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1.
bioRxiv ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38187525

RESUMO

Artemisinin (ART) combination therapies have been critical in reducing malaria morbidity and mortality, but these important drugs are threatened by growing resistance associated with mutations in Pfcoronin and Pfkelch13 . Here, we describe the mechanism of Pfcoronin -mediated ART resistance. Pf Coronin interacts with Pf Actin and localizes to the parasite plasma membrane (PPM), the digestive vacuole (DV) membrane, and membrane of a newly identified preDV compartment-all structures involved in the trafficking of hemoglobin from the RBC for degradation in the DV. Pfcoronin mutations alter Pf Actin homeostasis and impair the development and morphology of the preDV. Ultimately, these changes are associated with decreased uptake of red blood cell cytosolic contents by ring-stage Plasmodium falciparum . Previous work has identified decreased hemoglobin uptake as the mechanism of Pfkelch 13-mediated ART resistance. This work demonstrates that Pf Coronin appears to act via a parallel pathway. For both Pfkelch13 -mediated and Pfcoronin -mediated ART resistance, we hypothesize that the decreased hemoglobin uptake in ring stage parasites results in less heme-based activation of the artemisinin endoperoxide ring and reduced cytocidal activity. This study deepens our understanding of ART resistance, as well as hemoglobin uptake and development of the DV in early-stage parasites.

2.
PLoS Pathog ; 19(6): e1011448, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37339122

RESUMO

Insecticide resistance is under strong selective pressure in Anopheles mosquitoes due to widespread usage of insecticides in vector control strategies. Resistance mechanisms likely cause changes that profoundly affect mosquito physiology, yet it remains poorly understood how selective pressures imposed by insecticides may alter the ability of the mosquito to host and transmit a Plasmodium infection. From pyrethroid-resistant field-derived Anopheles gambiae s.l. mosquitoes, we established resistant (RES) and susceptible (SUS) colonies by either selection for, or loss of insecticide resistance. We show increased oocyst intensity and growth rate as well as increased sporozoite prevalence and intensity in RES compared to SUS females infected with Plasmodium falciparum. The increase in infection intensity in RES females was not associated with the presence of the kdrL1014F mutation and was not impacted by inhibition of Cytochrome P450s. The lipid transporter lipophorin (Lp), which was upregulated in RES compared to SUS, was at least partly implicated in the increased intensity of P. falciparum but not directly involved in the insecticide resistance phenotype. Interestingly, we observed that although P. falciparum infections were not affected when RES females were exposed to permethrin, these females had decreased lipid abundance in the fat body following exposure, pointing to a possible role for lipid mobilization in response to damage caused by insecticide challenge. The finding that selection for insecticide resistance can increase P. falciparum infection intensities and growth rate reinforces the need to assess the overall impact on malaria transmission dynamics caused by selective pressures mosquitoes experience during repeated insecticide challenge.


Assuntos
Anopheles , Inseticidas , Malária Falciparum , Malária , Animais , Feminino , Inseticidas/farmacologia , Plasmodium falciparum/fisiologia , Resistência a Inseticidas/genética , Anopheles/fisiologia , Mosquitos Vetores/genética , Lipídeos , Controle de Mosquitos
4.
Nat Microbiol ; 6(12): 1575-1582, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34819638

RESUMO

Wolbachia, a maternally inherited intracellular bacterial species, can manipulate host insect reproduction by cytoplasmic incompatibility (CI), which results in embryo lethality in crosses between infected males and uninfected females. CI is encoded by two prophage genes, cifA and cifB. Wolbachia, coupled with the sterile insect technique, has been used in field trials to control populations of the dengue vector Aedes albopictus, but CI-inducing strains are not known to infect the malaria vector Anopheles gambiae. Here we show that cifA and cifB can induce conditional sterility in the malaria vector An. gambiae. We used transgenic expression of these Wolbachia-derived genes in the An. gambiae germline to show that cifB is sufficient to cause embryonic lethality and that cifB-induced sterility is rescued by cifA expression in females. When we co-expressed cifA and cifB in male mosquitoes, the CI phenotype was attenuated. In female mosquitoes, cifB impaired fertility, which was overcome by co-expression of cifA. Our findings pave the way towards using CI to control malaria mosquito vectors.


Assuntos
Anopheles/microbiologia , Anopheles/fisiologia , Proteínas de Bactérias/metabolismo , Herança Extracromossômica , Mosquitos Vetores/microbiologia , Mosquitos Vetores/fisiologia , Wolbachia/metabolismo , Aedes/genética , Aedes/microbiologia , Aedes/fisiologia , Animais , Anopheles/genética , Proteínas de Bactérias/genética , Feminino , Infertilidade Masculina , Malária/transmissão , Masculino , Mosquitos Vetores/genética , Wolbachia/genética
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