Journal of Translational Medicine | |
Azithromycin is able to control Toxoplasma gondii infection in human villous explants | |
Eloisa A V Ferro3  José R Mineo4  Maria C Santos1  Olindo A Martins-Filho2  Deise A O Silva4  Celene M O S Alves3  Angelica O Gomes3  Neide M Silva4  Mariana B Angeloni3  Bellisa F Barbosa3  Letícia S Castro-Filice3  | |
[1] Department of Gynecology and Obstetrics, Faculty of Medicine, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil;Laboratory of Chagas Disease, René Rachou Research Center, Fundação Oswaldo Cruz, Belo Horizonte, MG 30190-002, Brazil;Laboratory of Immunophysiology of Reproduction, Institute of Biomedical Sciences, Universidade Federal de Uberlândia, Av. Pará 1720, Uberlândia, MG 38400-902, Brazil;Laboratory of Immunopathology, Institute of Biomedical Sciences, Universidade Federal de Uberlândia, Av. Pará 1720, Uberlândia, MG 38400-902, Brazil | |
关键词: Toxoplasma gondii; Sex hormones; Cytokines; Trophoblast; Human placental villi; Azithromycin; | |
Others : 812493 DOI : 10.1186/1479-5876-12-132 |
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received in 2013-12-19, accepted in 2014-05-14, 发布年份 2014 | |
【 摘 要 】
Background
Although Toxoplasma gondii infection is normally asymptomatic, severe cases of toxoplasmosis may occur in immunosuppressed patients or congenitally infected newborns. When a fetal infection is established, the recommended treatment is a combination of pyrimethamine, sulfadiazine and folinic acid (PSA). The aim of the present study was to evaluate the efficacy of azithromycin to control T. gondii infection in human villous explants.
Methods
Cultures of third trimester human villous explants were infected with T. gondii and simultaneously treated with either PSA or azithromycin. Proliferation of T. gondii, as well as production of cytokines and hormones by chorionic villous explants, was analyzed.
Results
Treatment with either azithromycin or PSA was able to control T. gondii infection in villous explants. After azithromycin or PSA treatment, TNF-α, IL-17A or TGF-β1 levels secreted by infected villous explants did not present significant differences. However, PSA-treated villous explants had decreased levels of IL-10 and increased IL-12 levels, while treatment with azithromycin increased production of IL-6. Additionally, T. gondii-infected villous explants increased secretion of estradiol, progesterone and HCG + β, while treatments with azithromycin or PSA reduced secretion of these hormones concurrently with decrease of parasite load.
Conclusions
In conclusion, these results suggest that azithromycin may be defined as an effective alternative drug to control T. gondii infection at the fetal-maternal interface.
【 授权许可】
2014 Castro-Filice et al.; licensee BioMed Central Ltd.
【 预 览 】
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【 参考文献 】
- [1]Faucher B, Garcia-Meric P, Franck J, Minodier P, Francois P, Gonnet S, L’Ollivier C, Piarroux R: Long-term ocular outcome in congenital toxoplasmosis: a prospective cohort of treated children. J Infect 2012, 64:104-109.
- [2]Oreshkova T, Dimitrov R, Mourdjeva M: A cross-talk of decidual stromal cells, trophoblast, and immune cells: a prerequisite for the success of pregnancy. Am J Reprod Immunol 2012, 68:366-373.
- [3]Robinson DP, Klein SL: Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 2012, 62:263-271.
- [4]Wallon M, Peyron F, Cornu C, Vinault S, Abrahamowicz M, Kopp CB, Binquet C: Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years. Clin Infect Dis 2013, 56:1223-1231.
- [5]Bar-Oz B, Diav-Citrin O, Shechtman S, Tellem R, Arnon J, Francetic I, Berkovitch M, Ornoy A: Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study. Eur J Obstet Gynecol Reprod Biol 2008, 141:31-34.
- [6]Elsheikha HM: Congenital toxoplasmosis: priorities for further health promotion action. Public Health 2008, 122:335-353.
- [7]Tamaru S, Kikuchi A, Takagi K, Wakamatsu M, Horikoshi T, Ogiso Y: Fetal therapy of severe symptomatic toxoplasmosis using azithromycin. J Obstet Gynaecol Res 2011, 37:953-957.
- [8]Montoya JG, Remington JS: Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis 2008, 47:554-566.
- [9]Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA: Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001, 153:961-968.
- [10]Vijayalaxmi KK, Vishalakshi M: Evaluation of the genotoxic effects of pyrimethamine, an antimalarial drug, in the in vivo mouse. Teratog Carcinog Mutagen 2000, 20:65-71.
- [11]Degerli K, Kilimcioglu AA, Kurt O, Tamay AT, Ozbilgin A: Efficacy of azithromycin in a murine toxoplasmosis model, employing a Toxoplasma gondii strain from Turkey. Acta Trop 2003, 88:45-50.
