Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia.
Adolescent
Adult
Antigens, Protozoan
/ genetics
Child
Cross-Sectional Studies
Diagnostic Tests, Routine
/ adverse effects
Ethiopia
/ epidemiology
Evolution, Molecular
Female
Gene Deletion
Genotype
Geography
Humans
Malaria, Falciparum
/ diagnosis
Male
Plasmodium falciparum
/ genetics
Prevalence
Prospective Studies
Protozoan Proteins
/ genetics
Selection, Genetic
Young Adult
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
16
05
2021
accepted:
16
08
2021
pubmed:
29
9
2021
medline:
26
10
2021
entrez:
28
9
2021
Statut:
ppublish
Résumé
In Africa, most rapid diagnostic tests (RDTs) for falciparum malaria recognize histidine-rich protein 2 antigen. Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes escape detection by these RDTs, but it is not known whether these deletions confer sufficient selective advantage to drive rapid population expansion. By studying blood samples from a cohort of 12,572 participants enroled in a prospective, cross-sectional survey along Ethiopia's borders with Eritrea, Sudan and South Sudan using RDTs, PCR, an ultrasensitive bead-based immunoassay for antigen detection and next-generation sequencing, we estimate that histidine-rich protein 2-based RDTs would miss 9.7% (95% confidence interval 8.5-11.1) of P. falciparum malaria cases owing to pfhrp2 deletion. We applied a molecular inversion probe-targeted deep sequencing approach to identify distinct subtelomeric deletion patterns and well-established pfhrp3 deletions and to uncover recent expansion of a singular pfhrp2 deletion in all regions sampled. We propose a model in which pfhrp3 deletions have arisen independently multiple times, followed by strong positive selection for pfhrp2 deletion owing to RDT-based test-and-treatment. Existing diagnostic strategies need to be urgently reconsidered in Ethiopia, and improved surveillance for pfhrp2 deletion is needed throughout the Horn of Africa.
Identifiants
pubmed: 34580442
doi: 10.1038/s41564-021-00962-4
pii: 10.1038/s41564-021-00962-4
pmc: PMC8478644
mid: NIHMS1733833
doi:
Substances chimiques
Antigens, Protozoan
0
HRP-2 antigen, Plasmodium falciparum
0
HRP3 protein, Plasmodium falciparum
0
Protozoan Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1289-1299Subventions
Organisme : NIAID NIH HHS
ID : K24 AI134990
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD007168
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI132547
Pays : United States
Organisme : World Health Organization
ID : 001
Pays : International
Organisme : Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund)
ID : EPHI5405
Informations de copyright
© 2021. The Author(s).
Références
False-negative RDT Results and Implications of New Reports of P. falciparum Histidine-rich Protein 2/3 Gene Deletions (World Health Organization, 2016).
Verma, A. K., Bharti, P. K. & Das, A. HRP-2 deletion: a hole in the ship of malaria elimination. Lancet Infect. Dis. 18, 826–827 (2018).
pubmed: 30064667
doi: 10.1016/S1473-3099(18)30420-1
Wellems, T. E. & Howard, R. J. Homologous genes encode two distinct histidine-rich proteins in a cloned isolate of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 83, 6065–6069 (1986).
pubmed: 3016741
pmcid: 386439
doi: 10.1073/pnas.83.16.6065
Howard, R. J. et al. Secretion of a malarial histidine-rich protein (Pf HRP II) from Plasmodium falciparum-infected erythrocytes. J. Cell Biol. 103, 1269–1277 (1986).
pubmed: 3533951
doi: 10.1083/jcb.103.4.1269
Li, B. et al. Performance of pfHRP2 versus pLDH antigen rapid diagnostic tests for the detection of Plasmodium falciparum: a systematic review and meta-analysis. Arch. Med. Sci. 13, 541–549 (2017).
pubmed: 28507567
pmcid: 5420633
doi: 10.5114/aoms.2017.67279
Baker, J. et al. Genetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic tests. J. Infect. Dis. 192, 870–877 (2005).
pubmed: 16088837
doi: 10.1086/432010
Good Practices for Selecting and Procuring Rapid Diagnostic Tests for Malaria (World Health Organization, 2011).
