Abstract
A resistência aos antimaláricos, especialmente do parasita Plasmodium falciparum, contribui para que o tratamento continue a ser um grande desafio para o combate à malária, continuando esta doença a ser um grave problema de saúde pública, principalmente nos países de baixa renda. No entanto, apesar de causar milhões de infeções e milhares de mortes anualmente, a malária tem vindo a selecionar variantes genéticos humanos, que se revelam como protetores contra a doença e contribuem para uma maior sobrevivência do hospedeiro humano. O aumento da concentração do metabolito 2,3-DPG poderá estar envolvido no mecanismo de proteção conferido pela deficiência em piruvato cinase (PK) eritrocitária. Para compreender o efeito da adição do composto sintético 2,3-DPG no desenvolvimento parasitário em culturas in vitro de P. falciparum foi analisada a maturação e resposta transcriptómica do parasita. A maturação parasitária em culturas tratadas e não tratadas com 2,3-DPG foi monitorizada através de citometria de fluxo, ao longo do ciclo eritrocitário completo e a expressão génica foi analisada através da sequenciação de RNA por nanoporos (Oxford Nanopore Technologies) de bibliotecas de cDNA do estadio de trofozoíto. O composto afetou a maturação do parasita e a sua progenia. O estudo da resposta transcricional mostrou um efeito na resposta do parasita relacionada com a sua sobrevivência num ambiente hostil. O estudo mais aprofundado da deficiência em PK, especialmente o efeito de 2,3-DPG, poderá contribuir para o aparecimento de novos agentes antimaláricos.
Translated Abstract of the contribution
Resistance to antimalarials, especially the Plasmodium falciparum parasite,remains a major challenge in the fight against malaria, particularly inlow-income countries where the disease continues to be a serious public healthproblem, causing millions of infections and thousands of deaths annually.However, despite its devastating impact, malaria has led to the selection ofhuman genetic factors that confer protection against the disease, therebyenhancing the survival of the human host. One such protective mechanism mayinvolve the increased concentration of the 2,3-DPG metabolite, which isassociated with erythrocyte pyruvate kinase (PK) deficiency.
To gain insights into the effect of adding the synthetic compound 2,3-DPGon parasite development in in vitro cultures of P. falciparum, weanalyzed both the maturation and transcriptomic response of the parasite.Parasitic maturation in cultures treated and untreated with 2,3-DPG wasmonitored by flow cytometry throughout the complete erythrocyte cycle, whilegene expression was analyzed by nanopore RNA sequencing (Oxford NanoporeTechnologies) from cDNA libraries prepared from the trophozoite stage. Thecompound exhibited an impact on parasite maturation and its progeny. The studyof the transcriptional response revealed an effect on the parasite's survivalmechanism in a hostile environment.
Further investigation into PK deficiency, particularly the effect of2,3-DPG, may offer valuable insights for the development of new antimalarialagents. Understanding the interactions between the parasite and the hostresponse can potentially lead to the discovery of novel therapeutic strategiesto combat malaria effectively.
Financing: PTDC_BIA-CEL_28456_2017 and GHTM—UID/04413/2020
Translated Abstract of the contribution
Resistance to antimalarials, especially the Plasmodium falciparum parasite,remains a major challenge in the fight against malaria, particularly inlow-income countries where the disease continues to be a serious public healthproblem, causing millions of infections and thousands of deaths annually.However, despite its devastating impact, malaria has led to the selection ofhuman genetic factors that confer protection against the disease, therebyenhancing the survival of the human host. One such protective mechanism mayinvolve the increased concentration of the 2,3-DPG metabolite, which isassociated with erythrocyte pyruvate kinase (PK) deficiency.
To gain insights into the effect of adding the synthetic compound 2,3-DPGon parasite development in in vitro cultures of P. falciparum, weanalyzed both the maturation and transcriptomic response of the parasite.Parasitic maturation in cultures treated and untreated with 2,3-DPG wasmonitored by flow cytometry throughout the complete erythrocyte cycle, whilegene expression was analyzed by nanopore RNA sequencing (Oxford NanoporeTechnologies) from cDNA libraries prepared from the trophozoite stage. Thecompound exhibited an impact on parasite maturation and its progeny. The studyof the transcriptional response revealed an effect on the parasite's survivalmechanism in a hostile environment.
Further investigation into PK deficiency, particularly the effect of2,3-DPG, may offer valuable insights for the development of new antimalarialagents. Understanding the interactions between the parasite and the hostresponse can potentially lead to the discovery of novel therapeutic strategiesto combat malaria effectively.
Financing: PTDC_BIA-CEL_28456_2017 and GHTM—UID/04413/2020
Translated title of the contribution | Protective effect of pyruvate kinase deficiency against malaria – transcriptomic analysis of the Plasmodium falciparum parasite under the action of the compound 2,3-diphosphoglycerate (2,3-DPG) |
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Original language | Portuguese |
Pages | 49-49 |
Number of pages | 1 |
Publication status | Published - 20 Apr 2023 |
Event | 6º Congresso Nacional de Medicina Tropical - IHMT, Lisboa, Portugal Duration: 20 Apr 2023 → 21 Apr 2023 https://6cnmt.admeus.pt/?page=43 |
Conference
Conference | 6º Congresso Nacional de Medicina Tropical |
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Abbreviated title | 6º CNMT |
Country/Territory | Portugal |
City | Lisboa |
Period | 20/04/23 → 21/04/23 |
Internet address |