Mapping the genomic landscape of multidrug resistance in<i>Plasmodium falciparum</i>and its impact on parasite fitness

Mok, Sachel; Yeo, Tomas; Hong, Dengwei; Shears, Melanie J.; Ross, Leila; Ward, Kurt E.; Dhingra, Satish K.; Kanai, Mariko; Bridgford, Jessica L.; Tripathi, Abhai K.; Mlambo, Godfree; Burkhard, Anna Y.; Fairhurst, Kate J.; Gil‐Iturbe, Eva; Park, Heekuk; Rozenberg, Felix D; Kim, Jonathan; Mancia, Filippo; Quick, Matthias; Uhlemann, Anne‐Catrin; Sinnis, Photini; Fidock, David A.

doi:10.1101/2023.06.02.543338

Cited by 5 publications

(1 citation statement)

References 73 publications

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“…At present, a well-established correlation between pfhrp2/3 deletions and pfk13 mutations, as well as their collective impact on parasite fitness, remains unclear. In vitro experimentations have indicated that the pfk13 C580Y mutation entails modest fitness costs when accompanied by multicopy pm2/3 , while it remains fitness-neutral in the presence of single pm2/3 copies 30 . We hypothesise a comparable scenario of fitness cost interplay between pfk13 mutations and pfhrp2/3 deletions.…”

Section: Discussionmentioning

confidence: 99%

The spread of a validated molecular marker of artemisinin partial resistancepfkelch13R622I and association withpfhrp2/3deletions in Eritrea

Mihreteab,

Anderson,

Molina - de la Fuente

et al. 2023

Preprint

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Eritrea was the first African country to switch away from exclusive use of HRP2-based RDTs for the detection of P. falciparum due to high prevalence of pfhrp2/3-deleted P. falciparum parasites causing false-negative RDT results. While heavy reliance on malaria RDTs played a significant role in the rapid expansion of pfhrp2/3-deleted parasites in Eritrea, we hypothesize that the use of antimalarial (artesunate-amodiaquine) may have also contributed to their spread. We conducted a retrospective investigation of mutations in the propeller domain of the P. falciparum kelch13 gene in samples collected in 2016 (n=50) from the Northern Red Sea Zone before the RDT switch away from HRP2-RDTs and in samples collected in 2018-2020 (n=587) from the Gash Barka, Anseba and Debub Zones after the RDT switch. No mutations were identified in the 2016 samples. However, in 2018-2019 samples, we detected five different single non-synonymous mutations. The most prevalent mutation was pfk13 R622I, which was detected in samples collected from all health centres, with an overall prevalence of 11.9% (ranging from 5.9% to 28%). Parasites carrying the R622I mutation have diverse microsatellite marker haplotypes, indicating that they had evolved multiple times from different genetic backgrounds. The prevalence pfk13 R622I was significantly higher in single pfhrp3-deleted parasites (18.0%) compared to parasites without pfhrp2/3 deletions (6.2%) and dual pfhrp2/3-deleted parasites (9.0%), suggesting association between the pfk13 R622I mutation and the pfhrp2/3 deletions in Eritrea. Continuous monitoring the trends in pfhrp2/3 and pfk13 mutants is needed to inform effective malaria management strategies in Eritrea.

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Section: Discussionmentioning

confidence: 99%

The spread of a validated molecular marker of artemisinin partial resistancepfkelch13R622I and association withpfhrp2/3deletions in Eritrea

Mihreteab,

Anderson,

Molina - de la Fuente

et al. 2023

Preprint

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Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility

Ibrahim,

Mohring,

Manko

et al. 2024

Nat Commun

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Plasmodium malariae parasites are widely observed across the tropics and sub-tropics. This slow-growing species, known to maintain chronic asymptomatic infections, has been associated with reduced antimalarial susceptibility. We analyse 251 P. malariae genomes from 28 countries, and leveraging 131,601 high-quality SNPs, demonstrate segregation of African and Asian isolates. Signals of recent evolutionary selection were identified in genes encoding putative surface proteins (pmmsp1) and putative erythrocyte invasion proteins (pmdpap3, pmrbp2, pmnif4). Amino acid substitutions were identified in orthologs of genes associated with antimalarial susceptibility including 2 amino acid substitutions in pmdhfr aligning with pyrimethamine resistance mutations in P. falciparum. Additionally, we characterise pmdhfr mutation F57L and demonstrate its involvement in reduced susceptibility to pyrimethamine in an in vitro parasite assay. We validate CRISPR-Cas9 mediated ortholog replacement in P. knowlesi parasites to determine the function of pmdhfr mutations and demonstrate that circulating pmdhfr genotypes are less susceptible to pyrimethamine.

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SKSR1 identified as key virulence factor inCryptosporidiumby genetic crossing

He,

Sun,

Hou

et al. 2024

Preprint

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Cryptosporidium parvum is a major cause of severe diarrhea. Although isolates of this zoonotic parasite exhibit significant differences in infectivity and virulence, the genetic determinants for these traits are not clear. In this study, we used classical genetics to cross two C. parvum isolates of different virulence and used bulked segregant analysis of whole-genome sequence data from the progeny to identify quantitative trait loci (QTL) associated with Cryptosporidium infectivity and virulence. Of the 26 genes in three QTL, two had loss-of-function mutations in the low-virulence isolates. Deletion of the SKSR1 gene or expression of the frame-shift mutant sequence reduced the pathogenicity of infection in vivo. SKSR1 is a polymorphic secretory protein expressed in small granules and secreted into the parasite-host interface. These results demonstrate that SKSR1 is an important virulence factor in Cryptosporidium, and suggest that this extended family may contribute to pathogenesis.

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Mapping the genomic landscape of multidrug resistance inPlasmodium falciparumand its impact on parasite fitness

Cited by 5 publications

References 73 publications

The spread of a validated molecular marker of artemisinin partial resistancepfkelch13R622I and association withpfhrp2/3deletions in Eritrea

The spread of a validated molecular marker of artemisinin partial resistancepfkelch13R622I and association withpfhrp2/3deletions in Eritrea

Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility

SKSR1 identified as key virulence factor inCryptosporidiumby genetic crossing

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