Lack of Association of the S769N Mutation in Plasmodium falciparum SERCA (PfATP6) with Resistance to Artemisinins

Cui, Long; Wang, Zenglei; Jiang, Hongying; Parker, Daniel M.; Wang, Haiyan; Su, Xin-zhuan

doi:10.1128/aac.05943-11

Cited by 39 publications

(40 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several reports have implicated ATP6 as a target of the front-line artemisinin family of antimalarials (70), but recent efforts have demonstrated that this is not the case (71,72). However, these calcium stores can be released from the endoplasmic reticulum to the cytosol by increased levels of inositol trisphosphate, likely via a yet-to-be-identified inositol trisphosphate receptor or ryanodine receptor associated with the endoplasmic reticulum (51).…”

Section: A Selected Group Of Putative Surface-exposed Sporozoite Protmentioning

confidence: 99%

Total and Putative Surface Proteomics of Malaria Parasite Salivary Gland Sporozoites

Lindner

Swearingen

Harupa

et al. 2013

Molecular & Cellular Proteomics

179

274

View full text Add to dashboard Cite

Malaria infections of mammals are initiated by the transmission of Plasmodium salivary gland sporozoites during an Anopheles mosquito vector bite. Sporozoites make their way through the skin and eventually to the liver, where they infect hepatocytes. Blocking this initial stage of infection is a promising malaria vaccine strategy. Therefore, comprehensively elucidating the protein composition of sporozoites will be invaluable in identifying novel targets for blocking infection. Previous efforts to identify the proteins expressed in Plasmodium mosquito stages were hampered by the technical difficulty of separating the parasite from its vector; without effective purifications, the large majority of proteins identified were of vector origin. Here we describe the proteomic profiling of highly purified salivary gland sporozoites from two Plasmodium species: human-infective Plasmodium falciparum and rodent-infective Plasmodium yoelii. The combination of improved sample purification and high mass accuracy mass spectrometry has facilitated the most complete proteome coverage to date for a pre-erythrocytic stage of the parasite. A total of 1991 P. falciparum sporozoite proteins and 1876 P. yoelii sporozoite proteins were identified, with >86% identified with high sequence coverage. The proteomic data were used to confirm the presence of components of three features critical for sporozoite infection of the mammalian host: the sporozoite motility and invasion apparatus (glideosome), sporozoite signaling pathways, and the contents of the apical secretory organelles. Furthermore, chemical labeling and identification of proteins on live sporozoites revealed previously uncharacterized complexity of the putative sporozoite surface-exposed proteome. Taken together, the data constitute the most comprehensive analysis to date of the protein expression of salivary gland sporozoites and reveal novel potential surface-exposed proteins that might be valuable targets for antibody blockage of infection. Molecular & Cellular

show abstract

Section: A Selected Group Of Putative Surface-exposed Sporozoite Protmentioning

confidence: 99%

Total and Putative Surface Proteomics of Malaria Parasite Salivary Gland Sporozoites

Lindner

Swearingen

Harupa

et al. 2013

Molecular & Cellular Proteomics

179

274

View full text Add to dashboard Cite

show abstract

“…We originally targeted the pfatpase6 gene, because it carried an SNP (S769N) that was associated with lowered sensitivity to artemether in an earlier investigation in French Guiana 20 ; however, we did not detect the S769N mutation in our preliminary sample (data not shown). With more recent studies unable to confirm the association of the S769N mutation with artemisinin resistance in other populations 21,22 and the recent identification of the K13-propeller as a strong candidate for artemisinin resistance, we decided to refocus our investigation on K13-propeller polymorphisms. To contribute to the growing knowledge about the global genetic diversity of the K13-propeller and establish a baseline for future surveillance of potential artemisinin resistance in Haiti, we sequenced an 810-base pair region of the K13-propeller from P. falciparum samples collected in Haiti between 2010 and 2013.…”

mentioning

confidence: 99%

Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus are Absent in Plasmodium falciparum Isolates from Haiti

