Screening and characterization of antimalarial resistance related genetic structural variations in P. falciparum
The emergence of parasite resistance to antimalarials has been impeding the efforts in malaria elimination. Continuous surveillance of treatment failures from the clinical population informs the efficacy of the currently used antimalarial treatment and provide essential clues in deciphering the m...
Saved in:
| 主要作者: | |
|---|---|
| 其他作者: | |
| 格式: | Thesis-Doctor of Philosophy |
| 語言: | English |
| 出版: |
Nanyang Technological University
2022
|
| 主題: | |
| 在線閱讀: | https://hdl.handle.net/10356/156357 |
| 標簽: |
添加標簽
沒有標簽, 成為第一個標記此記錄!
|
| 機構: | Nanyang Technological University |
| 語言: | English |
| 總結: | The emergence of parasite resistance to antimalarials has been impeding the
efforts in malaria elimination. Continuous surveillance of treatment failures from
the clinical population informs the efficacy of the currently used antimalarial
treatment and provide essential clues in deciphering the molecular mechanism
of resistance. Screening of resistance biomarkers from clinical isolates has
undermined the identification of large genetic variants, mainly due to technical
challenges imposed by low quantity of genetic material and low complexity
Plasmodium genome, making the analysis prone to bias.
This study screened large genetic structural variations from 413 clinical samples
collected in Greater Mekong Subregions, the epicentre of antimalarial treatment
failures. Samples were obtained in collaboration with Tracking Resistance to
Artemisinin Collaboration (TRAC) studies. Large structural variants were screened
using an optimized microarray based Comparative Genomic Hybridization
(aCGH) technique. We identified Copy Number Amplification in pfmdr1, pfgch1,
and pfpm2, previously reported in association with mainly Mefloquine,
Sulfadoxine-Pyrimethamine, and Piperaquine resistance, respectively. In addition,
we also identified novel CNV in pfvit and pfyhm2 within the same locus, known
for function in iron detoxification and mitochondrial electron transport chain,
respectively.
Four variant genes: pfpm2, pfvit, pfcyp19b, and pfk13, were chosen for biological
and phenotypical characterization using an in vitro parasite model. The overall
work suggested the CYP19B as a potential downstream effector of K13 C580Y
allele as well as PMII and K13 probable compensatory/synergistic relationship in
Ring stage; the stage had been shown to exhibit reduced susceptibility to
Artemisinin treatment. Collectively, this work presented an additional potential
molecular mechanism to the current notion of antimalarial resistance. |
|---|