Role of TNF α, IL-6 and CXCL10 in Dengue disease severity
Abstract
Background and Objectives: Dengue virus infections (Dengue) have become increasingly common in Pakistan and can result in case fatalities if not managed appropriately. Patients with Dengue virus infection may be asymptomatic or present with Dengue fever (DF), Dengue with warning signs (DWS) or severe Dengue (SD). Severity in Dengue is coincident with an exacerbated production of lymphocyte-induced cytokines and chemokines which are associated with plasma leakage. We investigated the association of circulating levels of cytokines such as Interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and CXCL-10 in Dengue patients with differing severity of disease.
Materials and Methods: Dengue infection was confirmed by testing for human IgM to the Dengue virus. Dengue patients (n=58) and healthy controls (n=33) were recruited. Dengue patients were grouped into those with DF (n=39), DWS (n=15) and SD (n=4). Serum IL-6, TNFα and CXCL10 levels were tested by ELISA. The Mann Whitney U test was used for statistical analysis.
Results: Circulating levels of TNFα (p≤0.001) and CXCL10 (p≤0.001) levels were increased in Dengue patients as compared with controls. When patients were stratified for disease severity, it was observed that CXCL10 was increased in DWS as compared to DF (p=0.046). IL-6 levels were increased in patients with SD as compared to those with DWS (p=0.044). TNFα levels were not found to differ between different groups of Dengue patients.
Conclusion: Raised CXCL10 and TNFα levels were associated with increased clinical severity of Dengue infection and probably increased disease progression due to excessive inflammation and increased vascular changes in the
patients.
Rodenhuis-Zybert IA, Wilschut J, Smit JM. Dengue virus life cycle: viral and host factors modulating infectivity. Cell Mol Life Sci 2010; 67:2773-2786.
Stanaway JD, Shepard DS, Undurraga EA, Halasa YA, Coffeng LE, Brady OJ, et al. The global burden of dengue: an analysis from the global burden of disease study 2013. Lancet Infect Dis 2016; 16:712-723.
Haider Z, Ahmad FZ, Mahmood A, Waseem T, Shafiq I, Raza T, et al. Dengue fever in Pakistan: a paradigm shift; changing epidemiology and clinical patterns. Perspect Public Health 2015; 135:294-298.
Tahir U, Khan UH, Zubair MS, Bahar EM. Wolbachia pipientis: A potential candidate for combating and eradicating Dengue epidemics in Pakistan. Asian Pac J Trop Med 2015; 8:989-998.
WHO. Dengue guidelines for diagnosis, treatment, prevention and control. Geneva: World Health Organization, 2009.
A. Castillo-Macías, M.C. Salinas-Carmona, Torres-López E. Immunology of viral infections with a high impact in Mexico: Dengue, Chikungunya, and Zika. Medicina Universitaria 2017; 19:198-207.
Pfeffer K. Biological functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev 2003; 14:185-191.
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813:878-888.
Chen JP, Lu HL, Lai SL, Campanella GS, Sung JM, Lu MY, 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; 177:3185-3192.
Hasan Z, Razzak S, Farhan M, Rahim M, Islam N, Samreen A, et al. Increasing usage of rapid diagnostics for Dengue virus detection in Pakistan. J Pak Med Assoc 2017; 67:548-551.
Chaturvedi UC, Agarwal R, Elbishbishi EA, Mustafa AS. Cytokine cascade in Dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol 2000; 28:183-188.
Chareonsirisuthigul T, Kalayanarooj S, Ubol S. Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells. J Gen Virol 2007; 88:365-375.
Chaturvedi UC, Nagar R. Nitric oxide in Dengue and Dengue haemorrhagic fever: necessity or nuisance? FEMS Immunol Med Microbiol 2009; 56:9-24.
Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, et al. Early immune activation in acute Dengue illness is related to development of plasma leakage and disease severity. J Infect Dis 1999; 179:755-762.
Jeewandara C, Gomes L, Wickramasinghe N, Gutowska-Owsiak D, Waithe D, Paranavitane SA, et al. Platelet activating factor contributes to vascular leak in acute Dengue infection. PLoS Negl Trop Dis 2015; 9:e0003459.
Mongkolsapaya J, Dejnirattisai W, Xu XN, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, et al. Original antigenic sin and apoptosis in the pathogenesis of Dengue hemorrhagic fever. Nat Med 2003; 9:921-927.
Vitarana T, de Silva H, Withana N, Gunasekera C. Elevated tumour necrosis factor in Dengue fever and Dengue haemorrhagic fever. Ceylon Med J 1991; 36:63-65.
Juffrie M, Meer GM, Hack CE, Haasnoot K, Sutaryo, Veerman AJ, et al. Inflammatory mediators in Dengue virus infection in children: interleukin-6 and its relation to C-reactive protein and secretory phospholipase A2. Am J Trop Med Hyg 2001; 65:70-75.
Restrepo BN, Isaza DM, Salazar CL, Ramirez R, Ospina M, Alvarez LG. Serum levels of interleukin-6, tumor necrosis factor-alpha and interferon-gamma in infants with and without dengue. Rev Soc Bras Med Trop 2008; 41:6-10.
Butthep P, Chunhakan S, Yoksan S, Tangnararatchakit K, Chuansumrit A. Alteration of cytokines and chemokines during febrile episodes associated with endothelial cell damage and plasma leakage in Dengue hemorrhagic fever. Pediatr Infect Dis J 2012; 31:e232-238.
Bethell DB, Flobbe K, Cao XT, Day NP, Pham TP, Buurman WA, et al. Pathophysiologic and prognostic role of cytokines in Dengue hemorrhagic fever. J Infect Dis 1998; 177:778-782.
Malavige GN, Fernando S, Fernando DJ, Seneviratne SL. Dengue viral infections. Postgrad Med J 2004; 80:588-601.
Rothman AL, Ennis FA. Immunopathogenesis of Dengue hemorrhagic fever. Virology 1999; 257:1-6.
Farber JM. Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol 1997; 61:246-257.
Hsieh MF, Lai SL, Chen JP, Sung JM, Lin YL, Wu-Hsieh BA, et al. Both CXCR3 and CXCL10/IFN-inducible protein 10 are required for resistance to primary infection by Dengue virus. J Immunol 2006; 177:1855-1863.
Conroy AL, Gelvez M, Hawkes M, Rajwans N, Tran V, Liles WC, 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.
| Files | ||
| Issue | Vol 10 No 3 (2018) | |
| Section | Original Article(s) | |
| Keywords | ||
| Dengue IL6 CXCL10 | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
