Entamoeba histolytica is an enteric tissue-invasive protozoan parasite causing amoebic colitis and liver abscesses in humans. Amoebic contact with host cells activates intracellular signaling pathways that lead to host cell death via generation of caspase-3, calpain, Ca2+ elevation, and reactive oxygen species (ROS). We previously reported that various NADPH oxidases (NOXs) are responsible for ROS-dependent death of various host cells induced by amoeba. In the present study, we investigated the specific NOX isoform involved in ROS-dependent death of hepatocytes induced by amoebas. Co-incubation of hepatoma HepG2 cells with live amoebic trophozoites resulted in remarkably increased DNA fragmentation compared to cells incubated with medium alone. HepG2 cells that adhered to amoebic trophozoites showed strong dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence, suggesting intracellular ROS accumulation within host cells stimulated by amoebic trophozoites. Pretreatment of HepG2 cells with the general NOX inhibitor DPI or NOX2-specific inhibitor GSK 2795039 reduced Entamoeba-induced ROS generation. Similarly, Entamoeba-induced LDH release from HepG2 cells was effectively inhibited by pretreatment with DPI or GSK 2795039. In NOX2-silenced HepG2 cells, Entamoeba-induced LDH release was also significantly inhibited compared with controls. Taken together, the results support an important role of NOX2-derived ROS in hepatocyte death induced by E. histolytica.
Citations
Citations to this article as recorded by
CysLT receptor-mediated NOX2 activation is required for IL-8 production in HMC-1 cells induced by Trichomonas vaginalis-derived secretory products Young Ah Lee, Myeong Heon Shin Parasites, Hosts and Diseases.2024; 62(3): 270. CrossRef
Optimization of 18 S rRNA metabarcoding for the simultaneous diagnosis of intestinal parasites Dongjun Kang, Jun Ho Choi, Myungjun Kim, Sohyeon Yun, Singeun Oh, Myung-hee Yi, Tai-Soon Yong, Young Ah Lee, Myeong Heon Shin, Ju Yeong Kim Scientific Reports.2024;[Epub] CrossRef
All living organisms are destined to die. Cells, the core of those living creatures, move toward the irresistible direction of death. The question of how to die is critical and is very interesting. There are various types of death in life, including natural death, accidental death, questionable death, suicide, and homicide. The mechanisms and molecules involved in cell death also differ depending on the type of death. The dysenteric amoeba, E. histolytica, designated by the German zoologist Fritz Schaudinn in 1903, has the meaning of tissue lysis; i.e., tissue destroying, in its name. It was initially thought that the amoebae lyse tissue very quickly leading to cell death called necrosis. However, advances in measuring cell death have allowed us to more clearly investigate the various forms of cell death induced by amoeba. Increasing evidence has shown that E. histolytica can cause host cell death through induction of various intracellular signaling pathways. Understanding of the mechanisms and signaling molecules involved in host cell death induced by amoeba can provide new insights on the tissue pathology and parasitism in human amoebiasis. In this review, we emphasized on the signaling role of NADPH oxidases in reactive oxygen species (ROS)-dependent cell death by pathogenic E. histolytica.
Citations
Citations to this article as recorded by
Involvement of NOX2-derived ROS in human hepatoma HepG2 cell death induced by Entamoeba histolytica Young Ah Lee, Myeong Heon Shin Parasites, Hosts and Diseases.2023; 61(4): 388. CrossRef
The pathogenic free-living amoeba Naegleria fowleri causes primary amoebic meningoencephalitis, a fatal infection, by penetrating the nasal mucosa and migrating to the brain via the olfactory nerves. N. fowleri can induce host cell death via lytic necrosis. Similar to phosphorylation, O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is involved in various cell-signaling processes, including apoptosis and proliferation, with O-GlcNAc addition and removal regulated by O-GlcNAc transferase and O-GlcNAcase (OGA), respectively. However, the detailed mechanism of host cell death induced by N. fowleri is unknown. In this study, we investigated whether N. fowleri can induce the modulation of O-GlcNAcylated proteins during cell death in Jurkat T cells. Co-incubation with live N. fowleri trophozoites increased DNA fragmentation. In addition, incubation with N. fowleri induced a dramatic reduction in O-GlcNAcylated protein levels in 30 min. Moreover, pretreatment of Jurkat T cells with the OGA inhibitor PUGNAc prevented N. fowleri–induced O-deGlcNAcylation and DNA fragmentation. These results suggest that O-deGlcNAcylation is an important signaling process that occurs during Jurkat T cell death induced by N. fowleri.
