Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity
Severe malaria caused by <i>Plasmodium falciparum</i> poses a major global health problem with high morbidity and mortality. <i>P. falciparum</i> harbors a family of pore-forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to pro...
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MDPI AG
2021-01-01
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| author | Abhishek Shivappagowdar Swati Garg Akriti Srivastava Rahul S. Hada Inderjeet Kalia Agam P. Singh Lalit C. Garg Soumya Pati Shailja Singh |
| author_facet | Abhishek Shivappagowdar Swati Garg Akriti Srivastava Rahul S. Hada Inderjeet Kalia Agam P. Singh Lalit C. Garg Soumya Pati Shailja Singh |
| author_sort | Abhishek Shivappagowdar |
| collection | DOAJ |
| description | Severe malaria caused by <i>Plasmodium falciparum</i> poses a major global health problem with high morbidity and mortality. <i>P. falciparum</i> harbors a family of pore-forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and, they contribute to disease pathogenesis by interacting with host cells. The severe malaria pathogenesis is associated with the dysfunction of various barrier cells, including endothelial cells (EC). Several factors, including PLPs secreted by parasites, contribute to the host cell dysfunction. Herein, we have tested the hypothesis that PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analyzed various dysfunctions in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca<sup>2+</sup> levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death, including Annexin/PI positivity, depolarized the mitochondrial membrane potential, and ROS generation. We have further performed the time-lapse video microscopy of barrier cells and found that the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rationale for the design of adjunct therapies against severe malaria. |
| first_indexed | 2024-03-09T04:40:38Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-09T04:40:38Z |
| publishDate | 2021-01-01 |
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| series | Toxins |
| spelling | doaj.art-0abe1ad4e00d4337a9498ab96e4478fc2023-12-03T13:21:35ZengMDPI AGToxins2072-66512021-01-011316210.3390/toxins13010062Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria SeverityAbhishek Shivappagowdar0Swati Garg1Akriti Srivastava2Rahul S. Hada3Inderjeet Kalia4Agam P. Singh5Lalit C. Garg6Soumya Pati7Shailja Singh8Department of Life Science, School of Natural Sciences, Shiv Nadar University, Chithera, Gautam Buddha Nagar, Uttar Pradesh 201314, IndiaSpecial Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, IndiaDepartment of Life Science, School of Natural Sciences, Shiv Nadar University, Chithera, Gautam Buddha Nagar, Uttar Pradesh 201314, IndiaDepartment of Life Science, School of Natural Sciences, Shiv Nadar University, Chithera, Gautam Buddha Nagar, Uttar Pradesh 201314, IndiaInfectious Disease Lab, National Institute of Immunology, New Delhi 110067, IndiaInfectious Disease Lab, National Institute of Immunology, New Delhi 110067, IndiaGene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, IndiaDepartment of Life Science, School of Natural Sciences, Shiv Nadar University, Chithera, Gautam Buddha Nagar, Uttar Pradesh 201314, IndiaSpecial Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, IndiaSevere malaria caused by <i>Plasmodium falciparum</i> poses a major global health problem with high morbidity and mortality. <i>P. falciparum</i> harbors a family of pore-forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and, they contribute to disease pathogenesis by interacting with host cells. The severe malaria pathogenesis is associated with the dysfunction of various barrier cells, including endothelial cells (EC). Several factors, including PLPs secreted by parasites, contribute to the host cell dysfunction. Herein, we have tested the hypothesis that PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analyzed various dysfunctions in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca<sup>2+</sup> levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death, including Annexin/PI positivity, depolarized the mitochondrial membrane potential, and ROS generation. We have further performed the time-lapse video microscopy of barrier cells and found that the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rationale for the design of adjunct therapies against severe malaria.https://www.mdpi.com/2072-6651/13/1/62malaria<i>Plasmodium falciparum</i>perforin like proteinsnecrosisblebbingcalcium |
| spellingShingle | Abhishek Shivappagowdar Swati Garg Akriti Srivastava Rahul S. Hada Inderjeet Kalia Agam P. Singh Lalit C. Garg Soumya Pati Shailja Singh Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity Toxins malaria <i>Plasmodium falciparum</i> perforin like proteins necrosis blebbing calcium |
| title | Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity |
| title_full | Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity |
| title_fullStr | Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity |
| title_full_unstemmed | Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity |
| title_short | Pathogenic Pore Forming Proteins of <i>Plasmodium</i> Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity |
| title_sort | pathogenic pore forming proteins of i plasmodium i triggers the necrosis of endothelial cells attributed to malaria severity |
| topic | malaria <i>Plasmodium falciparum</i> perforin like proteins necrosis blebbing calcium |
| url | https://www.mdpi.com/2072-6651/13/1/62 |
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