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Increased serum ferritin and interleukin-18 levels in children with dengue

  • Clinical Microbiology - Research Paper
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Brazilian Journal of Microbiology Aims and scope Submit manuscript

Abstract

Activated monocytes/macrophages that produce a cytokine storm play an important role in the pathogenesis of dengue. Interleukin-18 (IL-18) is a proinflammatory cytokine produced by monocyte/macrophages that is increased during dengue. Ferritin is an acute-phase reactant and expressed by cells of the reticulo-endothelial system in response to infection by dengue virus. The aims of this study were to analyze the simultaneous expression of both IL-18 and ferritins in children infected by diverse serotypes of dengue virus (DENV) and determine their association with dengue severity. In this regard, children with dengue (n = 25) and healthy controls with similar age and sex (n = 20) were analyzed for circulating ferritin and cytokines. Monocytes were isolated by Hystopaque gradient and co-cultured with DENV-2. IL-18 and ferritin contents in blood, and IL-18 in culture supernatants were determined by ELISA. Increased levels of ferritin and IL-18 (p < 0.0001) were observed in dengue patients, not associated to NS1expression or type of infection (primary or secondary). Highest values of both molecules (p < 0.001) were observed in dengue with warning signs and severe dengue. Differential effect on IL-18/ferritin production was observed associated to viral serotype infection. There were no correlations between ferritin vs. IL-18 production, ferritin vs. NS1 status, and IL-18 vs. NS1 status. Viral-infected monocyte cultures showed increased production of IL-18 (p < 0.001). In conclusion, increased circulating ferritin and IL-18 are expressed in children infected by different serotypes of DENV associated with dengue severity.

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References

  1. Betancur JF, Navarro EP, Echeverry A, Moncada PA, Cañas CA, Tobó GJ (2015) Hyperferritinemic syndrome: still’s disease and catastrophic antiphospholipid syndrome triggered by fulminant chikungunya infection: a case report of two patients. Clin Rheumatol 34:1989–1992

    Article  PubMed  Google Scholar 

  2. Bone RC (1992) Modulators of coagulation. A critical appraisal of their role in sepsis. Arch Intern Med 152:1381–1389

    Article  CAS  PubMed  Google Scholar 

  3. Casadevall A, Pirofski LA (1999) Host-pathogen interactions: redefining the basic concepts of virulence and pathogenicity. Infect Immun 67:3703–3713

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Chaiyaratana W, Chuansumrit A, Atamasirikul K, Tangnararatchakit K (2008) Serum ferritin levels in children with dengue infection. Southeast Asian J Trop Med Public Health 39:832–886

    CAS  PubMed  Google Scholar 

  5. Costa VV, Fagundes CT, Valadao DF, Cisalpino D, Dias AC, Silveira KD, Kangussu LM, Avila TV, Bonfim MR, Bonaventura D (2012) A model of DENV-3 infection that recapitulates severe disease and highlights the importance of IFN-gamma in host resistance to infection. PLoS Negl Trop Dis 6:e1663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De Koninck AS, Dierick J, Steyaert S, Taelman P (2014) Hemophagocytic lymphohistiocytosis and dengue infection: rare case report. Acta Clin Belg 69:210–213

    Article  PubMed  Google Scholar 

  7. Diamond MS, Edgil D, Roberts TG, Lu B, Harris E (2000) Infection of human cells by dengue virus is modulated by different cell types and viral strains. J Virol 74:7814–7823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Durbin AP, Vargas MJ, Wanionek K, Hammond SN, Gordon A, Rocha C, Balmaseda A, Harris E (2008) Phenotyping of peripheral blood mononuclear cells during acute dengue illness demonstrates infection and increased activation of monocytes in severe cases compared to classic dengue fever. Virology 376:429–435

