Skip to main content
SpringerLink
Log in

First Insight into Drug Resistance Genetic Markers, Glucose-6-Phosphate Dehydrogenase and Phylogenetic Patterns of Misdiagnosed Plasmodium vivax Malaria in Far North Region, Cameroon

  • Short Communication
  • Published:
Current Microbiology Aims and scope Submit manuscript

Abstract

Plasmodium falciparum (Pf) is the predominant malaria species in Africa, but growing rates of non-falciparum species such as P. vivax (Pv) have been reported recently. This study aimed at characterizing drug resistance genes, glucose-6-phosphate dehydrogenase gene (G6PD), and phylogenetic patterns of a Pv + Pf co-infection misdiagnosed as a Pf mono-infection in the Far North region of Cameroon. Only one non-synonymous mutation in the pvdhps gene A383G was found. Pv drug resistance gene sequences were phylogenetically closer to the reference SAL-I strain and isolates from Southeast Asia and Western Pacific countries. Analyzing co-infecting Pf revealed no resistance mutations in Pfmdr1 and Pfk13 genes, but mutations in Pfcrt (C72V73I74E75T76) and Pfdhfr–Pfdhps genes (A16C50I51R59N108L164 – A436A437K540G581S613) were observed. No G6PD deficiency-related mutations were found. This is first study from Cameroon reporting presence of putative drug resistance mutations in Pv infections, especially in the pvdhps gene, and also outlined the absence of a G6PD-deficiency trait in patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Data Availability

The original contributions presented here are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Code Availability

Sequences generated are deposited to NCBI nucleotide database under Accession Numbers OR483860-OR483867, OR499100-OR499101 and OR503034.

Abbreviations

ACT:

Artemisinin-based combination therapy

AHA:

Acute hemolytic anemia

CNSHA:

Chronic nonspherocytic hemolytic anemia

DNA:

Deoxyribonucleic acid

G6PD:

Glucose-6-phosphate dehydrogenase

G6PD-d:

Glucose-6-phosphate dehydrogenase deficiency

mt:

Mutant

PCR:

Polymerase chain reaction

Pf :

Plasmodium falciparum

Pfcrt :

Plasmodium falciparum Chloroquine resistance transporter

Pfdhfr :

Plasmodium falciparum Dihydrofolate reductase

Pvdhps :

Plasmodium falciparum Dihydropteroate synthase

Pfkelch13 :

Plasmodium falciparum Kelch protein 13

Pfmdr-1 :

Plasmodium falciparum Multidrug resistance protein 1

Pm :

Plasmodium malariae

Po :

Plasmodium ovale

PQ:

Primaquine

Pv :

Plasmodium vivax

Pvcrt :

Plasmodium vivax Chloroquine resistance transporter

Pvdhfr :

Plasmodium vivax Dihydrofolate reductase

Pvdhps :

Plasmodium vivax Dihydropteroate synthase

Pvkelch12 :

Plasmodium vivax Kelch protein 12

Pvmdr-1 :

Plasmodium vivax Multidrug resistance protein 1

SEA:

South East Asia

sSA:

Sub-Saharan Africa

wt:

Wild type

WHO:

World Health Organization

References

  1. World Health Organization (2022) World malaria report 2022. WHO/HTM/GM. ISBN 978 92 4 1564403

  2. Antonio-Nkondjio C, Ndo C, Njiokou F, Bigoga JD, Awono-Ambene P, Etang J, Ekobo AS, Wondji CS (2019) Review of malaria situation in Cameroon: technical viewpoint on challenges and prospects for disease elimination. Parasit Vectors 12:501. https://doi.org/10.1186/s13071-019-3753-8

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dongang Nana RR, Hawadak J, Kojom Foko LP, Kumar A, Chaudhry S, Arya A, Singh V (2023) Intermittent preventive treatment with sulfadoxine pyrimethamine for malaria: a global overview and challenges affecting optimal drug uptake in pregnant women. Pathog Glob Health 117:462–475. https://doi.org/10.1080/20477724.2022.2128563

    Article  CAS  Google Scholar 

  4. Kojom Foko LP, Kouemo Motse FD, Kamgain Mawabo L, Pande V, Singh V (2021) First evidence of local circulation of Plasmodium ovale curtisi and reliability of a malaria rapid diagnostic test among febrile outpatients in Douala, Cameroon. Infect Genet Evol 91:104797. https://doi.org/10.1016/j.meegid.2021.104797

