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Chlamydia Muridarum the Obligate Intracellular Pathogen Protects A MyD88-Dependent Early IL-17 Production Protects Mice against Airway Infection with the Obligate Intracellular Pathogen Chlamydia muridarum This information is current as of September 25, 2021. Xiaoyun Zhang, Lifen Gao, Lei Lei, Youmin Zhong, Peter Dube, Michael T. Berton, Bernard Arulanandam, Jinshun Zhang and Guangming Zhong J Immunol 2009; 183:1291-1300; Prepublished online 19 June 2009; Downloaded from doi: 10.4049/jimmunol.0803075 http://www.jimmunol.org/content/183/2/1291 http://www.jimmunol.org/ References This article cites 75 articles, 44 of which you can access for free at: http://www.jimmunol.org/content/183/2/1291.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A MyD88-Dependent Early IL-17 Production Protects Mice against Airway Infection with the Obligate Intracellular Pathogen Chlamydia muridarum1 Xiaoyun Zhang,*‡ Lifen Gao,* Lei Lei,* Youmin Zhong,* Peter Dube,* Michael T. Berton,* Bernard Arulanandam,† Jinshun Zhang,‡ and Guangming Zhong2* We found that IL-17, a signature cytokine of Th17, was produced early in the innate immunity phase after an intranasal infection with the obligate intracellular pathogen Chlamydia muridarum. The airway IL-17, which peaked at 48 h after infection, was dependent on live chlamydial organism replication and MyD88-mediated signaling pathways. Treatment with antibiotics or knockout of the MyD88 gene, but not Toll/IL receptor domain-containing adapter-inducing IFN-␤, can block the early IL-17 production. Treatment of mice with an anti-IL-17-neutralizing mAb enhanced growth of chlamydial organ- Downloaded from isms in the lung, dissemination to other organs, and decreased mouse survival, whereas treatment with an isotype-matched control IgG had no effect. Although IL-17 did not directly affect chlamydial growth in cell culture, it enhanced the production of other inflammatory cytokines and chemokines by Chlamydia-infected cells and promoted neutrophil infiltration in mouse airways during chlamydial infection, which may contribute to the antichlamydial effect of IL-17. These observations suggest that an early IL-17 response as an innate immunity component plays an important role in initiating host defense against infection with intracellular bacterial pathogens in the airway. The Journal of Immunology, 2009, 183: 1291–1300. http://www.jimmunol.org/ he obligate intracellular bacterial species Chlamydia tra- and its signature cytokine IL-17 in C. trachomatis infection has not chomatis, consisting of multiple serovars, can cause many been evaluated. T health problems in humans. Serovars A–C infect human Naive CD4ϩ T cells can be induced to express the transcription ocular epithelial cells, causing trachoma and potentially leading to factor retinoic acid-related orphan receptor ROR␥t and secrete IL- blindness (1). Serovars D–K infect human urogenital tract epithe- 17, developing into the so-called Th17 phenotype, in addition to lial tissues, which, if left untreated, can lead to pelvic inflammatory Th1 and Th2 (18–21). IL-17 is an inflammatory cytokine that diseases, ectopic pregnancy, and infertility (2, 3). The three L or plays a key role in many inflammatory diseases. For example, LGV (lymphogranuloma venereum) serovars (L1–L3) can cause treatment of mice with a neutralizing anti-IL-17 mAb suppressed by guest on September 25, 2021 systemic infections in humans (4–6). The mouse pneumonitis autoimmune inflammation in the CNS (22), and mice deficient in agent strain (designated as MoPn, now classified as a new species, generating Th17 cells were resistant to experimental autoimmune Chlamydia muridarum) can infect mice in both the airway and the encephalomyelitis, collagen-induced arthritis, and inflammatory urogenital tract. Although the C. muridarum organisms cause no bowel disease (22, 23). IL-17 has also been found to play an im- known diseases in humans, these organisms have been used to portant role in host defense against infection by pathogens (24), study C. trachomatis pathogenesis and immunology in various including viruses (25), bacteria (26), and fungi (27, 28). However, mouse models (7–13). Data from the mouse model studies have IL-17 is not always protective, and IL-17-mediated inflammatory shown that the CD4ϩ Th cell (Th1 but not Th2)-dominant and response may even increase host susceptibility and exacerbate pa- IFN-␥-dependent immunity is a major host protective determinant thologies induced by some microbial infections (29–32). In this for controlling chlamydial infection (14), although Abs and CD8ϩ study, we used a mouse model with C. muridarum