Citations
Citations to this article as recorded by
Primary amebic meningoencephalitis in children: A case report and literature review Binbin Song, Junwen Zheng, Dongchi Zhao IDCases.2024; 37: e02028. CrossRef
The enteric protozoan parasite Entamoeba histolytica is the causative agent of human amebiasis. During infection, adherence of E. histolytica through Gal/GalNAc lectin on the surface of the amoeba can induce caspase-3-dependent or -independent host cell death. Phosphorylinositol 3-kinase (PI3K) and protein kinase C (PKC) in E. histolytica play an important function in the adhesion, killing, or phagocytosis of target cells. In this study, we examined the role of amoebic PI3K and PKC in amoeba-induced apoptotic cell death in Jurkat T cells. When Jurkat T cells were incubated with E. histolytica trophozoites, phosphatidylserine (PS) externalization and DNA fragmentation in Jurkat cells were markedly increased compared to those of cells incubated with medium alone. However, when amoebae were pretreated with a PI3K inhibitor, wortmannin before being incubated with E. histolytica, E. histolytica-induced PS externalization and DNA fragmentation in Jurkat cells were significantly reduced compared to results for amoebae pretreated with DMSO. In addition, pretreatment of amoebae with a PKC inhibitor, staurosporine strongly inhibited Jurkat T cell death. However, E. histolytica-induced cleavage of caspase-3, -6, and -7 were not inhibited by pretreatment of amoebae with wortmannin or staurosporin. In addition, we found that amoebic PI3K and PKC have an important role on amoeba adhesion to host compartment. These results suggest that amebic PI3K and PKC activation may play an important role in caspase-independent cell death in Entamoeba-induced apoptosis.
Citations
Citations to this article as recorded by
PI3K/AKT signaling in parasites and parasite diseases: Role and therapeutic potential Lujun Yan, Yating Li, Xing Yang, Rui Li, Chunyin Zhu, Xuedong He, Xiaoliang Jin, Guanghui Zheng, Naunain Mehmood, William C. Cho, Shijun Bao, Houhui Song, Yadong Zheng Virulence.2025;[Epub] CrossRef
Formation and culture of cell spheroids by using magnetic nanostructures resembling a crown of thorns Shijiao Li, Jingjiang Qiu, Zhongwei Guo, Qiulei Gao, Chen-Yu Huang, Yilin Hao, Yifan Hu, Tianshui Liang, Ming Zhai, Yudong Zhang, Bangbang Nie, Wei-Jen Chang, Wen Wang, Rui Xi, Ronghan Wei Biofabrication.2024; 16(4): 045018. CrossRef
AGC family kinase of Entamoeba histolytica: Decoding the members biochemically Azhar Ahmad, Vikas Kumar, Tushar Kushwaha, Akash Kumar, Deepak Sehgal, Krishna K. Inampudi, Somlata, Katherine S. Ralston PLOS Pathogens.2024; 20(11): e1012729. CrossRef
Pathogenicity and virulence of
Entamoeba histolytica
, the agent of amoebiasis
Nancy Guillén Virulence.2023;[Epub] CrossRef
Apoptotic mimicry as a strategy for the establishment of parasitic infections: parasite- and host-derived phosphatidylserine as key molecule João Luiz Mendes Wanderley, Renato Augusto DaMatta, Marcello André Barcinski Cell Communication and Signaling.2020;[Epub] CrossRef
Entamoeba histolytica Up-Regulates MicroRNA-643 to Promote Apoptosis by Targeting XIAP in Human Epithelial Colon Cells Itzel López-Rosas, César López-Camarillo, Yarely M. Salinas-Vera, Olga N. Hernández-de la Cruz, Carlos Palma-Flores, Bibiana Chávez-Munguía, Osbaldo Resendis-Antonio, Nancy Guillen, Carlos Pérez-Plasencia, María Elizbeth Álvarez-Sánchez, Esther Ramírez-Mo Frontiers in Cellular and Infection Microbiology.2019;[Epub] CrossRef
Phosphatidylinositol Kinases and Phosphatases in Entamoeba histolytica Kumiko Nakada-Tsukui, Natsuki Watanabe, Tomohiko Maehama, Tomoyoshi Nozaki Frontiers in Cellular and Infection Microbiology.2019;[Epub] CrossRef
AGC family kinase 1 participates in trogocytosis but not in phagocytosis in Entamoeba histolytica
Somlata, Kumiko Nakada-Tsukui, Tomoyoshi Nozaki Nature Communications.2017;[Epub] CrossRef
