Publicação
Resistance to antimalarials : a pharmacogenomics approach for both parasite and human host
| Resumo: | Malaria is a vector-borne disease that affected up to 241 million people just last year, causing more than 602 thousand deaths in Africa alone. Global strategies for malaria control include artemisinin-based combination therapies (ACTs) as the recommended first line treatment for uncomplicated Plasmodium falciparum malaria. Unfortunately, drug resistance remains a recurring obstacle. An area still under-studied is the host-pathogen interactions in terms the emergence of drug resistance. Host pharmacogene variation can influence the dynamics of drug resistance selection. Therefore, the dual aim of this thesis is to identify new genetic causality for Plasmodium falciparum resistance against present and in the pipeline combination therapies, while considering the scarcely studied contribution of the patient pharmacogenetic profile. In Chapter I, by targeted sequencing we profiled main antimalarial drug-related pharmacogenes of a Gabonese population. Out of the 347 identified genetic variants, 18 were novel with notable deleterious predicted consequences. Importantly, 16.7% were population-specific, highlighting the diversity of the understudied African genetic landscape. In Chapter II we accessed the influence of CY2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine (ASAQ) treatment in Zanzibar. The notable prevalente CYP2C8*2 and CYP2C8*3 reduced-activity alleles, 17.5% and 2.7% respectively, were associated with increased occurrence adverse events, indicating the influence patient genotype status on ASAQ tolerability. In Chapter III we monitored the spread of piperaquine-related molecular markers in African settings. The unique long active follow-up of the trial allowed to capture the increase prevalence of pfcrt 76T and 356T, significantly associated with shorter re-infection time. In addition, the background increased of parasites harbouring copy number variation (CNV) of pfpm3, spotlight the need of extended follow-ups when treatment strategies include long half-live partner drugs. In Chapter IV we determined baseline frequencies of plasmepsins 2/3 CNV in Tanzania and Kenya and evaluated current distribution across Africa based on a literature review. |
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| Autores principais: | Pernaute-Lau, Leyre |
| Assunto: | ACT resistência antimaláricos farmacogenômica interações hospedeiro-patógeno resistance antimalarials pharmacogenomics host-pathogen interactions |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Malaria is a vector-borne disease that affected up to 241 million people just last year, causing more than 602 thousand deaths in Africa alone. Global strategies for malaria control include artemisinin-based combination therapies (ACTs) as the recommended first line treatment for uncomplicated Plasmodium falciparum malaria. Unfortunately, drug resistance remains a recurring obstacle. An area still under-studied is the host-pathogen interactions in terms the emergence of drug resistance. Host pharmacogene variation can influence the dynamics of drug resistance selection. Therefore, the dual aim of this thesis is to identify new genetic causality for Plasmodium falciparum resistance against present and in the pipeline combination therapies, while considering the scarcely studied contribution of the patient pharmacogenetic profile. In Chapter I, by targeted sequencing we profiled main antimalarial drug-related pharmacogenes of a Gabonese population. Out of the 347 identified genetic variants, 18 were novel with notable deleterious predicted consequences. Importantly, 16.7% were population-specific, highlighting the diversity of the understudied African genetic landscape. In Chapter II we accessed the influence of CY2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine (ASAQ) treatment in Zanzibar. The notable prevalente CYP2C8*2 and CYP2C8*3 reduced-activity alleles, 17.5% and 2.7% respectively, were associated with increased occurrence adverse events, indicating the influence patient genotype status on ASAQ tolerability. In Chapter III we monitored the spread of piperaquine-related molecular markers in African settings. The unique long active follow-up of the trial allowed to capture the increase prevalence of pfcrt 76T and 356T, significantly associated with shorter re-infection time. In addition, the background increased of parasites harbouring copy number variation (CNV) of pfpm3, spotlight the need of extended follow-ups when treatment strategies include long half-live partner drugs. In Chapter IV we determined baseline frequencies of plasmepsins 2/3 CNV in Tanzania and Kenya and evaluated current distribution across Africa based on a literature review. |
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