    Article  CAS  PubMed  Google Scholar 

  5. Kojom Foko LP, Hawadak J, Kouemo Motse FD, Eboumbou Moukoko EC, Kamgain Mawabo L, Pande V, Singh V (2022) Non-falciparum species and submicroscopic infections in three epidemiological malaria facets in Cameroon. BMC Infect Dis 22:900. https://doi.org/10.1186/s12879-022-07901-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kojom Foko LP, Arya A, Sharma A, Singh V (2021) Epidemiology and clinical outcomes of severe Plasmodium vivax malaria in India. J Infect 82:231–246. https://doi.org/10.1016/j.jinf.2021.03.028

    Article  PubMed  Google Scholar 

  7. Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ (2014) Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis 14:982–991. https://doi.org/10.1016/S1473-3099(14)70855-2

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kojom Foko LP, Kumar A, Hawadak J, Singh V (2023) Plasmodium cynomolgi in humans: current knowledge and future directions of an emerging zoonotic malaria parasite. Infection 51:623–640. https://doi.org/10.1007/s15010-022-01952-2

    Article  CAS  PubMed  Google Scholar 

  9. Luzzatto L, Ally M, Notaro R (2020) Glucose-6-phosphate dehydrogenase deficiency. Blood 136:1225–1240. https://doi.org/10.1182/blood.2019000944

    Article  PubMed  Google Scholar 

  10. Roman DNR, Rosalie NNA, Kumar A, Luther KMM, Singh V, Albert MS (2018) Asymptomatic Plasmodium malariae infections in children from suburban areas of Yaoundé, Cameroon. Parasitol Int 67:29–33. https://doi.org/10.1016/j.parint.2017.02.009

    Article  PubMed  Google Scholar 

  11. Nguiffo-Nguete D, Nongley Nkemngo F, Ndo C, Agbor JP, Boussougou-Sambe ST, Salako Djogbénou L, Ntoumi F, Adegnika AA, Borrmann S, Wondji CS (2023) Plasmodium malariae contributes to high levels of malaria transmission in a forest–savannah transition area in Cameroon. Parasit Vectors 16:31. https://doi.org/10.1186/s13071-022-05635-7

    Article  PubMed  PubMed Central  Google Scholar 

  12. Djeunang Dongho GB, Gunalan K, L’Episcopia M et al (2021) Plasmodium vivax infections detected in a large number of febrile Duffy-negative Africans in Dschang, Cameroon. Am J Trop Med Hyg 104:987–992. https://doi.org/10.4269/ajtmh.20-1255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Snounou G, Viriyakosol S, Jarra W, Thaithong S, Brown KN (1993) Identification of the four human malaria parasite species in field samples by the polymerase chain reaction and detection of a high prevalence of mixed infections. Mol Biochem Parasitol 58:283–292. https://doi.org/10.1016/0166-6851(93)90050-8

    Article  CAS  PubMed  Google Scholar 

  14. Fuehrer HP, Stadler MT, Buczolich K, Bloeschl I, Noedl H (2012) Two techniques for simultaneous identification of Plasmodium ovale curtisi and Plasmodium ovale wallikeri by use of the small-subunit rRNA gene. J Clin Microbiol 50:4100–4102. https://doi.org/10.1128/JCM.02180-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arya A, Kojom Foko LP, Chaudhry S, Sharma A, Singh V (2021) Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: a systematic review of clinical studies from two malaria endemic regions—India and sub-Saharan Africa. Int J Parasitol Drugs Drug Resist 15:43–56. https://doi.org/10.1016/j.ijpddr.2020.11.006

    Article  CAS  PubMed  Google Scholar 

  16. Kojom Foko LP, Narang G, Jakhan J, Tamang S, Moun A, Singh V (2023) Nationwide spatiotemporal drug resistance genetic profiling from over three decades in Indian Plasmodium falciparum and Plasmodium vivax isolates. Malar J 22:236. https://doi.org/10.1186/s12936-023-04651-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kumar S, Stecher G, Li M, Knyaz C, Tamura K (2018) MEGA X: molecular evolutionary genetics analysis across computing platforms. Mol Biol Evol 35:1547–1549. https://doi.org/10.1093/molbev/msy096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Luzzatto L, Nannelli C, Notaro R (2016) Glucose-6-phosphate dehydrogenase deficiency. Hematol Oncol Clin N Am 30:373–393. https://doi.org/10.1016/j.hoc.2015.11.006