Cheng, Q. et al. Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting. Malar. J. 13, 283 (2014).
pubmed: 25052298
pmcid: 4115471
doi: 10.1186/1475-2875-13-283
Poti, K. E., Sullivan, D. J., Dondorp, A. M. & Woodrow, C. J. HRP2: transforming malaria diagnosis, but with caveats. Trends Parasitol. 36, 112–126 (2020).
pubmed: 31848119
doi: 10.1016/j.pt.2019.12.004
Gamboa, D. et al. A large proportion of P. falciparum isolates in the Amazon region of Peru lack pfhrp2 and pfhrp3: implications for malaria rapid diagnostic tests. PLoS ONE 5, e8091 (2010).
pubmed: 20111602
pmcid: 2810332
doi: 10.1371/journal.pone.0008091
Grignard, L. et al. A novel multiplex qPCR assay for detection of Plasmodium falciparum with histidine-rich protein 2 and 3 (pfhrp2 and pfhrp3) deletions in oolyclonal infections. EBioMedicine 55, 102757 (2020).
pubmed: 32403083
pmcid: 7218259
doi: 10.1016/j.ebiom.2020.102757
Plucinski, M. M. et al. Screening for Pfhrp2/3-deleted Plasmodium falciparum, non-falciparum, and low-density malaria infections by a multiplex antigen assay. J. Infect. Dis. 219, 437–447 (2019).
pubmed: 30202972
doi: 10.1093/infdis/jiy525
Parr, J. B., Anderson, O., Juliano, J. J. & Meshnick, S. R. Streamlined, PCR-based testing for pfhrp2- and pfhrp3-negative Plasmodium falciparum. Malar. J. 17, 137 (2018).
pubmed: 29609602
pmcid: 5879555
doi: 10.1186/s12936-018-2287-4
Berhane, A. et al. Major threat to malaria control programs by Plasmodium falciparum lacking histidine-rich protein 2, Eritrea. Emerg. Infect. Dis. 24, 462–470 (2018).
pubmed: 29460730
pmcid: 5823352
doi: 10.3201/eid2403.171723
Akinyi, S. et al. Multiple genetic origins of histidine-rich protein 2 gene deletion in Plasmodium falciparum parasites from Peru. Sci. Rep. 3, 2797 (2013).
pubmed: 24077522
pmcid: 3786299
doi: 10.1038/srep02797
Parr, J. B. et al. Pfhrp2-deleted Plasmodium falciparum parasites in the Democratic Republic of the Congo: a national cross-sectional survey. J. Infect. Dis. 216, 36–44 (2017).
pubmed: 28177502
doi: 10.1093/infdis/jix347
Sepúlveda, N. et al. Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis. Infect. Genet. Evol. 62, 211–219 (2018).
pubmed: 29729386
doi: 10.1016/j.meegid.2018.04.039
Gibbons, J. et al. Lineage-specific expansion of Plasmodium falciparum parasites with pfhrp2 deletion in the Greater Mekong subregion. J. Infect. Dis. 222, 1561–1569 (2020).
pubmed: 32386321
pmcid: 7529045
doi: 10.1093/infdis/jiaa250
MalariaGEN et al.An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples. Wellcome Open Res. 6, 42 (2021).
pmcid: 8008441
doi: 10.12688/wellcomeopenres.16168.2
Otto, T. D. et al. Long read assemblies of geographically dispersed Plasmodium falciparum isolates reveal highly structured subtelomeres. Wellcome Open Res. 3, 52 (2018).
pubmed: 29862326
pmcid: 5964635
doi: 10.12688/wellcomeopenres.14571.1
World Health Organization. False-negative RDT results and implications of new P. falciparum histidine-rich protein 2/3 gene deletions (WHO, 2016).
