Toxoplasma gondii is an intracellular parasite that causes severe disease when the infection occurs during pregnancy. Adenosine is a purine nucleoside involved in numerous physiological processes; however, the role of adenosine receptors in T. gondii-induced trophoblast cell function has not been investigated until now. The goal of the present study was to evaluate the intracellular signaling pathways regulated by adenosine receptors using a HTR-8/SVneo trophoblast cell model of T. gondii infection. HTR8/SVneo human extravillous trophoblast cells were infected with or without T. gondii and then evaluated for cell morphology, intracellular proliferation of the parasite, adenosine receptor expression, TNF-α production and mitogen-activated protein (MAP) kinase signaling pathways triggered by adenosine A3 receptor (A3AR). HTR8/SVneo cells infected with T. gondii exhibited an altered cytoskeletal changes, an increased infection rate and reduced viability in an infection time-dependent manner. T. gondii significantly promoted increased TNF-α production, A3AR protein levels and p38, ERK1/2 and JNK phosphorylation compared to those observed in uninfected control cells. Moreover, the inhibition of A3AR by A3AR siRNA transfection apparently suppressed the T. gondii infection-mediated upregulation of TNF-α, A3AR production and MAPK activation. In addition, T. gondii-promoted TNF-α secretion was dramatically attenuated by pretreatment with PD098059 or SP600125. These results indicate that A3AR-mediated activation of ERK1/2 and JNK positively regulates TNF-α secretion in T. gondii-infected HTR8/SVneo cells.
Citations
Citations to this article as recorded by
LINC00152 knockdown exerts repressive effects on epithelial-mesenchymal transition in bladder cancer Guoping Wang, Meijun Han, Fei Chen, Jinquan Liu, Jie Zhang Cytotechnology.2025;[Epub] CrossRef
Structural Simplification from Tricyclic to Bicyclic Scaffolds: A Long-Term Investigation in the Field of Adenosine Receptor Antagonists Costanza Ceni, Sara Calenda, Giulia Vagnoni, Daniela Catarzi, Flavia Varano, Vittoria Colotta Cells.2025; 14(18): 1480. CrossRef
Suppression by central adenosine A3 receptors of the cholinergic defense against cardiovascular aberrations of sepsis: role of PI3K/MAPKs/NFκB signaling Amany E. El-Naggar, Mai M. Helmy, Sahar M. El-Gowilly, Mahmoud M. El-Mas Frontiers in Pharmacology.2024;[Epub] CrossRef
Modeling the human placental barrier to understand Toxoplasma gondii´s vertical transmission Paula Faral-Tello, Romina Pagotto, Mariela Bollati-Fogolín, Maria E. Francia Frontiers in Cellular and Infection Microbiology.2023;[Epub] CrossRef
TNF-α/anti-TNF-αdrugs and its effect on pregnancy outcomes Fang-fang Dai, Min Hu, Yu-wei Zhang, Rong-hui Zhu, Li-ping Chen, Zhi-dian Li, Yan-jie Huang, Wei Hu, Yan-xiang Cheng Expert Reviews in Molecular Medicine.2022;[Epub] CrossRef
Toxoplasma gondii is an apicomplexan zoonotic protozoan parasite that infects most species of warm-blooded animals, including humans. The heavy incidence and severe or lethal damage caused by T. gondii infection clearly indicate a need for the development of an effective vaccine. T. gondii GRA8 is a member of the dense granules protein family and is used as a marker of acute infection. In the present study, we evaluated the protective immunity induced by DNA vaccination based on a recombinant eukaryotic plasmid, pDsRed2-GRA8, against acute toxoplasmosis in mice. BALB/c mice were intramuscularly immunized with the pDsRed2-GRA8 plasmid and then challenged by infection with the highly virulent GFP-RH strain of T. gondii. The specific immune responses and protective efficacy against T. gondii of this vaccine were analyzed by measuring cytokine and serum antibody titers, splenocyte proliferation assays, and the survival times of mice after challenge. Our results showed that mice immunized with pDsRed2-GRA8 demonstrated specific humoral and cellular responses, induced higher IgG antibody titers with predominant IgG2a production; increased levels of IL-10, IL-12 (p70), IFN-γ, TNF-α, and splenocyte proliferation; and prolonged survival times compared to those of control mice. The present study showed that DNA immunization with pDsRed2-GRA8 induced humoral and cellular immune responses, and all immunized mice showed greater Th1-type immune responses and longer survival times than those of control mice. These results indicated that T. gondii GRA8 DNA immunization induces a partial protective effect against acute toxoplasmosis.