airway infection T cell-mediated immunity may also contribute to the host resis- to evaluate the role of IL-17 in chlamydial infection. We found that tance to chlamydial infection (15–17). However, the role of Th17 IL-17 was transiently produced early in the innate immunity phase after an intranasal infection with C. muridarum, and this early IL-17 production was dependent on live chlamydial organism rep- lication and MyD88-mediated signaling pathways. Neutralizing *Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, TX 78229; †Department of Biology, University of Texas, San the early IL-17 response significantly enhanced replication of C. Antonio, TX 78249; and ‡Department of Biochemistry, Hebei North University, muridarum and decreased mouse survival. These observations rep- Zhangjiakou Hebei, China resent the first demonstration that an early IL-17 response as an Received for publication September 17, 2008. Accepted for publication May 6, 2009. innate immunity component may play an important role in initi- The costs of publication of this article were defrayed in part by the payment of page ating host defense against infection with intracellular bacterial charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. pathogens in the airway. 1 This work was supported in part by grants (to G.Z.) from the National Institutes of Health. Materials and Methods 2 Address correspondence and reprint requests to Dr. Guangming Zhong, Depart- Chlamydial organisms and chlamydial infection in cell culture ment of Microbiology and Immunology, University of Texas Health Science Cen- ter, 7703 Floyd Curl Drive, San Antonio, TX 78229. E-mail address: Zhongg@ C. muridarum Nigg strain (also called MoPn) or C. trachomatis serovar L2 uthscsa.edu organisms were grown, purified, and titrated as previously described (33). Aliquots of the organisms were stored at Ϫ80°C until use. HeLa or L929 Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 cells (both from American Type Culture Collection) were maintained in www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803075 1292 IL-17 IN CHLAMYDIAL AIRWAY INFECTION DMEM (Life Technologies) with 10% FCS (Life Technologies) at 37°C in 96-well plates at 5 ϫ 106/ml for lymphocyte restimulation experiments an incubator supplied with 5% CO2. To produce mouse lung fibroblast as described below. The mediastinal lymph nodes and spleen organs cells, whole lungs were removed from exsanguinated female C57BL/6 were also harvested from these mice for in vitro lymphocyte restimu- mice (8–12 wk old), transferred to DMEM, minced into 2- to 3-mm pieces, lation assay. Briefly, the tissues were minced, and single-cell suspen- and subsequently treated with freshly made collagenase type XI (0.7 mg/ sions were made. The nucleated splenocytes or lymph node cells ml) and DNase I type IV (30 ␮g/ml) in DMEM at 37°C for 30 min fol- (mainly lymphocytes) plated at 5 ϫ 106/ml were restimulated with UV- lowed by smashing the lung tissue with stainless steel mesh. Cell suspen- inactivated C. muridarum organisms at 1 ϫ 106 IFUs/ml for 3 days. The sions were filtered through 70-␮m pore size nylon cell strainers (Corning culture supernatants were used for cytokine measurements. Costar), washed, and resuspended in DMEM supplemented with 10% FCS. Titrating live chlamydial organisms in mouse organs Cells were grown at 37°C in a humidified 5% CO2 atmosphere in 24-well ϫ 6 plates with coverslips at a density of 1 10 /ml for 4 days. After detached To quantitate the live C. muridarum organisms in mouse lung, spleen, cells were washed away, the confluent fibroblast cell monolayers were and kidney, the organ homogenates produced as described above were cultured for another 24 h before being used for experiments as indicated titrated on HeLa cell monolayers in duplicates as described previously below. The C. muridarum and L2 organisms or mouse tissue homogenate (13). Briefly, serially diluted homogenate samples were inoculated onto samples were used to infect cells. Briefly, HeLa, L929, or mouse primary HeLa cell monolayers grown on coverslips in 24-well plates. After in- lung fibroblast cells grown on glass coverslips in 24-well plates were pre- cubation for 24 h in the presence of 2 ␮g/ml cycloheximide, the cultures ␮ treated with DMEM containing 30 g/ml DEAE-dextran (Sigma-Aldrich) were processed for immunofluorescence assay as described below. The for 10 min. After the DEAE-dextran solution was removed, chlamydial inclusions were counted under a fluorescence microscope. Five random organisms diluted in DMEM were allowed to attach to the cell monolayers fields were counted per coverslip.
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