Entamoeba histolytica, which causes amoebic colitis and occasionally liver abscess in humans, is able to induce host cell death. However, signaling mechanisms of colon cell death induced by E. histolytica are not fully elucidated. In this study, we investigated the signaling role of NOX in cell death of HT29 colonic epithelial cells induced by E. histolytica. Incubation of HT29 cells with amoebic trophozoites resulted in DNA fragmentation that is a hallmark of apoptotic cell death. In addition, E. histolytica generate intracellular reactive oxygen species (ROS) in a contact-dependent manner. Inhibition of intracellular ROS level with treatment with DPI, an inhibitor of NADPH oxidases (NOXs), decreased Entamoeba-induced ROS generation and cell death in HT29 cells. However, pan-caspase inhibitor did not affect E. histolytica-induced HT29 cell death. In HT29 cells, catalytic subunit NOX1 and regulatory subunit Rac1 for NOX1 activation were highly expressed. We next investigated whether NADPH oxidase 1 (NOX1)-derived ROS is closely associated with HT29 cell death induced by E. histolytica. Suppression of Rac1 by siRNA significantly inhibited Entamoeba-induced cell death. Moreover, knockdown of NOX1 by siRNA, effectively inhibited E. histolytica-triggered DNA fragmentation in HT29 cells. These results suggest that NOX1-derived ROS is required for apoptotic cell death in HT29 colon epithelial cells induced by E. histolytica.
Citations
Citations to this article as recorded by
Involvement of NOX2-derived ROS in human hepatoma HepG2 cell death induced by Entamoeba histolytica Young Ah Lee, Myeong Heon Shin Parasites, Hosts and Diseases.2023; 61(4): 388. CrossRef
Signaling Role of NADPH Oxidases in ROS-Dependent Host Cell Death Induced by Pathogenic Entamoeba histolytica Young Ah Lee, Seobo Sim, Kyeong Ah Kim, Myeong Heon Shin The Korean Journal of Parasitology.2022; 60(3): 155. CrossRef
The interaction betweenEntamoeba histolyticaand enterobacteria shed light on an ancient antibacterial response Nancy Guillén Cellular Microbiology.2019;[Epub] CrossRef
NOX4 activation is involved in ROS‐dependent Jurkat T‐cell death induced by Entamoeba histolytica Young Ah Lee, Kyeong Ah Kim, Arim Min, Myeong Heon Shin Parasite Immunology.2019;[Epub] CrossRef
O-deGlcNAcylation is required for Entamoeba histolytica-induced HepG2 cell death Young Ah Lee, Arim Min, Myeong Heon Shin Microbial Pathogenesis.2018; 123: 285. CrossRef
GOLPH3 expression promotes the resistance of HT29 cells to 5‑fluorouracil by activating multiple signaling pathways Ming‑Zhen Wang, Cheng‑Zhi Qiu, Wai‑Shi Yu, Yan‑Ta Guo, Chun‑Xiao Wang, Zhi‑Xiong Chen Molecular Medicine Reports.2017;[Epub] CrossRef
Infection Strategies of Intestinal Parasite Pathogens and Host Cell Responses Bruno M. Di Genova, Renata R. Tonelli Frontiers in Microbiology.2016;[Epub] CrossRef
A whole-genome RNAi screen uncovers a novel role for human potassium channels in cell killing by the parasite Entamoeba histolytica Chelsea Marie, Hans P. Verkerke, Dan Theodorescu, William A. Petri Scientific Reports.2015;[Epub] CrossRef
Degradation of the Transcription Factors NF-κB, STAT3, and STAT5 Is Involved in Entamoeba histolytica-Induced Cell Death in Caco-2 Colonic Epithelial Cells Kyeong Ah Kim, Arim Min, Young Ah Lee, Myeong Heon Shin The Korean Journal of Parasitology.2014; 52(5): 459. CrossRef
Protective action of NADPH oxidase inhibitors and role of NADPH oxidase in pathogenesis of colon inflammation in mice Rima Ramonaite World Journal of Gastroenterology.2014; 20(35): 12533. CrossRef
Small GTPases of the Ras superfamily regulate intestinal epithelial homeostasis and barrier function via common and unique mechanisms Alí Francisco Citalán-Madrid, Alexander García-Ponce, Hilda Vargas-Robles, Abigail Betanzos, Michael Schnoor Tissue Barriers.2013; 1(5): e26938. CrossRef
