The Diversity of the
            <i>Plasmodium falciparum</i>
            K13 Propeller Domain Did Not Increase after Implementation of Artemisinin-Based Combination Therapy in Uganda

Conrad, Melissa D.; Nsobya, Sam; Rosenthal, Philip J.

doi:10.1128/aac.01234-19

Cited by 15 publications

(10 citation statements)

References 59 publications

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“…C469F and A675V are considered artemisinin resistance candidate mutations ( 4 ) and have previously been seen in East Africa ( 7 , 13 , 14 ). G533A and V555A have also been previously reported in Africa but have not yet been evaluated for resistance ( 7 , 13 ). A578S is a common K13 polymorphism across Africa but is not linked to artemisinin resistance ( 1 ).…”

Section: Discussionmentioning

confidence: 99%

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Increase in Kelch 13 Polymorphisms in Plasmodium falciparum, Southern Rwanda

Bergmann¹,

Loon²,

Habarugira³

et al. 2021

Emerg. Infect. Dis.

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Artemisinin resistance in Plasmodium falciparum is associated with nonsynonymous mutations in the Kelch 13 ( K13 ) propeller domain. We found that 12.1% (8/66) of clinical P. falciparum isolates from Huye district, Rwanda, exhibited K13 mutations, including R561H, a validated resistance marker. K13 mutations appear to be increasing in this region.

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Section: Discussionmentioning

confidence: 99%

“…We found other nonsynonymous polymorphisms only once among the isolates tested. C469F and A675V are considered artemisinin resistance candidate mutations (4) and have previously been seen in East Africa (7,13,14). G533A and V555A have also been previously reported in Africa but have not yet been evaluated for resistance (7,13).…”

Section: Discussionmentioning

confidence: 99%

Increase in Kelch 13 Polymorphisms in Plasmodium falciparum, Southern Rwanda

Bergmann¹,

Loon²,

Habarugira³

et al. 2021

Emerg. Infect. Dis.

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“…Another mutation at the same locus, 469F, was seen in parasites from Equatorial Guinea [1]. Of note, sequencing of 1183 samples collected from 7 sites across Uganda from 1999 to 2015 did not identify any isolates with PfK13 469F/Y, 561H, or 675V mutations [30].…”

mentioning

confidence: 92%

Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda

Asua

Conrad

Aydemir

et al. 2020

The Journal of Infectious Diseases

157

120

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Background In Uganda artemether-lumefantrine is recommended for malaria treatment and sulfadoxine-pyrimethamine (SP) for chemoprevention during pregnancy, but drug resistance may limit efficacies. Methods Genetic polymorphisms associated with sensitivities to key drugs were characterized in samples collected from 16 sites across Uganda in 2018 and 2019 by ligase detection reaction fluorescent microsphere, molecular inversion probe, dideoxy sequencing, and qPCR assays. Results Considering transporter polymorphisms associated with resistance to aminoquinolines, the prevalence of PfCRT 76T decreased, but varied markedly between sites (0-48% in 2018; 0-22% in 2019); additional PfCRT polymorphisms and plasmepsin-2/3 amplifications associated elsewhere with resistance to piperaquine were not seen. For PfMDR1, in 2019 the 86Y mutation was absent at all sites, the 1246Y mutation had prevalence ≤20% at 14/16 sites, and gene amplification was not seen. Considering mutations associated with high level SP resistance, prevalences of PfDHFR 164L (up to 80%) and PfDHPS 581G (up to 67%) were high at multiple sites. Considering PfK13 propeller domain mutations associated with artemisinin delayed clearance, prevalence of the 469Y and 675V mutations has increased at multiple sites in northern Uganda (up to 23% and 40%, respectively). Conclusions We demonstrate concerning spread of mutations that may limit efficacies of key antimalarial drugs.

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“…Artemisinin resistance has been associated in with multiple nonsynonymous single nucleotide polymorphisms (NS-SNPs) in the propeller domain of the gene encoding the P. falciparum K13 protein (K13PD) (47,48). In Africa, significantly prolonged clearance has yet to be observed (49).…”

Section: Changes In Blood Cell Counts Are Characteristic Of Plasmodium Infectionmentioning

confidence: 99%

Analysis of Spleen Histopathology, Splenocyte composition and Hematological Parameters in Mice Infected withPlasmodium bergheiK173

Wang

Z³

et al. 2021

Preprint

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Malaria is a fatal disease that presents clinically as a continuum of symptoms and severity, which are determined by complex host-parasite interactions. Clearance of infection is believed to be accomplished by the spleen and mononuclear phagocytic system (MPS), both in the presence and absence of artemisinin treatment. The spleen filters infected RBCs from circulation through immune-mediated recognition of the infected RBCs followed by phagocytosis. Using different strains of mice infected with P. berghei K173 (PbK173), the mechanisms leading to splenomegaly, histopathology, splenocyte activation and proliferation, and their relationship to control of parasitemia and host mortality were examined. Survival time of mice infected with PbK173 varied, although the infection was uniformly lethal. Mice of the C57BL/6 strain were the most resistant, while mice of the strain ICR were the most susceptible. BALB/c and KM mice were intermediate. In the course of PbK173 infection, both strains of mice experienced significant splenomegaly. Parasites were observed in the red pulp at 3 days post infection in all animals. All spleens retained late trophozoite stages as well as a fraction of earlier ring-stage parasites. The percentages of macrophages in infected C57BL/6 and KM mice were higher than uninfected mice on 8 dpi. Spleens of infected ICR and KM mice exhibited structural disorganization and remodeling. Furthermore, parasitemia was significantly higher in KM versus C57BL/6 mice at 8 dpi. The percentages of macrophages in ICR infected mice were lower than uninfected mice, and the parasitemia was higher than other strains. The results presented here demonstrate the rate of splenic mechanical filtration and the splenic macrophages likely contribute to an individual’s total parasite burden. This in turn can influence the pathogenesis of malaria. Finally, different genetic backgrounds of mice have different splenic mechanisms for controlling malaria infection.

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The Diversity of the Plasmodium falciparum K13 Propeller Domain Did Not Increase after Implementation of Artemisinin-Based Combination Therapy in Uganda

Cited by 15 publications

References 59 publications

Increase in Kelch 13 Polymorphisms in Plasmodium falciparum, Southern Rwanda

Increase in Kelch 13 Polymorphisms in Plasmodium falciparum, Southern Rwanda

Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda

Analysis of Spleen Histopathology, Splenocyte composition and Hematological Parameters in Mice Infected withPlasmodium bergheiK173

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