Gametocyte Development and Carriage in Ghanaian Individuals with Uncomplicated Plasmodium falciparum Malaria

Bismarck Dinko Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, Ho, Ghana;

Search for other papers by Bismarck Dinko in
Current site
Google Scholar
PubMed Close
,
Felix Ansah West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra, Ghana;

Search for other papers by Felix Ansah in
Current site
Google Scholar
PubMed Close
,
Comfort Agyare-Kwabi Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, Ho, Ghana;

Search for other papers by Comfort Agyare-Kwabi in
Current site
Google Scholar
PubMed Close
,
Senyo Tagboto Department of Internal Medicine, School of Medicine, University of Health and Allied Sciences, Ho, Volta Region, Ghana;

Search for other papers by Senyo Tagboto in
Current site
Google Scholar
PubMed Close
,
Linda Eva Amoah Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana;

Search for other papers by Linda Eva Amoah in
Current site
Google Scholar
PubMed Close
,
Britta C. Urban Faculty of Biological Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom;

Search for other papers by Britta C. Urban in
Current site
Google Scholar
PubMed Close
,
Colin J. Sutherland Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom;

Search for other papers by Colin J. Sutherland in
Current site
Google Scholar
PubMed Close
,
Gordon A. Awandare West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra, Ghana;

Search for other papers by Gordon A. Awandare in
Current site
Google Scholar
PubMed Close
,
Kim C. Williamson Microbiology and Immunology Department, Uniformed Services University of the Health Sciences, Bethesda, Maryland;

Search for other papers by Kim C. Williamson in
Current site
Google Scholar
PubMed Close
,
Fred N. Binka Department of Epidemiology and Biostatistics, School of Public Health, University of Health and Allied Sciences, Ho, Volta Region, Ghana;

Search for other papers by Fred N. Binka in
Current site
Google Scholar
PubMed Close
, and
Kirk W. Deitsch Department of Microbiology and Immunology, Weill Cornell Medical College, New York

Search for other papers by Kirk W. Deitsch in
Current site
Google Scholar
PubMed Close
DOI:
https://doi.org/10.4269/ajtmh.18-0077
Volume/Issue:
Volume 99: Issue 1
Page(s):
57–64
Restricted access
Get Permissions

Plasmodium falciparum gametocytes develop over 9–12 days while sequestered in deep tissues. On emergence into the bloodstream, they circulate for varied amounts of time during which certain host factors might influence their further development. We aimed to evaluate the potential association of patient clinical parameters with gametocyte development and carriage via in vivo methods. Seventy-two patients were enrolled from three hospitals in the Volta region of Ghana in 2016. Clinical parameters were documented for all patients, and gametocyte prevalence by microscopy was estimated at 12.5%. By measuring RNA transcripts representing two distinct gametocyte developmental stages using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), we obtained a more precise estimate of gametocyte carriage while also inferring gametocyte maturation. Fifty-three percent of the study participants harbored parasites expressing transcripts of the immature gametocyte-specific gene (PF3D7_1477700), whereas 36% harbored PF3D7_1438800 RNA-positive parasites, which is enriched in mid and mature gametocytes, suggesting the presence of more immature stages. Linear logistic regression showed that patients older than 5 years but less than 16 years were more likely to carry gametocytes expressing both PF3D7_1477700 and PF3D7_1438800 compared with younger participants, and gametocytemia was more likely in mildly anemic individuals compared with those with severe/moderate anemia. These data provide further evidence that a greater number of malaria patients harbor gametocytes than typically estimated by microscopy and suggest a possible association between age, fever, anemia, and gametocytemia.

    • Supplemental Materials (PDF 11 KB)

Author Notes

Address correspondence to Bismarck Dinko, Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, PMB 31, Ho, Volta Region, Ghana. E-mail: bdinko@uhas.edu.gh

Financial support: This project was funded by an NIH/Fogarty Global Health Fellowship through the Vanderbilt-Emory-Cornell-Duke Consortium awarded to B. D. Support was also received from the laboratories of K. W. D. and G. A. A., and the University of Health and Allied Sciences in Ho.

