Dendritic cell is one of the first innate immune cell to encounter T. gondii after the parasite crosses the host intestinal epithelium. T. gondii requires intact DC as a carrier to infiltrate into host central nervous system (CNS) without being detected or eliminated by host defense system. The mechanism by which T. gondii avoids innate immune defense of host cell, especially in the dendritic cell is unknown. Therefore, we examined the role of host PI3K/AKT signaling pathway activation by T. gondii in dendritic cell. T. gondii infection or T. gondii excretory/secretory antigen (TgESA) treatment to the murine dendritic cell line DC2.4 induced AKT phosphorylation, and treatment of PI3K inhibitors effectively suppressed the T. gondii proliferation but had no effect on infection rate or invasion rate. Furthermore, it is found that T. gondii or TgESA can reduce H2O2-induced intracellular reactive oxygen species (ROS) as well as host endogenous ROS via PI3K/AKT pathway activation. While searching for the main source of the ROS, we found that NADPH oxidase 4 (NOX4) expression was controlled by T. gondii infection or TgESA treatment, which is in correlation with previous observation of the ROS reduction by identical treatments. These findings suggest that the manipulation of the host PI3K/AKT signaling pathway and NOX4 expression is an essential mechanism for the down-regulation of ROS, and therefore, for the survival and the proliferation of T. gondii.
Citations
Citations to this article as recorded by
Small molecule kinase inhibitor altiratinib inhibits brain cyst forming bradyzoites of Toxoplasma gondii Yeong Hoon Kim, Hye-Jin Ahn, Hwa Sun Kim, Ho-Woo Nam Journal of Microbiology.2025; 63(2): e2409001. CrossRef
The role of Nrf2 signaling in parasitic diseases and its therapeutic potential Mohammadamin Vatankhah, Reza Panahizadeh, Ali Safari, Alireza Ziyabakhsh, Behnam Mohammadi-Ghalehbin, Narges Soozangar, Farhad Jeddi Heliyon.2024; 10(12): e32459. CrossRef
Brain –cyst-driven genes expression in Toxoplasma Gondii Tehran strain: a parasitic-immunogenicity assessment by dint of RNA-Seq Marzieh Asadi, Zahra Babaei, Ali Afgar, Mohammad Hossein Banabazi, Naser ZiaAli, Ahmad Daryani, Ehsan Aghajani, Milad Mahdavi, Mohamadreza Attari, Farzaneh Zarrinkar Veterinary Research Communications.2024; 48(4): 2563. CrossRef
BjussuLAAO-II, an l-amino acid oxidase from Bothrops jararacussu snake venom, impairs Toxoplasma gondii infection in human trophoblast cells and villous explants from the third trimester of pregnancy Thales Alves de Melo Fernandes, Samuel Cota Teixeira, Tássia Rafaela Costa, Alessandra Monteiro Rosini, Guilherme de Souza, Lorena Polloni, Bellisa de Freitas Barbosa, Marcelo José Barbosa Silva, Eloisa Amália Vieira Ferro, Veridiana de Melo Rodrigues Ávi Microbes and Infection.2023; 25(6): 105123. CrossRef
Toxoplasma gondii
inhibits the expression of autophagy-related genes through AKT-dependent inactivation of the transcription factor FOXO3a
Andres Felipe Diez, Louis-Philippe Leroux, Sophie Chagneau, Alexandra Plouffe, Mackenzie Gold, Visnu Chaparro, Maritza Jaramillo, Anita A. Koshy mBio.2023;[Epub] CrossRef
Regulation of phosphoinositide metabolism in Apicomplexan parasites Angela Arabiotorre, Vytas A. Bankaitis, Aby Grabon Frontiers in Cell and Developmental Biology.2023;[Epub] CrossRef
FAF1 downregulation by Toxoplasma gondii enables host IRF3 mobilization and promotes parasite growth Fei‐Fei Gao, Juan‐Hua Quan, In‐Wook Choi, Yeon‐Jae Lee, Seul‐Gi Jang, Jae‐Min Yuk, Young‐Ha Lee, Guang‐Ho Cha Journal of Cellular and Molecular Medicine.2021; 25(19): 9460. CrossRef
Due to the critical location and physiological activities of the retinal pigment epithelial (RPE) cell, it is constantly subjected to contact with various infectious agents and inflammatory mediators. However, little is known about the signaling events in RPE involved in Toxoplasma gondii infection and development. The aim of the study is to screen the host mRNA transcriptional change of 3 inflammation-related gene categories, PI3K/Akt pathway regulatory components, blood vessel development factors and ROS regulators, to prove that PI3K/Akt or mTOR signaling pathway play an essential role in regulating the selected inflammation-related genes. The selected genes include PH domain and leucine- richrepeat protein phosphatases (PHLPP), casein kinase2 (CK2), vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), glutamate-cysteine ligase (GCL), glutathione S-transferase (GST), and NAD(P)H: quinone oxidoreductase (NQO1). Using reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), we found that T. gondii up-regulates PHLPP2, CK2β, VEGF, GCL, GST, and NQO1 gene expression levels, but down-regulates PHLPP1 and PEDF mRNA transcription levels. PI3K inhibition and mTOR inhibition by specific inhibitors showed that most of these host gene expression patterns were due to activation of PI3K/Akt or mTOR pathways with some exceptional cases. Taken together, our results reveal a new molecular mechanism of these gene expression change dependent on PI3K/Akt or mTOR pathways and highlight more systematical insight of how an intracellular T. gondii can manipulate host genes to avoid host defense.