Menegon, M. et al. Identification of Plasmodium falciparum isolates lacking histidine-rich protein 2 and 3 in Eritrea. Infect. Genet. Evol. 55, 131–134 (2017).
pubmed: 28889944
doi: 10.1016/j.meegid.2017.09.004
Thomson, R. et al. Prevalence of Plasmodium falciparum lacking histidine-rich proteins 2 and 3: a systematic review. Bull. World Health Organ. 98, 558–568F (2020).
pubmed: 32773901
pmcid: 7411324
doi: 10.2471/BLT.20.250621
Golassa, L., Messele, A., Amambua-Ngwa, A. & Swedberg, G. High prevalence and extended deletions in Plasmodium falciparum hrp2/3 genomic loci in Ethiopia. PLoS ONE 15, e0241807 (2020).
pubmed: 33152025
pmcid: 7644029
doi: 10.1371/journal.pone.0241807
Gefen-Halevi, S. et al. HRP2/3 mutation in recrudescent Plasmodium falciparum malaria case acquired in Ethiopia. J. Travel Med. 28, taaa196 (2020).
doi: 10.1093/jtm/taaa196
Alemayehu, G. S. et al. Detection of high prevalence of Plasmodium falciparum histidine-rich protein 2/3 gene deletions in Assosa zone, Ethiopia: implication for malaria diagnosis. Malar. J. 20, 109 (2021).
pubmed: 33622309
pmcid: 8095343
doi: 10.1186/s12936-021-03629-x
National Malaria Elimination Roadmap (Federal Democratic Republic of Ethiopia Ministry of Health, 2017).
World Malaria Report 2019 (World Health Organization, 2019); https://www.who.int/publications/i/item/world-malaria-report-2019
Taffese, H. S. et al. Malaria epidemiology and interventions in Ethiopia from 2001 to 2016. Infect. Dis. Poverty 7, 103 (2018).
pubmed: 30392470
pmcid: 6217769
doi: 10.1186/s40249-018-0487-3
Template Protocols to Support Surveillance and Research for pfhrp2/pfhrp3 Gene Deletions (World Health Organization, 2020); https://www.who.int/malaria/publications/atoz/hrp2-deletion-protocol/en/
Morgan, A. P. et al. Falciparum malaria from coastal Tanzania and Zanzibar remains highly connected despite effective control efforts on the archipelago. Malar. J. 19, 47 (2020).
pubmed: 31992305
pmcid: 6988337
doi: 10.1186/s12936-020-3137-8
Parr, J. B. et al. Analysis of false-negative rapid diagnostic tests for symptomatic malaria in the Democratic Republic of the Congo. Sci. Rep. 11, 6495 (2021).
Aydemir, O. et al. Drug-resistance and population structure of Plasmodium falciparum across the Democratic Republic of Congo using high-throughput molecular inversion probes. J. Infect. Dis. 218, 946–955 (2018).
pubmed: 29718283
pmcid: 6093412
doi: 10.1093/infdis/jiy223
Nunes, M. C., Okada, M., Scheidig-Benatar, C., Cooke, B. M. & Scherf, A. Plasmodium falciparum FIKK kinase members target distinct components of the erythrocyte membrane. PLoS ONE 5, e11747 (2010).
pubmed: 20668526
pmcid: 2909202
doi: 10.1371/journal.pone.0011747
Jaskiewicz, E., Jodłowska, M., Kaczmarek, R. & Zerka, A. Erythrocyte glycophorins as receptors for Plasmodium merozoites. Parasit. Vectors 12, 317 (2019).
pubmed: 31234897
pmcid: 6591965
doi: 10.1186/s13071-019-3575-8
Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).
pubmed: 12397357
doi: 10.1038/nature01140
Malaria Rapid Diagnostic Test Performance: Summary Results of WHO Product Testing of Malaria RDTs: Round 1-8 (2008–2018) (World Health Organization, 2018).
Berhane, A. et al. Rapid diagnostic tests failing to detect Plasmodium falciparum infections in Eritrea: an investigation of reported false negative RDT results. Malar. J. 16, 105 (2017).
pubmed: 28264689
pmcid: 5339986
doi: 10.1186/s12936-017-1752-9
Boush, M. A. et al. Plasmodium falciparum isolate with histidine-rich protein 2 gene deletion from Nyala City, Western Sudan. Sci. Rep. 10, 12822 (2020).
pubmed: 32733079
pmcid: 7393171
doi: 10.1038/s41598-020-69756-8
Cunningham, J. Tracking the global distribution and prevalence of pfhrp2/3 gene deletions. In Tropical Medicine 2020, Annual Meeting of the American Society for Tropical Medicine and Hygiene, Symposium 167 (2020).