Authors’ addresses: Bismarck Dinko and Comfort Agyare-Kwabi, Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, Ho, Ghana, E-mails: bdinko@uhas.edu.gh and cagyare-kwabi@uhas.edu.gh. Felix Ansah and Gordon A. Awandare, West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra, Ghana, E-mails: ansahfelix66@yahoo.com and gawandare@ug.edu.gh. Senyo Tagboto, Department of Internal Medicine, School of Medicine, University of Health and Allied Sciences, Ho, Volta Region, Ghana, E-mail: senyo2@hotmail.com. Linda Eva Amoah, Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana, E-mail: levaamoah@noguchi.ug.edu.gh. Britta C. Urban, Faculty of Biological Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom, E-mail: britta.urban@lstmed.ac.uk. Colin J. Sutherland, Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom, E-mail: colin.sutherland@lshtm.ac.uk. Kim C. Williamson, Microbiology and Immunology Department, Uniformed Services University of the Health Sciences, Bethesda, MD, E-mail: kim.williamson@usuhs.edu. Fred N. Binka, Department of Epidemiology and Biostatistics, School of Public Health, University of Health and Allied Sciences, Ho, Volta Region, Ghana, E-mail: fred.binka@gmail.com. Kirk W. Deitsch, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, E-mail: kwd2001@med.cornell.edu.

Copyright:
© The American Society of Tropical Medicine and Hygiene 2018
Received:
29 Jan 2018
|
Accepted:
23 Feb 2018
|
Published Online:
23 Apr 2018
Cover The American Journal of Tropical Medicine and Hygiene
The American Journal of Tropical Medicine and Hygiene
Print ISSN:
0002-9637
Online ISSN:
1476-1645
  • 1.

    WHO, 2017. World Malaria Report 2017. Geneva, Switzerland: World Health Organization. Available at: http://www.who.int/malaria/media/world-malaria-report-2017/en/. Accessed February 19, 2018.

  • 2.

    Dinko B, Ayivor-Djanie R, Abugri J, Agboli E, Kye-Duodu G, Tagboto S, Tampuori J, Adzaku F, Binka FN, Awandare GA, 2016. Comparison of malaria diagnostic methods in four hospitals in the Volta region of Ghana. MalariaWorld J 7: 5.

    • Search Google Scholar
    • Export Citation
  • 3.

    Smalley ME, Abdalla S, Brown J, 1981. The distribution of Plasmodium falciparum in the peripheral blood and bone marrow of Gambian children. Trans R Soc Trop Med Hyg 75: 103–105.

    • Search Google Scholar
    • Export Citation
  • 4.

    Carter R, Graves PM, 1988. Gametocytes. Wernsdorfer WH, McGregor I, eds. Malaria: Principles and Practice of Malariology. London, United Kingdom: Churchill Livingstone, 253–320.

  • 5.

    Alano P, 2007. Plasmodium falciparum gametocytes: still many secrets of a hidden life. Mol Microbiol 66: 291–302.

  • 6.

    Joice R et al. 2014. Plasmodium falciparum transmission stages accumulate in the human bone marrow. Sci Transl Med 6: 244re5.

  • 7.

    Hawking F, Wilson ME, Gammage K, 1971. Evidence for cyclic development and short-lived maturity in the gametocytes of Plasmodium falciparum. Trans R Soc Trop Med Hyg 65: 549–559.

    • Search Google Scholar
    • Export Citation
  • 8.

    Sinden RE, Carter R, Drakeley C, Leroy D, 2012. The biology of sexual development of Plasmodium: the design and implementation of transmission-blocking strategies. Malar J 11: 70.

    • Search Google Scholar
    • Export Citation
  • 9.

    Gebru T, Lalremruata A, Kremsner PG, Mordmüller B, Held J, 2017. Life-span of in vitro differentiated Plasmodium falciparum gametocytes. Malar J 16: 330.

    • Search Google Scholar
    • Export Citation
  • 10.

    Eichner M, Diebner HH, Molineaux L, Collins WE, Jeffery GM, Dietz K, 2001. Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malaria therapy data. Trans R Soc Trop Med Hyg 95: 497–501.

    • Search Google Scholar
    • Export Citation
  • 11.

    Price R, Nosten F, Simpson JA, Luxemburger C, Phaipun L, ter Kuile F, van Vugt M, Chongsuphajaisiddhi T, White NJ, 1999. Risk factors for gametocyte carriage in uncomplicated falciparum malaria. Am J Trop Med Hyg 60: 1019–1023.

    • Search Google Scholar
    • Export Citation
  • 12.

    Gouagna LC, Bancone G, Yao F, Yameogo B, Dabiré KR, Costantini C, Simporé J, Ouedraogo JB, Modiano D, 2010. Genetic variation in human HBB is associated with Plasmodium falciparum transmission. Nat Genet 42: 328–331.

    • Search Google Scholar
    • Export Citation
  • 13.