Insight into the current
Toxoplasma gondii
DNA vaccine: a review article
Xirui Zhang, Hao Yuan, Yasser S. Mahmmod, Zipeng Yang, Mengpo Zhao, Yining Song, Shengjun Luo, Xiu-Xiang Zhang, Zi-Guo Yuan Expert Review of Vaccines.2023; 22(1): 66. CrossRef
Co-Immunization with DNA Vaccines Expressing SABP1 and SAG1 Proteins Effectively Enhanced Mice Resistance to Toxoplasma gondii Acute Infection Xiaoyu Sang, Xiang Li, Ran Chen, Ying Feng, Ting He, Xiaohan Zhang, Saeed El-Ashram, Ebtsam Al-Olayan, Na Yang Vaccines.2023; 11(7): 1190. CrossRef
Evaluation of anti‐tick efficiency in rabbits induced by DNA vaccines encoding Haemaphysalis longicornis lipocalin homologue Xiang‐Yuan Fan, Xiao‐Can Xu, Ya‐Xue Wu, Xiao‐Ya Liu, Feng Yang, Yong‐Hong Hu Medical and Veterinary Entomology.2022; 36(4): 511. CrossRef
Review of DNA Vaccine Approaches Against the Parasite Toxoplasma gondii Rosalie C. Warner, Ryan C. Chapman, Brianna N. Davis, Paul H. Davis Journal of Parasitology.2021;[Epub] CrossRef
A systematic review on the role of GRA proteins of Toxoplasma gondii in host immunization Fatemeh Rezaei, Mahdi Sharif, Shahabeddin Sarvi, Seyed Hossein Hejazi, Sargis Aghayan, Abdol Sattar Pagheh, Samira Dodangeh, Ahmad Daryani Journal of Microbiological Methods.2019; 165: 105696. CrossRef
Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines, which are important for innate immunity. NLRs, i.e., nucleotide-binding oligomerization domain (NOD)-like receptors, play a crucial role as innate immune sensors and form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1β. To elucidate the role of inflammasome components in T. gondii-infected THP-1 macrophages, we examined inflammasome-related gene expression and mechanisms of inflammasome-regulated cytokine IL-1β secretion. The results revealed a significant upregulation of IL-1β after T. gondii infection. T. gondii infection also upregulated the expression of inflammasome sensors, including NLRP1, NLRP3, NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and NAIP, in a time-dependent manner. The infection also upregulated inflammasome adaptor protein ASC and caspase-1 mRNA levels. From this study, we newly found that T. gondii infection regulates NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and neuronal apoptosis inhibitor protein (NAIP) gene expressions in THP-1 macrophages and that the role of the inflammasome-related genes may be critical for mediating the innate immune responses to T. gondii infection.