Citations
Citations to this article as recorded by
PTEN regulation in virus-associated cancers Shaian Tavakolian, Zahra Shokati Eshkiki, Abolfazl Akbari, Ebrahim Faghihloo, Seidamir Pasha Tabaeian Pathology - Research and Practice.2025; 266: 155749. CrossRef
MjTX-II, a Lys49-PLA2 from Bothrops moojeni snake venom, restricts Toxoplasma gondii infection via ROS and VEGF regulation Samuel Cota Teixeira, Thales Alves de Melo Fernandes, Guilherme de Souza, Alessandra Monteiro Rosini, Aryani Felixa Fajardo Martínez, Angelica Oliveira Gomes, Rosiane Nascimento Alves, Daiana Silva Lopes, Maria Vitoria da Silva, Emidio Beraldo-Neto, Patrí Chemico-Biological Interactions.2025; 409: 111417. CrossRef
Echinococcus multilocularis
protoscoleces enhance glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway
Tao Zhang, Yaogang Zhang, Zihan Yang, Yuan Jiang, Li Sun, Dengliang Huang, Meiyuan Tian, Yinhong Shen, Jun Deng, Jing Hou, Yanyan Ma Pathogens and Global Health.2023; 117(4): 409. CrossRef
The interplay between toxoplasmosis and host miRNAs: Mechanisms and consequences Ahmed S. Doghish, Mohamed A. Ali, Mahmoud A. Elrebehy, Hend H. Mohamed, Reda Mansour, Aml Ghanem, Ahmed Hassan, Mohammed S. Elballal, Ola Elazazy, Ahmed E. Elesawy, Sherif S. Abdel Mageed, Yara A. Nassar, Osama A. Mohammed, Ahmed I. Abulsoud Pathology - Research and Practice.2023; 250: 154790. CrossRef
Mammalian Target of Rapamycin Inhibitor Rapamycin Alleviates 7-Ketocholesterol Induced Inflammatory Responses and Vascular Endothelial Growth Factor Elevation by Regulating MAPK Pathway in Human Retinal Pigment Epithelium Cells Lin Yang, Peng Yu, Mei Chen, Bo Lei Journal of Ocular Pharmacology and Therapeutics.2022; 38(2): 189. CrossRef
The host mTOR pathway and parasitic diseases pathogenesis Sajad Rashidi, Reza Mansouri, Mohammad Ali-Hassanzadeh, Zahra Mojtahedi, Reza Shafiei, Amir Savardashtaki, Nasrin Hamidizadeh, Mohammadreza Karimazar, Paul Nguewa, Raúl Manzano-Román Parasitology Research.2021; 120(4): 1151. CrossRef
Upregulation of PEDF Predicts a Poor Prognosis and Promotes Esophageal Squamous Cell Carcinoma Progression by Modulating the MAPK/ERK Signaling Pathway Zui Chen, Di Che, Xiaoqiong Gu, Jiamin Lin, Jing Deng, Ping Jiang, Kaixiong Xu, Banglao Xu, Ting Zhang Frontiers in Oncology.2021;[Epub] CrossRef
Modulation of the mTOR pathway plays a central role in dendritic cell functions after Echinococcus granulosus antigen recognition Christian Rodriguez Rodrigues, María Celeste Nicolao, Maia Chop, Natalia Plá, Mora Massaro, Julia Loos, Andrea C. Cumino Scientific Reports.2021;[Epub] CrossRef
Ripasudil alleviated the inflammation of RPE cells by targeting the miR-136-5p/ROCK/NLRP3 pathway Zhao Gao, Qiang Li, Yunda Zhang, Xiaohong Gao, Haiyan Li, Zhigang Yuan BMC Ophthalmology.2020;[Epub] CrossRef
Dipenyleneiodonium Induces Growth Inhibition of Toxoplasma gondii through ROS Induction in ARPE-19 Cells Pu Reum Sun, Fei Fei Gao, Hei Gwon Choi, Wei Zhou, Jae-Min Yuk, Jaeyul Kwon, Young-Ha Lee, Guang-Ho Cha The Korean Journal of Parasitology.2019; 57(2): 83. CrossRef
Simultaneous Ribosome Profiling of Human Host Cells Infected with Toxoplasma gondii Michael J. Holmes, Premal Shah, Ronald C. Wek, William J. Sullivan, Ira J. Blader mSphere.2019;[Epub] CrossRef
First
Prev
