Skip to main content
Top
Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

Aberrant monocyte responses predict and characterize dengue virus infection in individuals with severe disease

Authors: Yean K. Yong, Hong Y. Tan, Soe Hui Jen, Esaki M. Shankar, Santha K. Natkunam, Jameela Sathar, Rishya Manikam, Shamala D. Sekaran

Published in: Journal of Translational Medicine | Issue 1/2017

Login to get access

Abstract

Background

Currently, several assays can diagnose acute dengue infection. However, none of these assays can predict the severity of the disease. Biomarkers that predicts the likelihood that a dengue patient will develop a severe form of the disease could permit more efficient patient triage and allows better supportive care for the individual in need, especially during dengue outbreaks.

Methods

We measured 20 plasma markers i.e. IFN-γ, IL-10, granzyme-B, CX3CL1, IP-10, RANTES, CXCL8, CXCL6, VCAM, ICAM, VEGF, HGF, sCD25, IL-18, LBP, sCD14, sCD163, MIF, MCP-1 and MIP-1β in 141 dengue patients in over 230 specimens and correlate the levels of these plasma markers with the development of dengue without warning signs (DWS−), dengue with warning signs (DWS+) and severe dengue (SD).

Results

Our results show that the elevation of plasma levels of IL-18 at both febrile and defervescence phase was significantly associated with DWS+ and SD; whilst increase of sCD14 and LBP at febrile phase were associated with severity of dengue disease. By using receiver operating characteristic (ROC) analysis, the IL-18, LBP and sCD14 were significantly predicted the development of more severe form of dengue disease (DWS+/SD) (AUC = 0.768, P < 0.0001; AUC = 0.819, P < 0.0001 and AUC = 0.647, P = 0.014 respectively). Furthermore, we also found that the levels of VEGF were directly correlated and sCD14 was inversely correlated with platelet count, suggesting that the endothelial activation and microbial translocation may played a role in pathogenesis of dengue disease.

