Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites
Due to their remarkable parasitocidal activity, artemisinins represent the key components of first-line therapies against Plasmodium falciparum malaria. However, the decline in efficacy of artemisinin-based drugs jeopardizes global efforts to control and ultimately eradicate the disease. To better u...
| Main Authors: | , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/89168 http://hdl.handle.net/10220/44831 |
| _version_ | 1826124424484487168 |
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| author | Rocamora, Frances Zhu, Lei Liong, Kek Yee Dondorp, Arjen Miotto, Olivo Mok, Sachel Bozdech, Zbynek |
| author2 | Cooper, Roland |
| author_facet | Cooper, Roland Rocamora, Frances Zhu, Lei Liong, Kek Yee Dondorp, Arjen Miotto, Olivo Mok, Sachel Bozdech, Zbynek |
| author_sort | Rocamora, Frances |
| collection | NTU |
| description | Due to their remarkable parasitocidal activity, artemisinins represent the key components of first-line therapies against Plasmodium falciparum malaria. However, the decline in efficacy of artemisinin-based drugs jeopardizes global efforts to control and ultimately eradicate the disease. To better understand the resistance phenotype, artemisinin-resistant parasite lines were derived from two clones of the 3D7 strain of P. falciparum using a selection regimen that mimics how parasites interact with the drug within patients. This long term in vitro selection induced profound stage-specific resistance to artemisinin and its relative compounds. Chemosensitivity and transcriptional profiling of artemisinin-resistant parasites indicate that enhanced adaptive responses against oxidative stress and protein damage are associated with decreased artemisinin susceptibility. This corroborates our previous findings implicating these cellular functions in artemisinin resistance in natural infections. Genomic characterization of the two derived parasite lines revealed a spectrum of sequence and copy number polymorphisms that could play a role in regulating artemisinin response, but did not include mutations in pfk13, the main marker of artemisinin resistance in Southeast Asia. Taken together, here we present a functional in vitro model of artemisinin resistance that is underlined by a new set of genetic polymorphisms as potential genetic markers. |
| first_indexed | 2024-10-01T06:20:23Z |
| format | Journal Article |
| id | ntu-10356/89168 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:20:23Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/891682023-02-28T16:56:39Z Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites Rocamora, Frances Zhu, Lei Liong, Kek Yee Dondorp, Arjen Miotto, Olivo Mok, Sachel Bozdech, Zbynek Cooper, Roland School of Biological Sciences Artemisinin Resistance Parasites Due to their remarkable parasitocidal activity, artemisinins represent the key components of first-line therapies against Plasmodium falciparum malaria. However, the decline in efficacy of artemisinin-based drugs jeopardizes global efforts to control and ultimately eradicate the disease. To better understand the resistance phenotype, artemisinin-resistant parasite lines were derived from two clones of the 3D7 strain of P. falciparum using a selection regimen that mimics how parasites interact with the drug within patients. This long term in vitro selection induced profound stage-specific resistance to artemisinin and its relative compounds. Chemosensitivity and transcriptional profiling of artemisinin-resistant parasites indicate that enhanced adaptive responses against oxidative stress and protein damage are associated with decreased artemisinin susceptibility. This corroborates our previous findings implicating these cellular functions in artemisinin resistance in natural infections. Genomic characterization of the two derived parasite lines revealed a spectrum of sequence and copy number polymorphisms that could play a role in regulating artemisinin response, but did not include mutations in pfk13, the main marker of artemisinin resistance in Southeast Asia. Taken together, here we present a functional in vitro model of artemisinin resistance that is underlined by a new set of genetic polymorphisms as potential genetic markers. MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) Published version 2018-05-18T06:11:42Z 2019-12-06T17:19:22Z 2018-05-18T06:11:42Z 2019-12-06T17:19:22Z 2018 Journal Article Rocamora, F., Zhu, L., Liong, K. Y., Dondorp, A., Miotto, O., Mok, S., et al. (2018). Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites. PLOS Pathogens, 14(3), e1006930-. 1553-7366 https://hdl.handle.net/10356/89168 http://hdl.handle.net/10220/44831 10.1371/journal.ppat.1006930 en PLOS Pathogens © 2018 Rocamora et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 29 p. application/pdf |
| spellingShingle | Artemisinin Resistance Parasites Rocamora, Frances Zhu, Lei Liong, Kek Yee Dondorp, Arjen Miotto, Olivo Mok, Sachel Bozdech, Zbynek Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites |
| title | Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites |
| title_full | Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites |
| title_fullStr | Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites |
| title_full_unstemmed | Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites |
| title_short | Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites |
| title_sort | oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites |
| topic | Artemisinin Resistance Parasites |
| url | https://hdl.handle.net/10356/89168 http://hdl.handle.net/10220/44831 |
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