Gatton, M. L. et al. Implications of parasites lacking Plasmodium falciparum histidine-rich protein 2 on malaria morbidity and control when rapid diagnostic tests are used for diagnosis. J. Infect. Dis. 215, 1156–1166 (2017).
pubmed: 28329034
doi: 10.1093/infdis/jix094
Watson, O. J. et al. Modelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan Africa. eLife 6, e25008 (2017).
pubmed: 28837020
pmcid: 5602420
doi: 10.7554/eLife.25008
Watson, O. J. et al. Impact of seasonal variations in Plasmodium falciparum malaria transmission on the surveillance of pfhrp2 gene deletions. eLife 8, e40339 (2019).
pubmed: 31045490
pmcid: 6533063
doi: 10.7554/eLife.40339
Kong, A. et al. HRP2 and HRP3 cross-reactivity and implications for HRP2-based RDT use in regions with Plasmodium falciparum hrp2 gene deletions. Malar. J. 20, 207 (2021).
pubmed: 33926477
pmcid: 8086288
doi: 10.1186/s12936-021-03739-6
Pal, P. et al. Plasmodium falciparum histidine-rich protein II compromises brain endothelial barriers and may promote cerebral malaria pathogenesis. mBio 7, e00617-16 (2016).
pubmed: 27273825
pmcid: 4959673
doi: 10.1128/mBio.00617-16
Pal, P. et al. Plasmodium falciparum histidine-rich protein II causes vascular leakage and exacerbates experimental cerebral malaria in mice. PLoS ONE 12, e0177142 (2017).
pubmed: 28475625
pmcid: 5419595
doi: 10.1371/journal.pone.0177142
Leffler, E. M. et al. Resistance to malaria through structural variation of red blood cell invasion receptors.Science 356, eaam639 (2017).
doi: 10.1126/science.aam6393
Saito, F. et al. Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors. Nature 552, 101–105 (2017).
pubmed: 29186116
pmcid: 5748893
doi: 10.1038/nature24994
Niang, M. et al. STEVOR is a Plasmodium falciparum erythrocyte binding protein that mediates merozoite invasion and rosetting. Cell Host Microbe 16, 81–93 (2014).
pubmed: 25011110
pmcid: 4382205
doi: 10.1016/j.chom.2014.06.004
National Malaria Guidelines (Federal Democratic Republic of Ethiopia Ministry of Health, 2017); https://www.humanitarianresponse.info/sites/www.humanitarianresponse.info/files/documents/files/eth_national_malaria_guidline_4th_edition.pdf
Plowe, C. V., Djimde, A., Bouare, M., Doumbo, O. & Wellems, T. E. Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa. Am. J. Trop. Med. Hyg. 52, 565–568 (1995).
pubmed: 7611566
doi: 10.4269/ajtmh.1995.52.565
Pickard, A. L. et al. Resistance to antimalarials in Southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob. Agents Chemother. 47, 2418–2423 (2003).
pubmed: 12878499
pmcid: 166057
doi: 10.1128/AAC.47.8.2418-2423.2003
MIPTools. GitHub https://github.com/bailey-lab/MIPTools (2021).
Verity, R. et al. The impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRC. Nat. Commun. 11, 2107 (2020).
pubmed: 32355199
pmcid: 7192906
doi: 10.1038/s41467-020-15779-8
MIPWrangler GitHub https://github.com/bailey-lab/MIPWrangler (2020).
Pedregosa, F. et al. Scikit-learn: machine learning in Python. J. Mach. Learn. Res. 12, 2825–2830 (2011).
Oyola, S. O. et al. Whole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplification. Malar. J. 15, 597 (2016).
pubmed: 27998271
pmcid: 5175302
doi: 10.1186/s12936-016-1641-7
Miles, A. et al. Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum. Genome Res. 26, 1288–1299 (2016).
pubmed: 27531718
pmcid: 5052046
doi: 10.1101/gr.203711.115
Gautier, M. & Vitalis, R. rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure. Bioinformatics 28, 1176–1177 (2012).
pubmed: 22402612
doi: 10.1093/bioinformatics/bts115
Chang, H. H. et al. THE REAL McCOIL: a method for the concurrent estimation of the complexity of infection and SNP allele frequency for malaria parasites. PLoS Comput. Biol. 13, e1005348 (2017).
pubmed: 28125584
pmcid: 5300274
doi: 10.1371/journal.pcbi.1005348