Conclusions

Given that the elevation IL-18, LBP and sCD14 among patients with severe form of dengue disease, our findings suggest a pathogenic role for an aberrant inflammasome and monocyte activation in the development of severe form of dengue disease.
Appendix
Available only for authorised users
Literature
2.
go back to reference Stanaway JD, Shepard DS, Undurraga EA, et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis. 2016;16:712–23.CrossRefPubMedPubMedCentral Stanaway JD, Shepard DS, Undurraga EA, et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis. 2016;16:712–23.CrossRefPubMedPubMedCentral
4.
go back to reference Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: past, present and future prospects. Clin Epidemiol. 2013;5:299–309.PubMedPubMedCentral Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: past, present and future prospects. Clin Epidemiol. 2013;5:299–309.PubMedPubMedCentral
5.
7.
go back to reference Rathakrishnan A, Klekamp B, Wang SM, et al. Clinical and immunological markers of dengue progression in a study cohort from a hyperendemic area in Malaysia. PLoS ONE. 2014;9:e92021.CrossRefPubMedPubMedCentral Rathakrishnan A, Klekamp B, Wang SM, et al. Clinical and immunological markers of dengue progression in a study cohort from a hyperendemic area in Malaysia. PLoS ONE. 2014;9:e92021.CrossRefPubMedPubMedCentral
8.
9.
go back to reference Leo YS, Gan VC, Ng EL, et al. Utility of warning signs in guiding admission and predicting severe disease in adult dengue. BMC Infect Dis. 2013;13:498.CrossRefPubMedPubMedCentral Leo YS, Gan VC, Ng EL, et al. Utility of warning signs in guiding admission and predicting severe disease in adult dengue. BMC Infect Dis. 2013;13:498.CrossRefPubMedPubMedCentral
10.
go back to reference Tsai CY, Lee IK, Lee CH, et al. Comparisons of dengue illness classified based on the 1997 and 2009 World Health Organization dengue classification schemes. J Microbiol Immunol Infect. 2013;46:271–81.CrossRefPubMed Tsai CY, Lee IK, Lee CH, et al. Comparisons of dengue illness classified based on the 1997 and 2009 World Health Organization dengue classification schemes. J Microbiol Immunol Infect. 2013;46:271–81.CrossRefPubMed
11.
go back to reference Pang J, Lindblom A, Tolfvenstam T, et al. Discovery and validation of prognostic biomarker models to guide triage among adult dengue patients at early infection. PLoS ONE. 2016;11:e0155993.CrossRefPubMedPubMedCentral Pang J, Lindblom A, Tolfvenstam T, et al. Discovery and validation of prognostic biomarker models to guide triage among adult dengue patients at early infection. PLoS ONE. 2016;11:e0155993.CrossRefPubMedPubMedCentral
12.
go back to reference Carrasco LR, Leo YS, Cook AR, et al. Predictive tools for severe dengue conforming to World Health Organization 2009 criteria. PLoS Negl Trop Dis. 2014;8:e2972.CrossRefPubMedPubMedCentral Carrasco LR, Leo YS, Cook AR, et al. Predictive tools for severe dengue conforming to World Health Organization 2009 criteria. PLoS Negl Trop Dis. 2014;8:e2972.CrossRefPubMedPubMedCentral
13.
go back to reference Mathew A, Rothman AL. Understanding the contribution of cellular immunity to dengue disease pathogenesis. Immunol Rev. 2008;225:300–13.CrossRefPubMed Mathew A, Rothman AL. Understanding the contribution of cellular immunity to dengue disease pathogenesis. Immunol Rev. 2008;225:300–13.CrossRefPubMed
14.
go back to reference Chaturvedi UC, Agarwal R, Elbishbishi EA, et al. Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol. 2000;28:183–8.CrossRefPubMed Chaturvedi UC, Agarwal R, Elbishbishi EA, et al. Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol. 2000;28:183–8.CrossRefPubMed
17.
go back to reference Mustafa AS, Elbishbishi EA, Agarwal R, et al. Elevated levels of interleukin-13 and IL-18 in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol. 2001;30:229–33.CrossRefPubMed Mustafa AS, Elbishbishi EA, Agarwal R, et al. Elevated levels of interleukin-13 and IL-18 in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol. 2001;30:229–33.CrossRefPubMed
18.
go back to reference Chen JP, Lu HL, Lai SL, et al. Dengue virus induces expression of CXC chemokine ligand 10/IFN-gamma-inducible protein 10, which competitively inhibits viral binding to cell surface heparan sulfate. J Immunol. 2006;177:3185–92.CrossRefPubMed Chen JP, Lu HL, Lai SL, et al. Dengue virus induces expression of CXC chemokine ligand 10/IFN-gamma-inducible protein 10, which competitively inhibits viral binding to cell surface heparan sulfate. J Immunol. 2006;177:3185–92.CrossRefPubMed
19.