    Article  CAS  PubMed  Google Scholar 

  9. Fagundes CT, Costa VV, Cisalpino D, Amaral FA, Souza PR, Souza RS, Ryffel B, Vieira LQ, Silva TA, Atrasheuskaya A (2011) IFN-gamma production depends on IL-12 and IL-18 combined action and mediates host resistance to dengue virus infection in a nitric oxide-dependent manner. PLoS Negl Trop Dis 5:e1449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fahmy M, Young SP (1993) Modulation of iron metabolism in monocyte cell line U937 by inflammatory cytokines: changes in transferrin uptake, iron handling and ferritin mRNA. Biochem J 296:175–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Henter JI, Elinder G, Ost A (1991) Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL study group of the histiocyte society. Semin Oncol 1:29–33

    Google Scholar 

  12. Henter JI, Horne A, Arico M, Egeler RM, Filipovich S, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J (2007) HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124–131

    Article  PubMed  Google Scholar 

  13. Jessie K, Fong MY, Devi S, Lam SK, Wong KT (2004) Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J Infect Dis 189:1411–1418

    Article  PubMed  Google Scholar 

  14. Joshi R, Phatarpekar A, Currimbhoy Z, Desai M (2011) Haemophagocytic lymphohistiocytosis: a case series from Mumbai. Ann Trop Paediatr 31:135–140

    Article  CAS  PubMed  Google Scholar 

  15. Kouri GP, Guzman MG, Bravo JR (1987) Why dengue haemorrhagic fever in Cuba? 2. An integral analysis. Trans R Soc Trop Med Hyg 81:821–823

    Article  CAS  PubMed  Google Scholar 

  16. Kouri GP, Guzman MG, Bravo JR, Triana C (1989) Dengue haemorrhagic fever/dengue shock syndrome: lessons from the Cuban epidemic, 1981. Bull W H O 67:375–380

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ludwiczek S, Aigner E, Theurl I, Weiss G (2003) Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101:4148–4154

    Article  CAS  PubMed  Google Scholar 

  18. Maeda H, Akaike T, Wu J, Noguchi Y, Sakata Y (1996) Bradykinin and nitric oxide in infectious disease and cancer. Immunopharmacology 33:222–230

    Article  CAS  PubMed  Google Scholar 

  19. Martina BE, Koraka P, Osterhaus AD (2009) Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev 22:564–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Muhl H, Kampfer H, Bosmann M, Frank S, Radeke H, Pfeilschifter J (2000) Interferon-gamma mediates gene expression of IL-18 binding protein in non leukocytic cells. Biochem Biophys Res Commun 267:960–963

    Article  CAS  PubMed  Google Scholar 

  21. Mustafa AS, Elbishbishi EA, Agarwal R, Chaturvedi UC (2001) Elevated levels of interleukin-13 and IL-18 in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol 30:229–233

    Article  CAS  PubMed  Google Scholar 

  22. Pagliari C, Quaresma JA, Fernandes ER, Stegun FW, Brasil RA, de Andrade HF Jr, Barros V, Vasconcelos PF, Duarte MI (2014) Immunopathogenesis of dengue hemorrhagic fever: contribution to the study of human liver lesions. J Med Virol 86:1193–1197

    Article  CAS  PubMed  Google Scholar 

  23. Parthasarathy N, Torti SV, Torti FM (2002) Ferritin binds to light chain of human H-kininogen and inhibits kallikrein-mediated bradykinin release. Biochem J 365:279–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rathakrishnan A, Wang SM, Hu Y, Khan AM, Ponnampalavanar S, Lum LC, Manikam R, Sekaran SD (2012) Cytokine expression profile of dengue patients at different phases of illness. PLoS One 7:e52215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rico-Hesse R, Harrison LM, Salas RA, Tovar D, Nisalak A, Ramos C, Boshell J, de Mesa MT, Nogueira RM, da Rosa AT (1997) Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Virology 230:244–251

    Article  CAS  PubMed  Google Scholar 

  26. Rico-Hesse R, Harrison LM, Nisalak A, Vaughn DW, Kalayanarooj S, Green S, Rothman AL, Ennis FA (1998) Molecular evolution of dengue type 2 virus in Thailand. Am J Trop Med Hyg 58:96–101