- [12]Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD: Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol 2003, 188:714-718.
- [13]Salman S, Rogerson SJ, Kose K, Griffin S, Gomorai S, Baiwog F, Winmai J, Kandai J, Karunajeewa HA, O’Halloran SJ, Siba P, Ilett KF, Mueller I, Davis TME, et al.: Pharmacokinetic properties of azithromycin in pregnancy. Antimicrob Agents Chemother 2010, 54:360-366.
- [14]Pitsouni E, Iavazzo C, Athanasiou S, Falagas ME: Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection during pregnancy: a meta-analysis of randomised controlled trials. Int J Antimicrob Agents 2007, 30:213-221.
- [15]Srivastava P, Bhengraj AR, Jha HC, Vardhan H, Jha R, Singh LC, Salhan S, Mittal A: Differing effects of azithromycin and doxycycline on cytokines in cells from Chlamydia trachomatis-infected women. DNA Cell Biol 2012, 31:392-401.
- [16]Briggs GG, Freeman RK, Yaffe SJ: Drugs in pregnancy and lactation. 9th edition. Philadelphia: Williams & Wilkins; 2011.
- [17]Chico RM, Chandramohan D: Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy. Expert Opin Drug Metab Toxicol 2011, 7:1153-1167.
- [18]Costa IN, Angeloni MB, Santana LA, Barbosa BF, Silva MC, Rodrigues AA, Rostkowsa C, Magalhaes PM, Pena JD, Silva DA, Mineo JR, Ferro EA, et al.: Azithromycin inhibits vertical transmission of Toxoplasma gondii in Calomys callosus (Rodentia: Cricetidae). Placenta 2009, 30:884-890.
- [19]Franco PS, Gomes AO, Barbosa BF, Angeloni MB, Silva NM, Teixeira-Carvalho A, Martins-Filho OA, Silva DA, Mineo JR, Ferro EA: Azithromycin and spiramycin induce anti-inflammatory response in human trophoblastic (BeWo) cells infected by Toxoplasma gondii but are able to control infection. Placenta 2011, 32:838-844.
- [20]Rubin BK: Immunomodulatory properties of macrolides: overview and historical perspective. Am J Med 2004, 117(Suppl 9A):2S-4S.
- [21]Gomes AO, Silva DAO, Silva NM, Barbosa BF, Franco PS, Angeloni MB, Fermino ML, Roque-Barreira MC, Bechi N, Paulesu LR, Dos Santos MC, Mineo JR, Ferro EA, et al.: Effect of macrophage migration inhibitory factor (MIF) in human placental explants infected with Toxoplasma gondii depends on gestational age. Am J Pathol 2011, 178:2792-2801.
- [22]Ferro EA, Silva DA, Bevilacqua E, Mineo JR: Effect of Toxoplasma gondii infection kinetics on trophoblast cell population in Calomys callosus, a model of congenital toxoplasmosis. Infect Immun 2002, 70:7089-7094.
- [23]Remington JS, McLeod R, Thulliez P, Desmonts G: Infectious diseases of the fetus and newborn infant. 6th edition. Philadelphia: Saunders; 2006.
- [24]Teo CF, Zhou XW, Bogyo M, Carruthers VB: Cysteine protease inhibitors block Toxoplasma gondii microneme secretion and cell invasion. Antimicrob Agents Chemother 2007, 51:679-688.
- [25]Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR: Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 1982, 126:131-138.
- [26]Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248-254.
- [27]Lopes CD, Silva NM, Ferro EA, Sousa RA, Firminot ML, Bernardes ES, Roque-Barreira MC, Pena JD: Azithromycin reduces ocular infection during congenital transmission of toxoplasmosis in the Calomys callosus model. J Parasitol 2009, 95:1005-1010.
- [28]Chico RM, Pittrof R, Greenwood B, Chandramohan D: Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy. Malar J 2008, 7:255. BioMed Central Full Text
- [29]Pereira MR, Henrich PP, Sidhu AB, Johnson D, Hardink J, Van Deusen J, Lin J, Gore K, O’Brien C, Wele M, Djimde A, Chandra R, Fidock DA, et al.: In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine. Antimicrob Agents Chemother 2011, 55:3115-3124.
- [30]Kanoh S, Rubin BK: Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev 2010, 23:590-615.
- [31]Choi EY, Jin JY, Choi JI, Choi IS, Kim SJ: Effect of azithromycin on Prevotella intermedia lipopolysaccharide-induced production of interleukin-6 in murine macrophages. Eur J Pharmacol 2014, 729:10-16.
- [32]Cai M, Bonella F, Dai H, Sarria R, Guzman J, Costabel U: Macrolides inhibit cytokine production by alveolar macrophages in bronchiolitis obliterans organizing pneumonia. Immunobiology 2013, 218:930-937.
