สืบค้นงานวิจัย
Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance
Dogovski C. - ไม่ระบุหน่วยงาน
ชื่อเรื่อง (EN): Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance
ผู้แต่ง / หัวหน้าโครงการ (EN): Dogovski C.
บทคัดย่อ (EN): Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance) is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas with ART resistance. © 2015 Dogovski et al.
บทคัดย่อ: ไม่พบข้อมูลจากหน่วยงานต้นทาง
ภาษา (EN): en
เอกสารแนบ (EN): https://www.scopus.com/inward/record.uri?eid=2-s2.0-84929493850&doi=10.1371%2fjournal.pbio.1002132&partnerID=40&md5=5f373f95088e235ddb36240a63bf0760
เผยแพร่โดย (EN): มหาวิทยาลัยมหิดล
คำสำคัญ (EN): Stress, Physiological
เจ้าของลิขสิทธิ์ (EN): มหาวิทยาลัยมหิดล
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Dogovski C.. "Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance". ไม่ระบุหน่วยงาน. ม.ป.ป.

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Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance
Dogovski C.
มหาวิทยาลัยมหิดล
ไม่ระบุวันที่เผยแพร่
Artemisinin-resistant Plasmodium falciparum malaria Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum Prevalence of Plasmodium falciparum molecular markers of antimalarial drug resistance in a residual malaria focus area in Sabah, Malaysia Differential roles of an Anopheline midgut GPI-anchored protein in mediating Plasmodium falciparum and Plasmodium vivax ookinete invasion Evolution of Fseg/Cseg dimorphism in region III of the Plasmodium falciparum eba-175 gene ECOPHYSIOLOGICAL RESPONSE OF YOUNG RUBBER BUDINGS TO DROUGHT STRESS Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes Insights into the naturally acquired immune response to Plasmodium vivax malaria Neutralizing antibodies against Plasmodium falciparum associated with successful cure after drug therapy
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