    Article  CAS  PubMed  Google Scholar 

  27. Roy Chaudhuri S, Bhattacharya S, Chakraborty M, Bhattacharjee K (2017) Serum ferritin: a backstage weapon in diagnosis of dengue fever. Interdiscip Perspect Infect Dis 2017:1–6

    Article  CAS  Google Scholar 

  28. Slaats J, ten Oever J, van de Veerdonk FL, Netea MG (2016) IL-1β/IL-6/CRP and IL-18/ferritin: distinct inflammatory programs in infections. PLoS Pathog 12:e1005973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Soundravally R, Agieshkumar B, Daisy M, Sherin J, Cleetus CC (2015) Ferritin levels predict severe dengue. Infection 43:13–19

    Article  CAS  PubMed  Google Scholar 

  30. Sung JM, Lee CK, Wu-Hsieh BA (2012) Intrahepatic infiltrating NK and CD8 T cells cause liver cell death in different phases of dengue virus infection. PLoS One 7:e46292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tan LH, Lum LC, Omar SF, Kan FK (2012) Hemophagocytosis in dengue: comprehensive report of six cases. J Clin Virol 55:79–82

    Article  PubMed  Google Scholar 

  32. Tran TN, Eubanks SK, Schaffer KJ, Zhou CY, Linder MC (1997) Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood 90:4979–4986

    CAS  PubMed  Google Scholar 

  33. Usmani GN, Woda BA, Newburger PE (2013) Advances in understanding the pathogenesis of HLH. Br J Haematol 161:609–622

    Article  CAS  PubMed  Google Scholar 

  34. van de Weg CA, Huits RM, Pannuti CS, Brouns RM, van den Berg RW, van den Ham HJ, Martina BE, Osterhaus AD, Netea MG, Meijers JC (2014) Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances. PLoS Negl Trop Dis 8:e3214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, Endy TP, Raengsakulrach B, Rothman AL, Ennis FA (2000) Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 181:2–9

    Article  CAS  PubMed  Google Scholar 

  36. Weiss G (2005) Modification of iron regulation by the inflammatory response. Best Pract Res Clin Haematol 18:183–201

    Article  CAS  PubMed  Google Scholar 

  37. Wu MF, Chen ST, Yang AH, Lin WW, Lin YL, Chen NJ, Tsai IS, Li L, Hsieh SL (2013) CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages. Blood 121:95–106

    Article  CAS  PubMed  Google Scholar 

  38. Yong YK, Tan HY, Jen SH, Shankar EM, Natkunam SK, Sathar J, Manikam R, Sekaran SD (2017) Aberrant monocyte responses predict and characterize dengue virus infection in individuals with severe disease. J Transl Med 15:121–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yoshifuji K, Oshina T, Sonokawa S, Noguchi Y, Suzuki S, Tanaka K, Kumagai T (2016) Domestic dengue infection with hemophagocytic lymphohistiocytosis successfully treated by early steroid therapy. Rinsho Ketsueki 57:864–868

    PubMed  Google Scholar 

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Acknowledgments

This investigation was supported by Misión Ciencias, Fonacit, and Instituto de Investigaciones Clínicas “Dr. Américo Negrette” Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela. Sponsors had no involvement in any aspect of manuscript preparation.

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Authors and Affiliations

  1. Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina, Universidad del Zulia, Apartado Postal 23, Maracaibo, Zulia, 4001-A, Venezuela

    Nereida Valero, Jesus Mosquera, Mariana Torres, Anyelo Duran & Maria Velastegui

  2. Universidad Estatal del Sur de Manabi, Jipijapa, Ecuador

    Nereida Valero, Javier Reyes & Teresa Veliz

  3. Facultad Ciencias de la Salud, Universidad Técnica de Ambato, Ambato, Ecuador

    Miriam Fernandez & Gerardo Fernandez

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  1. Nereida Valero
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  2. Jesus Mosquera
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Correspondence to Nereida Valero.

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Valero, N., Mosquera, J., Torres, M. et al. Increased serum ferritin and interleukin-18 levels in children with dengue. Braz J Microbiol 50, 649–656 (2019). https://doi.org/10.1007/s42770-019-00105-2

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