- [33]Banjanac M, Munic Kos V, Nujic K, Vrancic M, Belamaric D, Crnkovic S, Hlevnjak M, Erakovic Haber V: Anti-inflammatory mechanism of action of azithromycin in LPS-stimulated J774A.1 cells. Pharmacol Res 2012, 66:357-362.
- [34]Kamemoto A, Ara T, Hattori T, Fujinami Y, Imamura Y, Wang PL: Macrolide antibiotics like azithromycin increase lipopolysaccharide-induced IL-8 production by human gingival fibroblasts. Eur J Med Res 2009, 14:309-314. BioMed Central Full Text
- [35]Kurdowska A, Noble JM, Griffith DE: The effect of azithromycin and clarithromycin on ex vivo interleukin-8 (IL-8) release from whole blood and IL-8 production by human alveolar macrophages. J Antimicrob Chemother 2001, 47:867-870.
- [36]Castro AS, Alves CM, Angeloni MB, Gomes AO, Barbosa BF, Franco PS, Silva DA, Martins-Filho OA, Mineo JR, Mineo TW, Ferro EA: Trophoblast cells are able to regulate monocyte activity to control Toxoplasma gondii infection. Placenta 2013, 34:240-247.
- [37]Silver JS, Stumhofer JS, Passos S, Ernst M, Hunter CA: IL-6 mediates the susceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii. J Immunol 2011, 187:350-360.
- [38]Meisser A, Cameo P, Islami D, Campana A, Bischof P: Effects of interleukin-6 (IL-6) on cytotrophoblastic cells. Mol Hum Reprod 1999, 5:1055-1058.
- [39]Tsukihara S, Harada T, Deura I, Mitsunari M, Yoshida S, Iwabe T, Terakawa N: Interleukin-1beta-induced expression of IL-6 and production of human chorionic gonadotropin in human trophoblast cells via nuclear factor-kappaB activation. Am J Reprod Immunol 2004, 52:218-223.
- [40]Li Y, Matsuzaki N, Masuhiro K, Kameda T, Taniguchi T, Saji F, Yone K, Tanizawa O: Trophoblast-derived tumor necrosis factor-alpha induces release of human chorionic gonadotropin using interleukin-6 (IL-6) and IL-6-receptor-dependent system in the normal human trophoblasts. J Clin Endocrinol Metab 1992, 74:184-191.
- [41]Uchide N, Ohyama K, Bessho T, Takeichi M, Toyoda H: Possible roles of proinflammatory and chemoattractive cytokines produced by human fetal membrane cells in the pathology of adverse pregnancy outcomes associated with influenza virus infection. Mediators Inflamm 2012, 2012:270670.
- [42]Agrawal V, Hirsch E: Intrauterine infection and preterm labor. Semin Fetal Neonatal Med 2012, 17:12-19.
- [43]Coutinho LB, Gomes AO, Araujo EC, Barenco PV, Santos JL, Caixeta DR, Silva DA, Cunha-Junior JP, Ferro EA, Silva NM: The impaired pregnancy outcome in murine congenital toxoplasmosis is associated with a pro-inflammatory immune response, but not correlated with decidual inducible nitric oxide synthase expression. Int J Parasitol 2012, 42:341-352.
- [44]Krishnan L, Guilbert LJ, Russell AS, Wegmann TG, Mosmann TR, Belosevic M: Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-gamma response and increased production of T helper 2 cytokines. J Immunol 1996, 156:644-652.
- [45]Luft BJ, Remington JS: Effect of pregnancy on resistance to Listeria monocytogenes and Toxoplasma gondii infections in mice. Infect Immun 1982, 38:1164-1171.
- [46]Menendez C: Malaria during pregnancy: a priority area of malaria research and control. Parasitol Today 1995, 11:178-183.
- [47]Jones LA, Kreem S, Shweash M, Paul A, Alexander J, Roberts CW: Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. J Immunol 2010, 185:4525-4534.
- [48]Jones LA, Anthony JP, Henriquez FL, Lyons RE, Nickdel MB, Carter KC, Alexander J, Roberts CW: Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors. Immunology 2008, 125:59-69.
- [49]Escobedo G, Roberts CW, Carrero JC, Morales-Montor J: Parasite regulation by host hormones: an old mechanism of host exploitation? Trends Parasitol 2005, 21:588-593.
- [50]Pfaff AW, Villard O, Klein JP, Mousli M, Candolfi E: Regulation of Toxoplasma gondii multiplication in BeWo trophoblast cells: cross-regulation of nitric oxide production and polyamine biosynthesis. Int J Parasitol 2005, 35:1569-1576.
- [51]Fichera ME, Roos DS: A plastid organelle as a drug target in apicomplexan parasites. Nature 1997, 390:407-409.
- [52]Muller J, Hemphill A: Drug target identification in intracellular and extracellular protozoan parasites. Curr Top Med Chem 2011, 11:2029-2038.
- [53]McFadden GI, Roos DS: Apicomplexan plastids as drug targets. Trends Microbiol 1999, 7:328-333.