    Bousema T, Drakeley C, 2011. Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clin Microbiol Rev 24: 377–410.

    • Search Google Scholar
    • Export Citation
  • 14.

    Drakeley CJ, Secka I, Correa S, Greenwood BM, Targett GA, 1999. Host haematological factors influencing the transmission of Plasmodium falciparum gametocytes to Anopheles gambiae s.s. mosquitoes. Trop Med Int Health 4: 131–138.

    • Search Google Scholar
    • Export Citation
  • 15.

    Barnes KI, Little F, Mabuza A, Mngomezulu N, Govere J, Durrheim D, Roper C, Watkins B, White NJ, 2008. Increased gametocytemia after treatment: an early parasitological indicator of emerging sulfadoxine-pyrimethamine resistance in falciparum malaria. J Infect Dis 197: 1605–1613.

    • Search Google Scholar
    • Export Citation
  • 16.

    Drakeley C, Sutherland C, Bousema JT, Sauerwein RW, Targett GA, 2006. The epidemiology of Plasmodium falciparum gametocytes: weapons of mass dispersion. Trends Parasitol 22: 424–430.

    • Search Google Scholar
    • Export Citation
  • 17.

    Lobo CA, Kumar K, 1998. Sexual differentiation and development in the malaria parasite. Parasitol Today 14: 146–150.

  • 18.

    Nantakomol D et al. 2011. Circulating red cell-derived microparticles in human malaria. J Infect Dis 203: 700–706.

  • 19.

    Mantel PY et al. 2013. Malaria-infected erythrocyte-derived microvesicles mediate cellular communication within the parasite population and with the host immune system. Cell Host Microbe 13: 521–534.

    • Search Google Scholar
    • Export Citation
  • 20.

    Regev-Rudzki N et al. 2013. Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. Cell 153: 1120–1133.

  • 21.

    Brancucci NMB et al. 2017. Lysophosphatidylcholine regulates sexual stage differentiation in the human malaria parasite Plasmodium falciparum. Cell 171: 1532–1544.e15.

    • Search Google Scholar
    • Export Citation
  • 22.

    Eksi S, Haile Y, Furuya T, Ma L, Su X, Williamson KC, 2005. Identification of a subtelomeric gene family expressed during the asexual-sexual stage transition in Plasmodium falciparum. Mol Biochem Parasitol 143: 90–99.

    • Search Google Scholar
    • Export Citation
  • 23.

    Eksi S et al. 2012. Plasmodium falciparum gametocyte development 1 (Pfgdv1) and gametocytogenesis early gene identification and commitment to sexual development. PLoS Pathog 8: e1002964.

    • Search Google Scholar
    • Export Citation
  • 24.

    Kafsack BF et al. 2014. A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature 507: 248–252.

  • 25.

    Sinha A et al. 2014. A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. Nature 507: 253–257.

  • 26.

    Joice R et al. 2013. Inferring developmental stage composition from gene expression in human malaria. PLoS Comput Biol 9: e1003392.

  • 27.

    Plasmo DB, 2018. The Plasmodium Genome Resources. Available at: http://plasmodb.org/plasmo/. Accessed January 12, 2018.

  • 28.

    Kweku M, Liu D, Adjuik M, Binka F, Seidu M, Greenwood B, Chandramohan D, 2008. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. PLoS One 3: e4000.

    • Search Google Scholar
    • Export Citation
  • 29.

    Greenwood BM, Armstrong JR, 1991. Comparison of two simple methods for determining malaria parasite density. Trans R Soc Trop Med Hyg 85: 186–188.

    • Search Google Scholar
    • Export Citation
  • 30.

    Drakeley CJ, Eling W, Teelen K, Bousema JT, Sauerwein R, Greenwood BM, Targett GA, 2004. Parasite infectivity and immunity to Plasmodium falciparum gametocytes in Gambian children. Parasite Immunol 26: 159–165.

    • Search Google Scholar
    • Export Citation
  • 31.

    Chomczynski P, 1993. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques 15: 532–537.

    • Search Google Scholar
    • Export Citation
  • 32.

    Djimdé A et al. 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257–263.

  • 33.

    Duraisingh MT, Curtis J, Warhurst DC, 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. Exp Parasitol 89: 1–8.

    • Search Google Scholar
    • Export Citation
  • 34.

    Chang HH et al. 2016. Persistence of Plasmodium falciparum parasitemia after artemisinin combination therapy: evidence from a randomized trial in Uganda. Sci Rep 6: 26330.