The EhCPADH112 Complex of Entamoeba histolytica Interacts with Tight Junction Proteins Occludin and Claudin-1 to Produce Epithelial Damage Abigail Betanzos, Rosario Javier-Reyna, Guillermina García-Rivera, Cecilia Bañuelos, Lorenza González-Mariscal, Michael Schnoor, Esther Orozco, Johanna M. Brandner PLoS ONE.2013; 8(6): e65100. CrossRef
Entamoeba histolytica is an enteric tissue-invading protozoan parasite that can cause amebic colitis and liver abscess in humans. E. histolytica has the capability to kill colon epithelial cells in vitro; however, information regarding the role of calpain in colon cell death induced by ameba is limited. In this study, we investigated whether calpains are involved in the E. histolytica-induced cell death of HT-29 colonic epithelial cells. When HT-29 cells were co-incubated with E. histolytica, the propidium iodide stained dead cells markedly increased compared to that in HT-29 cells incubated with medium alone. This pro-death effect induced by ameba was effectively blocked by pretreatment of HT-29 cells with the calpain inhibitor, calpeptin. Moreover, knockdown of m- and ?-calpain by siRNA significantly reduced E. histolytica-induced HT-29 cell death. These results suggest that m- and ?-calpain may be involved in colon epithelial cell death induced by E. histolytica.
Citations
Citations to this article as recorded by
Involvement of NOX2-derived ROS in human hepatoma HepG2 cell death induced by Entamoeba histolytica Young Ah Lee, Myeong Heon Shin Parasites, Hosts and Diseases.2023; 61(4): 388. CrossRef
Signaling Role of NADPH Oxidases in ROS-Dependent Host Cell Death Induced by Pathogenic Entamoeba histolytica Young Ah Lee, Seobo Sim, Kyeong Ah Kim, Myeong Heon Shin The Korean Journal of Parasitology.2022; 60(3): 155. CrossRef
Infection Strategies of Intestinal Parasite Pathogens and Host Cell Responses Bruno M. Di Genova, Renata R. Tonelli Frontiers in Microbiology.2016;[Epub] CrossRef
Degradation of the Transcription Factors NF-κB, STAT3, and STAT5 Is Involved in Entamoeba histolytica-Induced Cell Death in Caco-2 Colonic Epithelial Cells Kyeong Ah Kim, Arim Min, Young Ah Lee, Myeong Heon Shin The Korean Journal of Parasitology.2014; 52(5): 459. CrossRef
Entamoeba histolytica Induces Cell Death of HT29 Colonic Epithelial Cells via NOX1-Derived ROS Kyeong Ah Kim, Ju Young Kim, Young Ah Lee, Arim Min, Young Yil Bahk, Myeong Heon Shin The Korean Journal of Parasitology.2013; 51(1): 61. CrossRef
Mechanisms of Adherence, Cytotoxicity and Phagocytosis Modulate the Pathogenesis of
Entamoeba Histolytica
Nathaniel CV Christy, William A Petri Future Microbiology.2011; 6(12): 1501. CrossRef
Free-living Naegleria fowleri leads to a fatal infection known as primary amebic meningoencephalitis in humans. Previously, the target cell death could be induced by phagocytic activity of N. fowleri as a contact-dependent mechanism. However, in this study we investigated the target cell death under a non-contact system using a tissue-culture insert. The human microglial cells, U87MG cells, co-cultured with N. fowleri trophozoites for 30 min in a non-contact system showed morphological changes such as the cell membrane destruction and a reduction in the number. By fluorescence-activated cell sorter (FACS) analysis, U87MG cells co-cultured with N. fowleri trophozoites in a non-contact system showed a significant increasse of apoptotic cells (16%) in comparison with that of the control or N. fowleri lysate. When U87MG cells were co-cultured with N. fowleri trophozoites in a non-contact system for 30 min, 2 hr, and 4 hr, the cytotoxicity of amebae against target cells was 40.5, 44.2, and 45.6%, respectively. By contrast, the cytotoxicity of non-pathogenic N. gruberi trophozoites was 10.2, 12.4, and 13.2%, respectively. These results suggest that the molecules released from N. fowleri in a contact-independent manner as well as phagocytosis in a contact-dependent manner may induce the host cell death.
