptophan serotonin Metab. Springer; 2003. p. 183–90.
28.
Babcock TA, Carlin JM. Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor α in interferon-treated epithelial cells. Cytokine. 2000;12:588–94.PubMed
29.
Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol. 2011;12:870–8.PubMed
30.
Carlin JM, Borden EC, Sondel PM, Byrne GI. Biologic response modifier induced indoleamine 2,3-dioxygenase activity in human peripheral blood mononuclear cell cultures. J Immunol. 1987;139:2414–8.PubMed
31.
Fujigaki S, Saito K, Sekikawa K, Tone S, Takikawa O, Fujii H, et al. Lipopolysaccharide induction of indoleamine 2 , 3-dioxygenase is mediated dominantly by an IFN- q -independent mechanism. Eur J Immunol. 2001;31:2313–8.PubMed
32.
Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8:277–84.PubMed
33.
Meijer CJLM, Weiderpass E, Arslan A, Posso H, Franceschi S, Ronderos M, et al. The natural course of Chlamydia trachomatis infection in asymptomatic Colombian Women : a 5-year follow-up study. J Infect Dis. 2005;191:907–16.PubMed
34.
Brunham RC, Rey-Ladino J. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine. Nat Rev Immunol. 2005;5(2):149–61.
35.
Mallone R, Mannering SI, Brooks-Worrell BM, Durinovic-Bello I, Cilio CM, Wong FS, et al. Isolation and preservation of peripheral blood mononuclear cells for analysis of islet antigen-reactive T cell responses : position statement of the T-cell workshop Committee of the Immunology of diabetes society. Clin Exp Immunol. 2010;163:33–49.PubMed
36.
Rudo L, Danica M, Fahey JV, Wira CR. Chlamydia trachomatis regulates innate immune barrier integrity and mediates cytokine and antimicrobial responses in human uterine ECC- ­ 1 epithelial cells. Am J Reprod Immunol. 2017;78(6):e12764.
37.
Cunningham K, Stansfield SH, Patel P, Menon S, Kienzle V, Allan JA, et al. The IL-6 response to Chlamydia from primary reproductive epithelial cells is highly variable and may be involved in differential susceptibility to the immunopathological consequences of chlamydial infection. BMC Immunol. 2013;14.
38.
Huston WM, Theodoropoulos C, Mathews SA, Timms P. Chlamydia trachomatis responds to heat shock, penicillin induced persistence, and IFN-gamma persistence by altering levels of the extracytoplasmic stress response protease HtrA. BMC Microbiol. 2008;8:190.PubMedPubMedCentral
39.
Huston WM, Swedberg JE, Harris JM, Walsh TP, Mathews SA, Timms P. The temperature activated HtrA protease from pathogen Chlamydia trachomatis acts as both a chaperone and protease at 37 C. FEBS Lett. 2007;581:3382–6.PubMed
40.
Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H. Characteristics of interferon induced tryptophan metabolism in human cells in vitro. Biochim Biophys Acta. 1989;1012:140–7.PubMed
41.
Byrne GI, Lehmann LK, Kirschbaum JG, Borden EC, Lee CM, Brown RR. Induction of tryptophan degradation In Vitro and In Vivo: a gamma-interferon-stimulated activity. J Interf Res. 1986;6:389–96.
42.
Moniz RJ, Chan AM, Gordon LK, Braun J, Arditi M, Kelly KA. Plasmacytoid dendritic cells modulate nonprotective T-cell responses to genital infection by Chlamydia muridarum. FEMS Immunol Med Microbiol. 2010;58:397–404.PubMedPubMedCentral
43.
Buckner LR, Lewis ME, Greene SJ, Foster TP, Quayle AJ. Chlamydia trachomatis infection results in a modest proinflammatory cytokine response and a decrease in T cell chemokine secretion in human polarized endocervical epithelial cells. Cytokine. 2013;63:151–65.PubMedPubMedCentral
44.
Marks E, Tam MA, Lycke NY. The female lower genital tract is a privileged compartment with IL-10 producing dendritic cells and poor Th1 immunity following Chlamydia trachomatis infection. PLoS Pathog. 2010;6:e1001179.PubMedPubMedCentral
45.