go back to reference Poole-Smith BK, Gilbert A, Gonzalez AL, et al. Discovery and characterization of potential prognostic biomarkers for dengue hemorrhagic fever. Am J Trop Med Hyg. 2014;91:1218–26.CrossRefPubMedPubMedCentral Poole-Smith BK, Gilbert A, Gonzalez AL, et al. Discovery and characterization of potential prognostic biomarkers for dengue hemorrhagic fever. Am J Trop Med Hyg. 2014;91:1218–26.CrossRefPubMedPubMedCentral
20.
go back to reference Chuang YC, Lei HY, Liu HS, et al. Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. Cytokine. 2011;54:222–31.CrossRefPubMed Chuang YC, Lei HY, Liu HS, et al. Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. Cytokine. 2011;54:222–31.CrossRefPubMed
21.
go back to reference Tuiskunen A, Wahlstrom M, Bergstrom J, et al. Phenotypic characterization of patient dengue virus isolates in BALB/c mice differentiates dengue fever and dengue hemorrhagic fever from dengue shock syndrome. Virol J. 2011;8:398.CrossRefPubMedPubMedCentral Tuiskunen A, Wahlstrom M, Bergstrom J, et al. Phenotypic characterization of patient dengue virus isolates in BALB/c mice differentiates dengue fever and dengue hemorrhagic fever from dengue shock syndrome. Virol J. 2011;8:398.CrossRefPubMedPubMedCentral
22.
go back to reference Voraphani N, Theamboonlers A, Khongphatthanayothin A, et al. Increased level of hepatocyte growth factor in children with dengue virus infection. Ann Trop Paediatr. 2010;30:213–8.CrossRefPubMed Voraphani N, Theamboonlers A, Khongphatthanayothin A, et al. Increased level of hepatocyte growth factor in children with dengue virus infection. Ann Trop Paediatr. 2010;30:213–8.CrossRefPubMed
24.
go back to reference Conroy AL, Gelvez M, Hawkes M, et al. Host biomarkers are associated with progression to dengue haemorrhagic fever: a nested case-control study. Int J Infect Dis. 2015;40:45–53.CrossRefPubMed Conroy AL, Gelvez M, Hawkes M, et al. Host biomarkers are associated with progression to dengue haemorrhagic fever: a nested case-control study. Int J Infect Dis. 2015;40:45–53.CrossRefPubMed
25.
go back to reference van de Weg CA, Koraka P, van Gorp EC, et al. Lipopolysaccharide levels are elevated in dengue virus infected patients and correlate with disease severity. J Clin Virol. 2012;53:38–42.CrossRefPubMed van de Weg CA, Koraka P, van Gorp EC, et al. Lipopolysaccharide levels are elevated in dengue virus infected patients and correlate with disease severity. J Clin Virol. 2012;53:38–42.CrossRefPubMed
26.
go back to reference van de Weg CA, Pannuti CS, de Araujo ES, et al. Microbial translocation is associated with extensive immune activation in dengue virus infected patients with severe disease. PLoS Negl Trop Dis. 2013;7:e2236.CrossRefPubMedPubMedCentral van de Weg CA, Pannuti CS, de Araujo ES, et al. Microbial translocation is associated with extensive immune activation in dengue virus infected patients with severe disease. PLoS Negl Trop Dis. 2013;7:e2236.CrossRefPubMedPubMedCentral
27.
go back to reference Novick D, Schwartsburd B, Pinkus R, et al. A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine. 2001;14:334–42.CrossRefPubMed Novick D, Schwartsburd B, Pinkus R, et al. A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine. 2001;14:334–42.CrossRefPubMed
28.
go back to reference Kim SH, Eisenstein M, Reznikov L, et al. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci USA. 2000;97:1190–5.CrossRefPubMedPubMedCentral Kim SH, Eisenstein M, Reznikov L, et al. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci USA. 2000;97:1190–5.CrossRefPubMedPubMedCentral
29.
go back to reference Tan HY, Yong YK, Andrade BB, et al. Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2015;29:421–31.CrossRefPubMed Tan HY, Yong YK, Andrade BB, et al. Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2015;29:421–31.CrossRefPubMed
31.
go back to reference Novick D, Kim SH, Fantuzzi G, et al. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity. 1999;10:127–36.CrossRefPubMed Novick D, Kim SH, Fantuzzi G, et al. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity. 1999;10:127–36.CrossRefPubMed
34.
go back to reference Pohan HT, Suhendro S, Bur R, Matondang A, Djauzi S, Inada K, Endo S. Interleukin-18 levels in adult dengue fever and dengue hemorrhagic fever. Med J Indones. 2004;13:86.CrossRef Pohan HT, Suhendro S, Bur R, Matondang A, Djauzi S, Inada K, Endo S. Interleukin-18 levels in adult dengue fever and dengue hemorrhagic fever. Med J Indones. 2004;13:86.CrossRef
35.
37.
go back to reference Michels M, de Mast Q, Netea MG, et al. Normal free interleukin-18 (IL-18) plasma levels in dengue virus infection and the need to measure both total IL-18 and IL-18 binding protein levels. Clin Vaccine Immunol. 2015;22:650–5.CrossRefPubMedPubMedCentral Michels M, de Mast Q, Netea MG, et al. Normal free interleukin-18 (IL-18) plasma levels in dengue virus infection and the need to measure both total IL-18 and IL-18 binding protein levels. Clin Vaccine Immunol. 2015;22:650–5.CrossRefPubMedPubMedCentral