    Article  Google Scholar 

  19. Oboh Aigbiremo M, Oyebola KM, Idowu ET, Badiane AS, Otubanjo OA, Ndiaye D (2020) Rising report of Plasmodium vivax in sub-Saharan Africa: implications for malaria elimination agenda. Sci Afr 10:e00596. https://doi.org/10.1016/j.sciaf.2020.e00596

    Article  Google Scholar 

  20. Matlani M, Kojom LP, Mishra N, Dogra V, Singh V (2020) Severe vivax malaria trends in the last two years: a study from a tertiary care centre, Delhi, India. Ann Clin Microbiol Antimicrob 19:49. https://doi.org/10.1186/s12941-020-00393-9

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chaturvedi R, Chhibber-Goel J, Verma I, Gopinathan S, Parvez S, Sharma A (2021) Geographical spread and structural basis of sulfadoxine-pyrimethamine drug-resistant malaria parasites. Int J Parasitol 51:505–525. https://doi.org/10.1016/j.ijpara.2020.12.011

    Article  CAS  PubMed  Google Scholar 

  22. Benavente ED, Manko E, Phelan J et al (2021) Distinctive genetic structure and selection patterns in Plasmodium vivax from South Asia and East Africa. Nat Commun 12:3160. https://doi.org/10.1038/s41467-021-23422-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jin X, Zhu S, Xu W, Chen J, Ruan W, Wang X (2021) Limited polymorphism in k13 gene of Plasmodium falciparum and k12 of Plasmodium vivax isolates imported from African and Asian countries between 2014 and 2019 in Hangzhou city, China. BMC Infect Dis 21:853. https://doi.org/10.1186/s12879-021-06579-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang M, Siddiqui FA, Fan Q, Luo E, Cao Y, Cui L (2016) Limited genetic diversity in the PvK12 Kelch protein in Plasmodium vivax isolates from Southeast Asia. Malar J 15:537. https://doi.org/10.1186/s12936-016-1583-0

    Article  PubMed  PubMed Central  Google Scholar 

  25. Niba PTN, Nji AM, Evehe MS et al (2021) Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis (1998–2020). Malar J 20:32. https://doi.org/10.1186/s12936-020-03543-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Uwimana A, Legrand E, Stokes BH et al (2020) Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat Med 26:1602–1608. https://doi.org/10.1038/s41591-020-1005-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Balikagala B, Fukuda N, Ikeda M et al (2021) Evidence of artemisinin-resistant malaria in Africa. N Engl J Med 385:1163–1171. https://doi.org/10.1056/NEJMoa2101746

    Article  CAS  PubMed  Google Scholar 

  28. Chauvin P, Menard S, Iriart X, Nsango SE, Tchioffo MT, Abate L, Awono-Ambéné PH, Morlais I, Berry A (2015) Prevalence of Plasmodium falciparum parasites resistant to sulfadoxine/pyrimethamine in pregnant women in Yaoundé Cameroon: emergence of highly resistant pfdhfr/pfdhps alleles. J Antimicrob Chemother 70:2566–2571. https://doi.org/10.1093/jac/dkv160

    Article  CAS  PubMed  Google Scholar 

  29. Mbanefo EC, Ahmed AM, Titouna A et al (2017) Association of glucose-6-phosphate dehydrogenase deficiency and malaria: a systematic review and meta-analysis. Sci Rep 7:45963. https://doi.org/10.1038/srep45963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lauden SM, Chongwain S, Achidi A, Helm E, Cusick SE, Krug A, Slusher TM, Lund TC (2019) Prevalence of glucose-6-phosphate dehydrogenase deficiency in Cameroonian blood donors. BMC Res Notes 12:195. https://doi.org/10.1186/s13104-019-4226-z

    Article  PubMed  PubMed Central  Google Scholar 

  31. Awah F, Uzoegwu P (2008) Malaria protection in glucose-6-phosphate dehydrogenase deficient individuals in Bamenda population of Cameroon. Glob J Pure Appl Sci 14:343–347. https://doi.org/10.4314/gjpas.v14i3.16819