Citations
Citations to this article as recorded by
Cloning of nf-profilin and intercellular interaction with nf-actin in Naegleria fowleri cysts Hae-Jin Sohn, A-Jeong Ham, A-Young Park, Jeong-Heon Lee, Sun Park, Ho-Joon Shin, Jong-Hyun Kim Scientific Reports.2025;[Epub] CrossRef
Advances in the study of extracellular vesicles of Naegleria fowleri and their role in contact-independent pathogenic mechanisms Ismael Castelan-Ramírez, Catalina Flores-Maldonado, Dolores Hernández-Martínez, Lizbeth Salazar-Villatoro, Alberto Daniel Saucedo-Campos, David Segura-Cobos, Adolfo René Méndez-Cruz, Maritza Omaña-Molina Parasites & Vectors.2025;[Epub] CrossRef
A comprehensive review on the neurological impact of parasitic infections Firooz Shahrivar, Ata Moghimi, Ramin Hosseinzadeh, Mohammad Hasan Kohansal, Ali Mortazavi, Tahereh Mikaeili Galeh, Ehsan Ahmadpour Microbial Pathogenesis.2025; 206: 107762. CrossRef
Molecular mechanisms and therapeutic strategies of Naegleria fowleri Carter (1970): a review of the fatal brain-eating amoeba N. Datta The Journal of V. N. Karazin Kharkiv National University, Series "Biology".2024; (42): 22. CrossRef
Differential Exoproteome and Biochemical Characterisation of Neoparamoeba perurans Kerrie Ní Dhufaigh, Natasha Botwright, Eugene Dillon, Ian O’Connor, Eugene MacCarthy, Orla Slattery Microorganisms.2021; 9(6): 1258. CrossRef
Naegleria fowleri Induces Jurkat T Cell Death via O-deGlcNAcylation Young Ah Lee, Kyeong Ah Kim, Myeong Heon Shin The Korean Journal of Parasitology.2021; 59(5): 501. CrossRef
Fowlerstefin, a cysteine protease inhibitor of Naegleria fowleri, induces inflammatory responses in BV-2 microglial cells in vitro Thị Lam Thái, Jung-Mi Kang, Hương Giang Lê, Jinyoung Lee, Won Gi Yoo, Ho-Joon Shin, Woon-Mok Sohn, Byoung-Kuk Na Parasites & Vectors.2020;[Epub] CrossRef
Cellular characterization of actin gene concerned with contact‐dependent mechanisms in Naegleria fowleri Hae‐Jin Sohn, Kyoung‐Ju Song, Heekyoung Kang, A‐Jeong Ham, Jae‐Ho Lee, Yong‐Joon Chwae, Kyongmin Kim, Sun Park, Jong‐Hyun Kim, Ho‐Joon Shin Parasite Immunology.2019;[Epub] CrossRef
Cytopathic Change and Inflammatory Response of Human Corneal Epithelial Cells Induced by Acanthamoeba castellanii Trophozoites and Cysts Hae-Jin Sohn, Ga-Eun Seo, Jae-Ho Lee, A-Jeong Ham, Young-Hwan Oh, Heekyoung Kang, Ho-Joon Shin The Korean Journal of Parasitology.2019; 57(3): 217. CrossRef
In Vitro Activity of Statins against Naegleria fowleri Aitor Rizo-Liendo, Ines Sifaoui, María Reyes-Batlle, Olfa Chiboub, Rubén L. Rodríguez-Expósito, Carlos J. Bethencourt-Estrella, Desirée San Nicolás-Hernández, Edyta B. Hendiger, Atteneri López-Arencibia, Pedro Rocha-Cabrera, José E. Piñero, Jacob Lorenzo- Pathogens.2019; 8(3): 122. CrossRef
