Archives of Virology

, Volume 164, Issue 4, pp 1095–1110 | Cite as

Evaluation of anti-dengue activity of Carica papaya aqueous leaf extract and its role in platelet augmentation

  • Navita Sharma
  • Kamla Prasad MishraEmail author
  • Sudipta Chanda
  • Varun Bhardwaj
  • Himanshi Tanwar
  • Lilly Ganju
  • Bhuvnesh Kumar
  • Shashi Bala Singh
Original Article


Dengue disease is characterized by a marked decrease in platelet count, which is life threatening. In the present study, we investigated the antiviral activity of an aqueous extract of Carica papaya leaves (PLE) against dengue virus (DENV) and its effect on platelet augmentation. The anti-dengue activity of PLE in DENV-infected THP-1 cells was examined by immunoblotting and flow cytometry. The effect of PLE on erythrocyte damage was investigated using hemolytic and anti-hemolytic assays. Virus-infected THP-1 cells were assayed for IFN-α secretion. The effect of PLE on platelet augmentation in rats with cyclophosphamide-induced thrombocytopenia was also investigated. The platelet count of blood from the retro-orbital plexus of rats was determined on the 1st, 4th, 7th, 11th and 14th day of study. On the 14th day, the rats were sacrificed for histopathological examination of the liver, kidney and spleen. Plasma of thrombocytopenic rats was tested for thrombopoietin (TPO) and IL-6 secretion. The data suggest that PLE significantly decreases the expression of the envelope and NS1 proteins in DENV-infected THP-1 cells. A marked decrease in intracellular viral load upon PLE treatment confirmed its antiviral activity. This also resulted in a significant decrease in erythrocyte damage and hydrogen-peroxide-induced lipid peroxidation. A significant increase in the number of platelets was found in thrombocytopenic rats treated with PLE, along with an increase in IL-6 and TPO levels. These findings suggest that PLE can potentially be used as an antiviral agent, as it helps in platelet augmentation and exhibits antiviral activity against DENV.



Dengue virus


Papaya leaf extract


Dengue hemorrhagic fever


Dengue shock syndrome


World Health Organization


Fetal bovine serum


Ultra performance liquid chromatography


Liquid chromatography mass spectrometry


Human peripheral blood mononuclear cells


Interferon alpha




Hematoxylin and eosin





The authors thank the Defence Research & Development Organization (DRDO), Government of India, for financial support. NS thanks the Council of Scientific and Industrial Research for providing a fellowship in the form of a Junior and Senior Research Fellowship. She also thanks Dr. Sachin Kolte (Associate Professor, MD Pathology, Safdarjung Hospital, Delhi, India) in helping in analyzing histopathological slides of different organs of rats.


This study was funded by the Defence Research & Development Organization (DRDO) [DIP-264]. NS thanks the Council of Scientific and Industrial Research CSIR for providing a fellowship in the form of a Junior and Senior Research Fellowship.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. All animal protocols were approved by the DIPAS Institutional Animal Ethics Committee (IAEC/DIPAS/2015-25, 18/10/2015).