Citations
Citations to this article as recorded by
Investigating the possible role of toxoplasmosis and Interleukin-1β variants on the immune response in Egyptian diabetic patients Asmaa Ibrahim, Nancy O. kamel, Fatma Rageh, Rasha Elgamal, Mohamed A. Sakr, Eman M. Osman, Samar s. Ahmed, Hend A. Yassin, Yasmine N. Kamel, Reham F. Othman, Manar Ezzelarab Ramadan Microbes and Infection.2025; 27(7): 105559. CrossRef
Early responses of primary human and bovine monocytes, monocytic THP-1 cells and THP-1 cell-derived macrophages to vital Toxoplasma gondii tachyzoites Dominik Hanke, Zahady D. Velásquez, Kathrin Büttner, Andreas Krueger, Ralf Ross, Andreas Hecker, Sybille Mazurek, Veronika Grau, Anja Taubert, Carlos Hermosilla, Katrin Richter, Iván Conejeros Frontiers in Immunology.2025;[Epub] CrossRef
Unraveling the NLRP family: Structure, function, activation, critical influence on tumor progression, and potential as targets for cancer therapy Xueqing Zhou, Yongguang Tao, Ying Shi Cancer Letters.2024; 605: 217283. CrossRef
Role of inflammasomes in Toxoplasma and Plasmodium infections Zhi-xin Wang, Wan-jun Jiao, Yong Yang, Hong-li Liu, Hai-long Wang Parasites & Vectors.2024;[Epub] CrossRef
NLRP13 inflammasome complex is hypermethylated in familial Mediterranean fever and global methylation correlates with the disease severity Feyzanur Yildirimtepe Caldiran, Koksal Deveci, Ercan Cacan Annals of Human Genetics.2023; 87(3): 115. CrossRef
Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells Ehsan Ahmadpour, Farhad Babaie, Tohid Kazemi, Sirous Mehrani Moghaddam, Ata Moghimi, Ramin Hosseinzadeh, Veeranoot Nissapatorn, Abdol Sattar Pagheh Pathogens.2023; 12(2): 253. CrossRef
P2X7 Receptor Modulation of the Gut Microbiota and the Inflammasome Determines the Severity of Toxoplasma gondii-Induced Ileitis Aline Cristina Abreu Moreira-Souza, Hayandra Ferreira Nanini, Thuany Prado Rangel, Sthefani Rodrigues Batista da Silva, Beatriz Pêgo Damasceno, Beatriz Elias Ribeiro, Cynthia M. Cascabulho, Fabiano Thompson, Camille Leal, Patrícia Teixeira Santana, Siane Biomedicines.2023; 11(2): 555. CrossRef
The role of NOD-like receptors in innate immunity Cássio Luiz Coutinho Almeida-da-Silva, Luiz Eduardo Baggio Savio, Robson Coutinho-Silva, David M. Ojcius Frontiers in Immunology.2023;[Epub] CrossRef
NLRP3 Plays a Key Role in Antihelminth Immunity in the Enteral and Parenteral Stages of Trichinella spiralis-Infected Mice Tian-Xu Pan, Hai-Bin Huang, Hui-Nan Lu, Guang-Xun Zhao, Yu Quan, Jun-Yi Li, Ying Xue, Zhi-Yu Zhu, Yue Wang, Chun-Wei Shi, Nan Wang, Gui-Lian Yang, Chun-Feng Wang, De’Broski R. Herbert Infection and Immunity.2023;[Epub] CrossRef
Toxoplasma gondii profilin induces NLRP3 activation and IL-1β production/secretion in THP-1 cells Hossein Pazoki, Hamed Mirjalali, Maryam Niyyati, Seyed Javad Seyed Tabaei, Nariman Mosaffa, Shabnam Shahrokh, Hamid Asadzadeh Ahdaei, Andreas Kupz, Mohammad Reza Zali Microbial Pathogenesis.2023; 180: 106120. CrossRef
Possible therapeutic targets for NLRP3 inflammasome-induced breast cancer Xixi Wang, Junyi Lin, Zhe Wang, Zhi Li, Minghua Wang Discover Oncology.2023;[Epub] CrossRef
Toxoplasma gondii Induces Pyroptosis in Human Placental Trophoblast and Amniotic Cells by Inducing ROS Production and Activation of Cathepsin B and NLRP1/NLRP3/NLRC4/AIM2 Inflammasome Juan-Hua Quan, Fei Fei Gao, Tian-Zhong Ma, Wei Ye, Xiang Gao, Ming-Zhu Deng, Lan-Lan Yin, In-Wook Choi, Jae-Min Yuk, Guang-Ho Cha, Young-Ha Lee, Jia-Qi Chu The American Journal of Pathology.2023; 193(12): 2047. CrossRef