Excretory and Secretory Proteins of Naegleria fowleri Induce Inflammatory Responses in BV‐2 Microglial Cells Jinyoung Lee, Jung‐Mi Kang, Tae Im Kim, Jong‐Hyun Kim, Hae‐Jin Sohn, Byoung‐Kuk Na, Ho‐Joon Shin Journal of Eukaryotic Microbiology.2017; 64(2): 183. CrossRef
Amphotericin B induces apoptosis-like programmed cell death in Naegleria fowleri and Naegleria gruberi Roberto Cárdenas-Zúñiga, Angélica Silva-Olivares, José D' Artagnan Villalba-Magdaleno, Virginia Sánchez-Monroy, Jesús Serrano-Luna, Mineko Shibayama Microbiology.2017; 163(7): 940. CrossRef
Production and characterization of monoclonal antibodies against cathepsin B and cathepsin B-Like proteins of Naegleria fowleri Gi-Sang Seong, Hae-Jin Sohn, Heekyoung Kang, Ga-Eun Seo, Jong-Hyun Kim, Ho-Joon Shin Experimental Parasitology.2017; 183: 171. CrossRef
Biology and pathogenesis of Naegleria fowleri Ruqaiyyah Siddiqui, Ibne Karim M. Ali, Jennifer R. Cope, Naveed Ahmed Khan Acta Tropica.2016; 164: 375. CrossRef
Naegleria fowleri after 50 years: is it a neglected pathogen? Moisés Martínez-Castillo, Roberto Cárdenas-Zúñiga, Daniel Coronado-Velázquez, Anjan Debnath, Jesús Serrano-Luna, Mineko Shibayama Journal of Medical Microbiology.2016; 65(9): 885. CrossRef
NLRP3 Inflammasome Activation in THP-1 Target Cells Triggered by Pathogenic Naegleria fowleri Jong-Hyun Kim, Hae-Jin Sohn, Jong-Kyun Yoo, Heekyoung Kang, Gi-Sang Seong, Yong-Joon Chwae, Kyongmin Kim, Sun Park, Ho-Joon Shin, J. A. Appleton Infection and Immunity.2016; 84(9): 2422. CrossRef
Novel cathepsin B and cathepsin B-like cysteine protease of Naegleria fowleri excretory–secretory proteins and their biochemical properties Jinyoung Lee, Jong-Hyun Kim, Hae-Jin Sohn, Hee-Jong Yang, Byoung-Kuk Na, Yong-Joon Chwae, Sun Park, Kyongmin Kim, Ho-Joon Shin Parasitology Research.2014; 113(8): 2765. CrossRef
Naegleria fowleriLysate Induces Strong Cytopathic Effects and Pro-inflammatory Cytokine Release in Rat Microglial Cells Yang-Jin Lee, Chang-Eun Park, Jong-Hyun Kim, Hae-Jin Sohn, Jinyoung Lee, Suk-Yul Jung, Ho-Joon Shin The Korean Journal of Parasitology.2011; 49(3): 285. CrossRef
Screening of Swiss hot spring resorts for potentially pathogenic free-living amoebae Christian Gianinazzi, Marc Schild, Beatrice Zumkehr, Fritz Wüthrich, Irina Nüesch, Regula Ryter, Nadia Schürch, Bruno Gottstein, Norbert Müller Experimental Parasitology.2010; 126(1): 45. CrossRef
Immunodominant antigens in Naegleria fowleri excretory–secretory proteins were potential pathogenic factors Jong-Hyun Kim, Ae-Hee Yang, Hae-Jin Sohn, Daesik Kim, Kyoung-Ju Song, Ho-Joon Shin Parasitology Research.2009; 105(6): 1675. CrossRef
First
Prev