38.
go back to reference Wu MF, Chen ST, Yang AH, et al. CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages. Blood. 2013;121:95–106.CrossRefPubMed Wu MF, Chen ST, Yang AH, et al. CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages. Blood. 2013;121:95–106.CrossRefPubMed
39.
go back to reference Hottz ED, Lopes JF, Freitas C, et al. Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood. 2013;122:3405–14.CrossRefPubMedPubMedCentral Hottz ED, Lopes JF, Freitas C, et al. Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood. 2013;122:3405–14.CrossRefPubMedPubMedCentral
40.
go back to reference Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–71.CrossRefPubMed Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–71.CrossRefPubMed
41.
go back to reference Cooke KR, Olkiewicz K, Erickson N, et al. The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. J Endotoxin Res. 2002;8:441–8.CrossRefPubMed Cooke KR, Olkiewicz K, Erickson N, et al. The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. J Endotoxin Res. 2002;8:441–8.CrossRefPubMed
42.
go back to reference Pastor Rojo O, Lopez San Roman A, Albeniz Arbizu E, et al. Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:269–77.CrossRefPubMed Pastor Rojo O, Lopez San Roman A, Albeniz Arbizu E, et al. Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:269–77.CrossRefPubMed
44.
go back to reference Wang F, Jiang H, Shi K, et al. Gut bacterial translocation is associated with microinflammation in end-stage renal disease patients. Nephrology. 2012;17:733–8.CrossRefPubMed Wang F, Jiang H, Shi K, et al. Gut bacterial translocation is associated with microinflammation in end-stage renal disease patients. Nephrology. 2012;17:733–8.CrossRefPubMed
45.
go back to reference Opal SM, Scannon PJ, Vincent JL, et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J Infect Dis. 1999;180:1584–9.CrossRefPubMed Opal SM, Scannon PJ, Vincent JL, et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J Infect Dis. 1999;180:1584–9.CrossRefPubMed
46.
go back to reference Landmann R, Zimmerli W, Sansano S, et al. Increased circulating soluble CD14 is associated with high mortality in gram-negative septic shock. J Infect Dis. 1995;171:639–44.CrossRefPubMed Landmann R, Zimmerli W, Sansano S, et al. Increased circulating soluble CD14 is associated with high mortality in gram-negative septic shock. J Infect Dis. 1995;171:639–44.CrossRefPubMed
47.
go back to reference van de Weg CA, Huits RM, Pannuti CS, et al. Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances. PLoS Negl Trop Dis. 2014;8:e3214.CrossRefPubMedPubMedCentral van de Weg CA, Huits RM, Pannuti CS, et al. Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances. PLoS Negl Trop Dis. 2014;8:e3214.CrossRefPubMedPubMedCentral
51.
go back to reference Aye KS, Charngkaew K, Win N, et al. Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Hum Pathol. 2014;45:1221–33.CrossRefPubMed Aye KS, Charngkaew K, Win N, et al. Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Hum Pathol. 2014;45:1221–33.CrossRefPubMed
52.
go back to reference Tseng CS, Lo HW, Teng HC, et al. Elevated levels of plasma VEGF in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol. 2005;43:99–102.CrossRefPubMed Tseng CS, Lo HW, Teng HC, et al. Elevated levels of plasma VEGF in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol. 2005;43:99–102.CrossRefPubMed
53.
go back to reference Jeewandara C, Gomes L, Wickramasinghe N, et al. Platelet activating factor contributes to vascular leak in acute dengue infection. PLoS Negl Trop Dis. 2015;9:e0003459.CrossRefPubMedPubMedCentral Jeewandara C, Gomes L, Wickramasinghe N, et al. Platelet activating factor contributes to vascular leak in acute dengue infection. PLoS Negl Trop Dis. 2015;9:e0003459.CrossRefPubMedPubMedCentral
54.
go back to reference Thakur P, Chakravarti A, Aggarwal S, et al. Elevated levels of vascular endothelial growth factor in adults with severe dengue infection. Virusdisease. 2016;27:48–54.CrossRefPubMedPubMedCentral Thakur P, Chakravarti A, Aggarwal S, et al. Elevated levels of vascular endothelial growth factor in adults with severe dengue infection. Virusdisease. 2016;27:48–54.CrossRefPubMedPubMedCentral
Metadata
Title
Aberrant monocyte responses predict and characterize dengue virus infection in individuals with severe disease
Authors
Yean K. Yong
Hong Y. Tan
Soe Hui Jen
Esaki M. Shankar
Santha K. Natkunam
Jameela Sathar
Rishya Manikam
Shamala D. Sekaran
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-017-1226-4

Other articles of this Issue 1/2017

Journal of Translational Medicine 1/2017 Go to the issue