Role of Microgliosis and NLRP3 Inflammasome in Parkinson’s Disease Pathogenesis and Therapy Fillipe M. de Araújo, Lorena Cuenca-Bermejo, Emiliano Fernández-Villalba, Silvia L. Costa, Victor Diogenes A. Silva, Maria Trinidad Herrero Cellular and Molecular Neurobiology.2022; 42(5): 1283. CrossRef
Latent Upregulation of Nlrp3, Nlrc4 and Aim2 Differentiates between Asymptomatic and Symptomatic Trichomonas vaginalis Infection Sonal Yadav, Vivek Verma, Rakesh Singh Dhanda, Sumeeta Khurana, Manisha Yadav Immunological Investigations.2022; 51(5): 1127. CrossRef
P. aeruginosa biofilm activates the NLRP3 inflammasomes in vitro Qi Tan, Qing Ai, Yu He, Fang Li, Jialin Yu Microbial Pathogenesis.2022; 164: 105379. CrossRef
In silico analysis of expression and DNA methylation profiles of NLRP13 inflammasome in tumor cells Feyzanur Yildirimtepe Caldiran, Caglar Berkel, Koksal Deveci, Ercan Cacan Human Gene.2022; 33: 201067. CrossRef
The strategies of NLRP3 inflammasome to combat Toxoplasma gondii Chanjin Yoon, Yu Seong Ham, Woo Jin Gil, Chul-Su Yang Frontiers in Immunology.2022;[Epub] CrossRef
Expression profiles of NOD-like receptors and regulation of NLRP3 inflammasome activation in Toxoplasma gondii-infected human small intestinal epithelial cells Jia-Qi Chu, Fei Fei Gao, Weiyun Wu, Chunchao Li, Zhaobin Pan, Jinhui Sun, Hao Wang, Cong Huang, Sang Hyuk Lee, Juan-Hua Quan, Young-Ha Lee Parasites & Vectors.2021;[Epub] CrossRef
RIPK3 Facilitates Host Resistance to Oral Toxoplasma gondii Infection Patrick W. Cervantes, Bruno Martorelli Di Genova, Billy Joel Erazo Flores, Laura J. Knoll, Jeroen P. J. Saeij Infection and Immunity.2021;[Epub] CrossRef
Soluble total antigen derived from Toxoplasma gondii tachyzoites increased the expression levels of NLRP1, NLRP3, NLRC4, AIM2, and the release of mature form of IL1β, but downregulated the expression of IL1β and IL18 genes in THP-1cell line Hossein Pazoki, Hanieh Mohammad Rahimi, Hamed Mirjalali, Maryam Niyyati, Nariman Mosaffa, Seyed Javad Seyed Tabaei, Shabnam Shahrokh, Hamid Asadzadeh Aghdaei, Mohammad Reza Zali Microbial Pathogenesis.2021; 158: 105072. CrossRef
Host inflammatory responses to intracellular invaders: Review study Ramesh Chandra Rai Life Sciences.2020; 240: 117084. CrossRef
Treatment of mice with S4B6 IL-2 complex prevents lethal toxoplasmosis via IL-12- and IL-18-dependent interferon-gamma production by non-CD4 immune cells Andreas Kupz, Saparna Pai, Paul R. Giacomin, Jennifer A. Whan, Robert A. Walker, Pierre-Mehdi Hammoudi, Nicholas C. Smith, Catherine M. Miller Scientific Reports.2020;[Epub] CrossRef
Neospora caninum infection induces an isolate virulence-dependent pro-inflammatory gene expression profile in bovine monocyte-derived macrophages Marta García-Sánchez, Laura Jiménez-Pelayo, Pilar Horcajo, Esther Collantes-Fernández, Luis Miguel Ortega-Mora, Javier Regidor-Cerrillo Parasites & Vectors.2020;[Epub] CrossRef
A Comparison of Transcriptional Diversity of Swine Macrophages Infected With TgHB1 Strain of Toxoplasma gondii Isolated in China Yongle Song, Lindong Song, Xiaoting Wan, Bang Shen, Rui Fang, Min Hu, Junlong Zhao, Yanqin Zhou Frontiers in Cellular and Infection Microbiology.2020;[Epub] CrossRef
Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action Jenni A. Hayward, Anukriti Mathur, Chinh Ngo, Si Ming Man Microbiology and Molecular Biology Reviews.2018;[Epub] CrossRef
P2X7 receptor mediates NLRP3-dependent IL-1β secretion and parasite proliferation in Toxoplasma gondii-infected human small intestinal epithelial cells Juan-Hua Quan, Rui Huang, Zhuang Wang, Shuai Huang, In-Wook Choi, Yu Zhou, Young-Ha Lee, Jia-Qi Chu Parasites & Vectors.2018;[Epub] CrossRef
First
Prev