    • Search Google Scholar
    • Export Citation
  • 35.

    WHO, 2011. Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity, Report, 2011. Available at: http://www.who.int/vmnis/indicators/haemoglobin.pdf. Accessed August 14, 2017.

  • 36.

    Schneider P, Bousema JT, Gouagna LC, Otieno S, van de Vegte-Bolmer M, Omar SA, Sauerwein RW, 2007. Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection. Am J Trop Med Hyg 76: 470–474.

    • Search Google Scholar
    • Export Citation
  • 37.

    Bousema JT et al. 2006. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J Infect Dis 193: 1151–1159.

    • Search Google Scholar
    • Export Citation
  • 38.

    Churcher TS, Bousema T, Walker M, Drakeley C, Schneider P, Ouédraogo AL, Basáñez MG, 2013. Predicting mosquito infection from Plasmodium falciparum gametocyte density and estimating the reservoir of infection. Elife 2: e00626.

    • Search Google Scholar
    • Export Citation
  • 39.

    Targett G et al. 2001. Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae. J Infect Dis 183: 1254–1259.

    • Search Google Scholar
    • Export Citation
  • 40.

    Carter R, Miller LH, 1979. Evidence for environmental modulation of gametocytogenesis in Plasmodium falciparum in continuous culture. Bull World Health Organ 57 (Suppl 1): 37–52.

    • Search Google Scholar
    • Export Citation
  • 41.

    Graves PM, Carter R, McNeill KM, 1984. Gametocyte production in cloned lines of Plasmodium falciparum. Am J Trop Med Hyg 33: 1045–1050.

  • 42.

    Dyer M, Day KP, 2000. Commitment to gametocytogenesis in Plasmodium falciparum. Parasitol Today 16: 102–107.

  • 43.

    Smalley ME, Brown J, 1981. Plasmodium falciparum gametocytogenesis stimulated by lymphocytes and serum from infected Gambian children. Trans R Soc Trop Med Hyg 75: 316–317.

    • Search Google Scholar
    • Export Citation
  • 44.

    Meerman L, Ord R, Bousema JT, van Niekerk M, Osman E, Hallett R, Pinder M, Walraven G, Sutherland CJ, 2005. Carriage of chloroquine-resistant parasites and delay of effective treatment increase the risk of severe malaria in Gambian children. J Infect Dis 192: 1651–1657.

    • Search Google Scholar
    • Export Citation
  • 45.

    Dunyo S, Milligan P, Edwards T, Sutherland C, Targett G, Pinder M, 2006. Gametocytaemia after drug treatment of asymptomatic Plasmodium falciparum. PLoS Clin Trials 1: e20.

    • Search Google Scholar
    • Export Citation
  • 46.

    WWARN Gametocyte Study Group, 2016. Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data. BMC Med 14: 79.

    • Search Google Scholar
    • Export Citation
  • 47.

    Rieckmann KH, McNamara JV, Kass L, Powell RD, 1969. Gametocytocidal and sporontocidal effects of primaquine upon two strains of Plasmodium falciparum. Mil Med 134: 802–819.

    • Search Google Scholar
    • Export Citation
  • 48.

    Ashley EA et al. Tracking Resistance to Artemisinin Collaboration (TRAC), 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 371: 411–423.

    • Search Google Scholar
    • Export Citation
  • 49.

    Beshir KB et al. 2013. Residual Plasmodium falciparum parasitemia in Kenyan children after artemisinin-combination therapy is associated with increased transmission to mosquitoes and parasite recurrence. J Infect Dis 208: 2017–2024.

    • Search Google Scholar
    • Export Citation
  • 50.

    Venkatesan M, Alifrangis M, Roper C, Plowe CV, 2013. Monitoring antifolate resistance in intermittent preventive therapy for malaria. Trends Parasitol 29: 497–504.

    • Search Google Scholar
    • Export Citation
  • 51.

    Kiarie WC, Wangai L, Agola E, Kimani FT, Hungu C, 2015. Chloroquine sensitivity: diminished prevalence of chloroquine-resistant gene marker pfcrt-76 13 years after cessation of chloroquine use in Msambweni, Kenya. Malar J 14: 328.

    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 65 65 18
Full Text Views 1210 631 1
PDF Downloads 179 50 0
 
Membership Banner
 
 
 
Affiliate Membership Banner
 
 
Research for Health Information Banner
 
 
CLOCKSS
 
 
 
Society Publishers Coalition Banner
Save