    Article  Google Scholar 

  32. Bernstein SC, Bowman JE, Noche Kaptue L (1980) Interaction of sickle cell trait and glucose-6-phosphate dehydrogenase deficiency in Cameroon. Hum Hered 30:7–11. https://doi.org/10.1159/000153080

    Article  CAS  PubMed  Google Scholar 

  33. Bernstein SC, Bowman JE, Noche Kaptue L (1980) Population studies in Cameroon: hemoglobin S, glucose-6-phosphate dehydrogenase deficiency and falciparum malaria. Hum Hered 30:251–258. https://doi.org/10.1159/000153138

    Article  CAS  PubMed  Google Scholar 

  34. Sobngwi E, Gautier JF, Kevorkian JP, Villette JM, Riveline JP, Zhang S, Vexiau P, Leal SM, Vaisse C, Mauvais-Jarvis F (2005) High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes. J Clin Endocrinol Metab 90:4446–4451. https://doi.org/10.1210/jc.2004-2545

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to patients who accepted to take part in the study, and Dr MALAMA Toussaint, Dr GANAVA Maurice and Mr. NINSU Cedric for help in collecting samples in North and Far North regions. Special thanks to Dr John O. Oladokun, PhD (Postdoctoral Extension Research Associate, Texas A&M University, Texas, USA) for his comments on English language editing and proofreading.

Funding

The authors are grateful to Department of Biotechnology (DBT), New Delhi, India; The World Academy of Sciences (TWAS), Trieste, Italy; and ICMR–National Institute of Malaria Research, New Delhi, India, for the fellowship (DBT–TWAS Postgraduate Fellowship Programme – 2017, N° 3240300010) jointly awarded to Dr. Loick P. Kojom Foko.

Author information

Author notes

  1. Jahnvi Jakhan and Suman Tamang have contributed equally to work and share second authorship.

Authors and Affiliations

  1. ICMR-National Institute of Malaria Research, Dwarka, Sector 8, New-Delhi, 110077, India

    Loick Pradel Kojom Foko, Jahnvi Jakhan, Suman Tamang, Joseph Hawadak & Vineeta Singh

  2. Department of Medical Laboratory Sciences, Faculty of Health Sciences, University of Buea, 63, Buea, Cameroon

    Francine Dorgelesse Kouemo Motse

Authors
  1. Loick Pradel Kojom Foko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jahnvi Jakhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suman Tamang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph Hawadak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francine Dorgelesse Kouemo Motse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vineeta Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LPKF and VS conceived and designed the study. LPKF performed laboratory experiments, analyzed data and drafted the first version of the manuscript. JJ and ST helped in laboratory experiments and performed sequencing. JH and FDKM helped in sample collection. JH created the map used in the study. JH, JJ, ST, FDKM and VS helped in data interpretation and revised the manuscript for important intellectual content. VS supervised the work at all stages. All authors read and approved the final paper.

Corresponding author

Correspondence to Vineeta Singh.

Ethics declarations

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

Approvals were sought from ethical committee of Delegation of Public Health in Littoral, North, and Far North regions, Ministry of Public Health, Cameroon (No 2596/AS/MINSANTE/DRSPL/BCASS, N° 1623/MINSANTE/DRSPN/PNLP/CR, and 0887/MINSANTE/DRSPEN/CR/PNLP/CR) to collect samples in each health facility (Pette district hospital, Mayo-Oulo district hospital, Laboratoire Sainte Thérèse, and Maroua District hospital). The study was also approved by institutional ethics committee of ICMR-NIMR, New Delhi, India (N° PHB/NIMR/EC/2020/55). All patients signed an informed consent form and in case of minors it was signed by a parent and/or legal guardian for study participation. All methods were carried out in accordance with relevant guidelines and regulations.

Consent to Participate

Informed consent was obtained from all individual participants included in the study. For children and minors, informed consent was obtained from parents or legal guardians.

Consent for Publication

The participant has consented to the submission of the short communication to the journal.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 22 kb)

Supplementary file2 (DOCX 207 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kojom Foko, L.P., Jakhan, J., Tamang, S. et al. First Insight into Drug Resistance Genetic Markers, Glucose-6-Phosphate Dehydrogenase and Phylogenetic Patterns of Misdiagnosed Plasmodium vivax Malaria in Far North Region, Cameroon. Curr Microbiol 81, 9 (2024). https://doi.org/10.1007/s00284-023-03522-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00284-023-03522-7

Search

Navigation