  1. 1.
    Alcon-LePoder S, Drouet MT, Roux P, Frenkiel MP, Arborio M, Durand-Schneider AM, Maurice M, Le Blanc I, Gruenberg J, Flamand M (2005) The secreted form of dengue virus nonstructural protein NS1 is endocytosed by hepatocytes and accumulates in late endosomes: implications for viral infectivity. J Virol 79:11403–11411CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Aguiar M, Stollenwerk N (2018) Dengvaxia: age as surrogate for serostatus. Lancet Infect Dis 18:245CrossRefGoogle Scholar
  3. 3.
    Aruoma OI, Colognato R, Fontana I, Gartlon J, Miglior L, Koike K, Coecke S, Lamy E, Mersch-Sundermann V, Laurenza I, Benzi L, Yoshino F, Kobayashi K, Lee MC (2006) Molecular effects of fermented papaya preparation on oxidative damage, MAP kinase activation and modulation of the benzo[a]pyrene mediated genotoxicity. Biofactors 26:147–159CrossRefGoogle Scholar
  4. 4.
    Awe EO, Makinde JM, Adeloye OA, Banjoko SO (2009) Membrane stabilizing activity of Russelia equisetiformis, Schlecht and Chan. J Nat Prod 2:3–9Google Scholar
  5. 5.
    Azeredo de EL, Monteiro RQ, de-Oliveira Pinto LM (2015) Thrombocytopenia in dengue: interrelationship between virus and the imbalance between coagulation and fibrinolysis and inflammatory mediators. Mediat Inflamm 2015:313842CrossRefGoogle Scholar
  6. 6.
    Baskaran C, Ratha BV, Velu S, Kumaran K (2012) The efficacy of Carica papaya leaf extract on some bacterial and a fungal strain by well diffusion method. Asian Pac J Trop Dis 2:S658–S662CrossRefGoogle Scholar
  7. 7.
    Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI (2013) The global distribution and burden of dengue. Nature 496:504–507CrossRefPubMedCentralGoogle Scholar
  8. 8.
    de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ et al (1994) Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369:533–538CrossRefGoogle Scholar
  9. 9.
    Diamond MS, Roberts TG, Edgil D, Lu B, Ernst J, Harris E (2000) Modulation of dengue virus infection in human cells by alpha, beta, and gamma interferons. J Virol 74:4957–4966CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Emeruwa AC (1982) Antibacterial substance from Carica papaya fruit extract. J Nat Prod 45:123–127CrossRefGoogle Scholar
  11. 11.
    Guy B, Barrere B, Malinowski C, Saville M, Teyssou R, Lang J (2011) From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine. Vaccine 29:7229–7241CrossRefGoogle Scholar
  12. 12.
    Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martínez E, Nathan MB, Pelegrino JL, Simmons C, Yoksan S, Peeling RW (2010) Dengue: a continuing global threat. Nat Rev Microbiol 8(12 Suppl):S7–S16CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Halstead SB (1988) Pathogenesis of dengue: challenges to molecular biology. Science 239:476–481CrossRefGoogle Scholar
  14. 14.
    Halstead SB (2017) Dengvaxia sensitizes seronegatives to vaccine enhanced disease regardless of age. Vaccine 35:6355–6358CrossRefGoogle Scholar
  15. 15.
    Hasheen FM (2007) Antibacterial activity of Carica papaya extract. Oxford University Press, New York, pp 15–25Google Scholar
  16. 16.
    Henchal EA, Putnak JR (1990) The dengue viruses. Clin Microbiol Rev 3:376–396CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Honda S, Saito M, Dimaano EM, Morales PA, Alonzo MT, Suarez LA, Koike N, Inoue S, Kumatori A, Matias RR, Natividad FF, Oishi K (2009) Increased phagocytosis of platelets from patients with secondary dengue virus infection by human macrophages. Am J Trop Med Hyg 80:841–845CrossRefGoogle Scholar
  18. 18.
    Jassim SAA, Naji MA (2003) Novel antiviral agents: a medicinal plants perspective. J Appl Microbiol 95:412–427CrossRefGoogle Scholar
  19. 19.
    Kho LK, Wulur H, Himawan T (1972) Blood and bone marrow changes in dengue haemorrhagic fever. Paediatr Indones 12:31–39Google Scholar
  20. 20.
