A genomic and evolutionary approach reveals non-genetic drug resistance in malaria
Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We prev...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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BioMed Central Ltd
2014
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| Online Access: | http://hdl.handle.net/1721.1/92449 https://orcid.org/0000-0003-2816-6195 |
| _version_ | 1811072715852873728 |
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| author | Rice, Daniel P. Ribacke, Ulf Silterra, Jacob Deik, Amy A. Moss, Eli L. Broadbent, Kate M. Neafsey, Daniel E. Desai, Michael M. Clish, Clary Mazitschek, Ralph Wirth, Dyann F. Herman, Jonathan D. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Rice, Daniel P. Ribacke, Ulf Silterra, Jacob Deik, Amy A. Moss, Eli L. Broadbent, Kate M. Neafsey, Daniel E. Desai, Michael M. Clish, Clary Mazitschek, Ralph Wirth, Dyann F. Herman, Jonathan D. |
| author_sort | Rice, Daniel P. |
| collection | MIT |
| description | Background:
Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated.
Results:
We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance.
Conclusions:
We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use. |
| first_indexed | 2024-09-23T09:10:52Z |
| format | Article |
| id | mit-1721.1/92449 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:10:52Z |
| publishDate | 2014 |
| publisher | BioMed Central Ltd |
| record_format | dspace |
| spelling | mit-1721.1/924492022-09-26T10:56:58Z A genomic and evolutionary approach reveals non-genetic drug resistance in malaria Rice, Daniel P. Ribacke, Ulf Silterra, Jacob Deik, Amy A. Moss, Eli L. Broadbent, Kate M. Neafsey, Daniel E. Desai, Michael M. Clish, Clary Mazitschek, Ralph Wirth, Dyann F. Herman, Jonathan D. Harvard University--MIT Division of Health Sciences and Technology Herman, Jonathan D. Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use. National Institutes of Health (U.S.) (T32 GM007306-39) 2014-12-22T19:51:48Z 2014-12-22T19:51:48Z 2014-11 2014-10 2014-12-19T20:06:33Z Article http://purl.org/eprint/type/JournalArticle 1465-6906 1474-7596 http://hdl.handle.net/1721.1/92449 Herman, Jonathan D, Daniel P Rice, Ulf Ribacke, Jacob Silterra, Amy A Deik, Eli L Moss, Kate M Broadbent, et al. “A Genomic and Evolutionary Approach Reveals Non-Genetic Drug Resistance in Malaria.” Genome Biology 15, no. 11 (November 2014). https://orcid.org/0000-0003-2816-6195 en http://dx.doi.org/10.1186/s13059-014-0511-2 Genome Biology Creative Commons Attribution http://creativecommons.org/licenses/by/4.0 Jonathan D Herman et al.; licensee BioMed Central Ltd. application/pdf BioMed Central Ltd BioMed Central Ltd |
| spellingShingle | Rice, Daniel P. Ribacke, Ulf Silterra, Jacob Deik, Amy A. Moss, Eli L. Broadbent, Kate M. Neafsey, Daniel E. Desai, Michael M. Clish, Clary Mazitschek, Ralph Wirth, Dyann F. Herman, Jonathan D. A genomic and evolutionary approach reveals non-genetic drug resistance in malaria |
| title | A genomic and evolutionary approach reveals non-genetic drug resistance in malaria |
| title_full | A genomic and evolutionary approach reveals non-genetic drug resistance in malaria |
| title_fullStr | A genomic and evolutionary approach reveals non-genetic drug resistance in malaria |
| title_full_unstemmed | A genomic and evolutionary approach reveals non-genetic drug resistance in malaria |
| title_short | A genomic and evolutionary approach reveals non-genetic drug resistance in malaria |
| title_sort | genomic and evolutionary approach reveals non genetic drug resistance in malaria |
| url | http://hdl.handle.net/1721.1/92449 https://orcid.org/0000-0003-2816-6195 |
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