Carter¹,

Boulter²,

Existe³

et al. 2015

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations.Discussions of global malaria elimination programs have been renewed in light of the decline in malaria-associated morbidity and mortality resulting from scaled-up vector-and parasite-targeted interventions over the past decade.1 A key strategy in malaria elimination programs is effective use of antimalarial drugs, particularly artemisinin-based combination therapies (ACTs), which are the first-line therapies in most malaria-endemic countries.1 However, malaria elimination goals face a new threat with the emergence of artemisinin resistance in southeast Asia.2-5 A recent study used both in vivo and in vitro methods to identify non-synonymous singlenucleotide polymorphisms (SNPs) at the PF3D7_1343700 kelch propeller domain (K13-propeller) in Cambodian Plasmodium falciparum associated with artemisinin resistance. 6Subsequent investigations at the K13-propeller locus in other southeast Asian populations, including those of Vietnam, Myanmar, Laos, and Thailand, confirm the association of non-synonymous SNPs at the K13-propeller with artemisinin resistance.7 However, these polymorphisms were not detected in sub-Saharan Africa P. falciparum samples from Gambia, Mali, Ghana, Burkina Faso, Congo, Democratic Republic of Congo, Kenya, Tanzania, Malawi, and Uganda, where little to no artemisinin resistance has been reported. [7][8][9] Furthermore, other non-synonymous SNPs were identified in the sub-Saharan African samples that were not observed in the southeast Asian P. falciparum samples. These findings suggest that polymorphisms in the K13-propeller could vary geographically, and therefore, genetic studies on the K13-propeller in other malaria-endemic countries are needed to assess the use of this locus as a tool to monitor the global emergence and spread of artemisinin resistance.Haiti is one of two remaining malaria-endemic countries in the Caribbean. It has several favorable elimination characteristics. 10 (1) One parasite species (P. falciparum) accounts for the majority, if not all, cases of malaria.11 (2) Malaria transmission is low.12...

show abstract

“…Also, in Southern-Iran, L263 and A623 were reported to be wild type (Zakeri et al 2012). The presence of S769N also made occasional impacts from few studies (Jambou et al 2005;Pillai et al 2012;Zakeri et al 2012) like that of the French Guiana (Legrand et al 2008) while there are reports which observed its absence in the P. falciparum isolates that were analyzed (Mugittu et al 2006;Sisowath et al 2007;Zhang et al 2008;Ferreira et al 2008;Menegon et al 2009;Wangai et al 2011;Kwansa-Bentum et al 2011;Tanabe et al 2011;Brasil et al 2012;Saha et al 2013) or even denied the association of this SNP with artemisinin resistance (Phompradit et al 2011;Cui et al 2012). Another study from Yaounde, Cameroon, where all these four mutations were tested, high prevalence of E431K was warranted and alarmed (Tahar et al 2009).…”

Section: Discussionmentioning

confidence: 89%

Monitoring artemisinin resistance in Plasmodium falciparum: comparison of parasite clearance time by microscopy and real-time PCR and evaluation of mutations in Pfatpase6 gene in Odisha state of India

et al. 2015

View full text Add to dashboard Cite

Antimalarial drug resistance including artemisinin resistance in Plasmodium falciparum malaria is a major concern in combating malaria throughout the world. Delayed parasite clearance time (PCT) is indicative of emergence of artemisinin resistance. Herein, PCT has been monitored with the help of gold standard technique microscopy accompanied by a more sensitive real-time assay for academic purpose. After the administration of artemisinin based combination therapy, artesunate + sulfadoxine pyrimethamine (AS + SP), all the subjects were followed up to day 42 for monitoring the therapeutic efficacy of AS + SP in Bisra Community Health Centre (CHC), Sundergarh district in the state of Odisha in India. Further, representative samples were analyzed for L263E, E431K, A623E and S769N SNPs in Pfatpase6 gene and copy number polymorphisms in Pfmdr1 gene. Though all the samples were found parasite negative according to microscopy by the end of day 3 and attained adequate clinical and parasitological response (ACPR) at the end of day 42, real-time PCR showed day 3 positivity in 12 of the total analyzed samples (n = 43). This was further validated by end-point diagnostic PCR and correlated with high initial parasite load. E431K mutation was observed in 2 of the 12 samples (16.7 %) while the controls (n = 18) were all wild. L263E, A623E and S769N were wild in all the analyzed samples (n = 30). Pfmdr1 copy number analysis showed no change in the said trait. Conclusively, real-time PCR could support microscopy for better monitoring of PCT and may provide as an additional but useful research tool for artemisinin resistance studies.

show abstract

Lack of Association of the S769N Mutation in Plasmodium falciparum SERCA (PfATP6) with Resistance to Artemisinins

Cited by 39 publications

References 62 publications

Total and Putative Surface Proteomics of Malaria Parasite Salivary Gland Sporozoites

Total and Putative Surface Proteomics of Malaria Parasite Salivary Gland Sporozoites

Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus are Absent in Plasmodium falciparum Isolates from Haiti

Monitoring artemisinin resistance in Plasmodium falciparum: comparison of parasite clearance time by microscopy and real-time PCR and evaluation of mutations in Pfatpase6 gene in Odisha state of India

Contact Info

Product

Resources

About