    Khongphatthanayothin A, Mahayosnond A, Poovorawan Y (2013) Possible cause of liver failure in patient with dengue shock syndrome. Emerg Infect Dis 19:1161–1163CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Latifah S, AbdKadir A, Yaakob H, Zulkifli RM (2013) Potential anti-dengue medicinal plants: a review. J Nat Med 67:677–689CrossRefGoogle Scholar
  22. 22.
    Libraty D, Young PR, Pickering D, EndyTP Kalayanarooj S, Green S (2002) High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 186:1165–1168CrossRefGoogle Scholar
  23. 23.
    Mehdipour S, Yasa N, Dehghan G, Khorasani R, Mohammadirad A, Rahimi R, Abdollahi M (2006) Antioxidant potentials of Iranian Carica papaya juice in vitro and in vivo are comparable to alpha-tocopherol. Phytother Res 20:591–594CrossRefGoogle Scholar
  24. 24.
    Mishra KP, Sharma N, Diwaker D, Ganju L, Singh SB (2013) Plant derived antivirals: a potential source of drug development. J Virol Antivir Res 2:2Google Scholar
  25. 25.
    Noriko O, Nam HD, Emi K, Akira K, Sathoshi I, Chikao M (2010) Aqueous extract of Carica papaya leaves exhibit anti tumour activity and immunomodulatory effects. J Etnopharmacol 27:760–767Google Scholar
  26. 26.
    Ojha A, Nandi D, Batra H, Singhal R, Annarapu GK, Bhattacharyya S, Seth T, Dar L, Medigeshi GR, Vrati S, Vikram NK, Guchhait P (2017) Platelet activation determines the severity of thrombocytopenia in dengue infection. Sci Rep 7:41697CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Parle M, Guruditta G (2011) Basketful benefits of papaya. Int Res J Pharm 2:6–12Google Scholar
  28. 28.
    Sathasivam K, Ramanathan S, Mansor SM, Haris MR, Wernsdorfer WH (2009) Thrombocyte counts in mice after the administration of papaya leaf suspension. Wien Klin Wochenschr 21(Suppl 3):19–22CrossRefGoogle Scholar
  29. 29.
    Sharma N, Mishra KP, Ganju L (2016) Salidroside exhibits anti-dengue virus activity by upregulating host innate immune factors. Arch Virol 161:3331–3344CrossRefGoogle Scholar
  30. 30.
    Silva JAT, Rashid Z, Nhut DT, Sivakumar D, Gera A, Souza MT, Tennant P (2007) Papaya (Carica papaya L.) biology and biotechnology. Tree For Sci Biotechnol 1:47–73Google Scholar
  31. 31.
    Subenthiran S, Choon CT, Cheong CK, Thayan R, Teck BM, Muniandy KP (2013) Carica papaya leaves juice significantly accelerates the rate of increase in platelet count among patients with dengue fever and dengue haemorrhagic fever. Evid Based Complement Altern Med 2013:616737CrossRefGoogle Scholar
  32. 32.
    Sun DS, King CC, Huang HS, Shih YL, Lee CC, Tsai WJ, Yu CC, Chang HH (2007) Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice. J Thromb Haemost 5:2291–2299CrossRefGoogle Scholar
  33. 33.
    WHO (1997) Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. World Health Organization, GenevaGoogle Scholar
  34. 34.
    WHO (2009) Dengue: guidelines for diagnosis, treatment, prevention and control. World Health Organization, GenevaGoogle Scholar
  35. 35.
    Yunita F, Hanani E, Kristianto J (2012) The effect of Carica papaya L. leaves extract capsules on platelets count and hematocrit level in dengue fever patient. Int J Med Aromat Plants 2:573–578Google Scholar
  36. 36.
    Zandi K, Teoh BT, Sam SS, Wong PF, Mustafa MR, Abubakar S (2012) Novel antiviral activity of baicalein against dengue virus. BMC Complement Altern Med 12:214CrossRefPubMedCentralGoogle Scholar
  37. 37.
    Zunjar V, Dash RP, Jivrajani M, Trivedi B, Nivsarkar M (2016) Antithrombocytopenic activity of carpaine and alkaloidal extract of Carica papaya Linn. leaves in busulfan induced thrombocytopenic Wistar rats. J Ethnopharmacol 181:20–25CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Navita Sharma
    • 1
  • Kamla Prasad Mishra
    • 1
    • 2
    Email author
  • Sudipta Chanda
    • 1
  • Varun Bhardwaj
    • 1
  • Himanshi Tanwar
    • 1
  • Lilly Ganju
    • 1
  • Bhuvnesh Kumar
    • 1
  • Shashi Bala Singh
    • 1
  1. 1.Defence Institute of Physiology and Allied Sciences (DIPAS), DRDONew DelhiIndia
  2. 2.O/o Director General (Life Sciences)Defence Research and Development OrganizationNew DelhiIndia

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