Zelante T, Iannitti RG, Fallarino F, Gargaro M, de Luca A, Moretti S, et al. Tryptophan feeding of the IDO1-AhR axis in host-microbial symbiosis. Front Immunol. 2014;5:1–4.
46.
Zelante T, Iannitti RG, Cunha C, DeLuca A, Giovannini G, Pieraccini G, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372–85.PubMed
47.
Vujkovic-Cvijin I, Swainson LA, Chu SN, Ortiz AM, Santee CA, Petriello A, et al. Gut-resident Lactobacillus abundance associates with IDO1 inhibition and Th17 dynamics in SIV-infected macaques. Cell Rep. 2015;13:1589–97.PubMedPubMedCentral
48.
Romani L, Zelante T, De Luca A, Iannitti RG, Moretti S, Bartoli A, et al. Microbiota control of a tryptophan-AhR pathway in disease tolerance to fungi. Eur J Immunol. 2014;44:3192–200.PubMed
49.
Crother TR, Schröder NWJ, Karlin J, Chen S, Shimada K, Slepenkin A, et al. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells. PLoS One. 2011;6:e20784.PubMedPubMedCentral
50.
Kelly KA, Champion CI, Jiang J The Role of T Regulatory Cells in Chlamydia trachomatis Genital Infection Chlamydia 2011. p. 91–112.
51.
Patton DL, Sweeney YTC, Stamm WE. Significant reduction in inflammatory response in the macaque model of chlamydial pelvic inflammatory disease with azithromycin treatment. J Infect Dis. 2005;192:129–35.PubMed
52.
Zhang L, Su Z, Zhang Z, Lin J, Li D-Q, Pflugfelder SC. Effects of azithromycin on gene expression profiles of Proinflammatory and anti-inflammatory mediators in the eyelid margin and conjunctiva of patients with Meibomian gland disease. JAMA Ophthalmol. 2015;133:1117.PubMedPubMedCentral
53.
Sun HS, Eng EWY, Jeganathan S, Sin AT, Patel PC, Gracey E, et al. Chlamydia trachomatis vacuole maturation in infected macrophages. J Leukoc Biol. 2012;92:815–27.PubMedPubMedCentral
54.
Datta B, Njau F, Thalmann J, Haller H, Wagner AD. Differential infection outcome of Chlamydia trachomatis in human blood monocytes and monocyte-derived dendritic cells. BMC Microbiol. 2014;14:1–14.
55.
Du K, Zhou M, Li Q, Liu X. Chlamydia trachomatis inhibits the production of pro-inflammatory cytokines in human PBMCs through induction of IL-10. J Med Microbiol. 2018;67:240–8.PubMed
56.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells. Nat Immunol. 2003;4:330–6.PubMed
57.
Chena G-Y, Chena C, Wanga L, Changa X, Zhenga P, Yang L. Broad expression of the FoxP3 locus in epithelial cells: a caution against an early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells. J Immunol. 2009;180:5163–6.
58.
Munn DH, Mellor AL. IDO and tolerance to tumors. Trends Mol Med. 2004;10:15–8.PubMed
59.
Ferdinande L, Demetteri P, Waeytens A, Taildeman J, Rottiers I, Rottlers P, et al. Inflamed intestinal mucosa features a specific epithelial expression patterns of Indoleamine 2, 3- dioxygenase. Int J iImunology Pharmacol. 2008;21:289–95.
60.
Jordan SJ, Gupta K, Ogendi BMO, Bakshi RK, Kapil R, Press CG, et al. The predominant CD4+ Th1 cytokine elicited to Chlamydia trachomatis infection in women is tumor necrosis factor alpha and not interferon gamma. Clin Vaccine Immunol. 2017;24:1–13.
Metadata
Title
High expression of IDO1 and TGF-β1 during recurrence and post infection clearance with Chlamydia trachomatis, are independent of host IFN-γ response
Authors
Noa Ziklo
Wilhelmina M. Huston
Kuong Taing
Peter Timms
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2019
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-019-3843-4

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