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Abstract

Dengue virus (DENV) causes the most prevalent arboviral infection of humans, resulting in a spectrum of outcomes, ranging from asymptomatic infection to dengue fever to severe dengue characterized by vascular leakage and shock. Previously, we determined that DENV nonstructural protein 1 (NS1) induces endothelial hyperpermeability, disrupts the endothelial glycocalyx layer (EGL) and triggers shedding of structural components, including sialic acid (Sia) and heparan sulfate. Here, using a murine model of dengue disease disease, we found high levels of Sia and NS1 circulating in mice with DENV-induced morbidity and lethal DENV infection. Further, we developed a liquid chromatography/mass spectrometry-based method for quantifying free Sia in serum and determined that the levels of free N-glycolylneuraminic acid were significantly higher in DENV-infected mice than in uninfected controls. These data provide additional evidence that DENV infection disrupts EGL components and warrant further research assessing Sia as a biomarker of severe dengue disease.

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2019-09-17
2019-10-13
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References

  1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW et al. The global distribution and burden of dengue. Nature 2013;496:504–507 [CrossRef]
    [Google Scholar]
  2. Guzman MG, Harris E, Dengue HE. Dengue. Lancet 2015;385:453–465 [CrossRef]
    [Google Scholar]
  3. Beatty PR, Puerta-Guardo H, Killingbeck SS, Glasner DR, Hopkins K et al. Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci Transl Med 2015;7:304ra141 [CrossRef]
    [Google Scholar]
  4. Modhiran N, Watterson D, Muller DA, Panetta AK, Sester DP et al. Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci Transl Med 2015;7:304ra142 [CrossRef]
    [Google Scholar]
  5. Orozco S, Schmid MA, Parameswaran P, Lachica R, Henn MR et al. Characterization of a model of lethal dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor. J Gen Virol 2012;93:2152–2157 [CrossRef]
    [Google Scholar]
  6. Shresta S, Sharar KL, Prigozhin DM, Beatty PR, Harris E. Murine model for dengue virus-induced lethal disease with increased vascular permeability. J Virol 2006;80:10208–10217 [CrossRef]
    [Google Scholar]
  7. Balsitis SJ, Williams KL, Lachica R, Flores D, Kyle JL et al. Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 2010;6:e1000790 [CrossRef]
    [Google Scholar]
  8. Puerta-Guardo H, Glasner DR, Harris E. Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability. PLoS Pathog 2016;12:e1005738 [CrossRef]
    [Google Scholar]
  9. Glasner DR, Ratnasiri K, Puerta-Guardo H, Espinosa DA, Beatty PR et al. Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components. PLoS Pathog 2017;13:e1006673 [CrossRef]
    [Google Scholar]
  10. Puerta-Guardo H, Glasner DR, Espinosa DA, Biering SB, Patana M et al. Flavivirus NS1 triggers tissue-specific vascular endothelial dysfunction reflecting disease tropism. Cell Rep 2019;26:e15981598–1613 [CrossRef]
    [Google Scholar]
  11. Betteridge KB, Arkill KP, Neal CR, Harper SJ, Foster RR et al. Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function. J Physiol 2017;595:5015–5035 [CrossRef]
    [Google Scholar]
  12. Cioffi DL, Pandey S, Alvarez DF, Cioffi EA. Terminal sialic acids are an important determinant of pulmonary endothelial barrier integrity. Am J Physiol Lung Cell Mol Physiol 2012;302:L1067–L1077 [CrossRef]
    [Google Scholar]
  13. Varki A, Gagneux P. Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci 2012;1253:16–36 [CrossRef]
    [Google Scholar]
  14. Tang THC, Alonso S, Ng LFP, Thein TL, Pang VJX et al. Increased serum hyaluronic acid and heparan sulfate in dengue fever: association with plasma leakage and disease severity. Sci Rep 2017;7:46191 [CrossRef]
    [Google Scholar]
  15. Suwarto S, Sasmono RT, Sinto R, Ibrahim E, Suryamin M. Association of endothelial glycocalyx and tight and adherens junctions with severity of plasma leakage in dengue infection. J Infect Dis 2017;215:992–999 [CrossRef]
    [Google Scholar]
  16. Zellweger RM, Prestwood TR, Shresta S. Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 2010;7:128–139 [CrossRef]
    [Google Scholar]
  17. Varki A, Schnaar RL, Schauer R et al. Sialic acids and other nonulosonic acids In Varki A, Cummings RD, Esko JD, Stanley P, Hart GW et al. (editors) Essentials of Glycobiology Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2015; pp179–195
    [Google Scholar]
  18. Ghaderi D, Taylor RE, Padler-Karavani V, Diaz S, Varki A. Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins. Nat Biotechnol 2010;28:863–867 [CrossRef]
    [Google Scholar]
  19. Varki A. Colloquium paper: uniquely human evolution of sialic acid genetics and biology. Proc Natl Acad Sci USA 2010;107:8939–8946 [CrossRef]
    [Google Scholar]
  20. Trung DT, Wills B. Systemic vascular leakage associated with dengue infections - the clinical perspective. Curr Top Microbiol Immunol 2010;338:57–66 [CrossRef]
    [Google Scholar]
  21. Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S et al. 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 2002;186:1165–1168 [CrossRef]
    [Google Scholar]
  22. Jayathilaka D, Gomes L, Jeewandara C, Jayarathna GSB, Herath D et al. Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection. Nat Commun 2018;9:5242 [CrossRef]
    [Google Scholar]
  23. Varki A, Schauer R. Sialic acids In Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P et al. (editors) Essentials of Glycobiology Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2009
    [Google Scholar]
  24. Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD et al. Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact. Proc Natl Acad Sci USA 2004;101:6104–6109 [CrossRef]
    [Google Scholar]
  25. Chen G-Y, Tang J, Zheng P, Liu Y. Cd24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 2009;323:1722–1725 [CrossRef]
    [Google Scholar]
  26. Amith SR, Jayanth P, Franchuk S, Siddiqui S, Seyrantepe V et al. Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on NEU1 sialidase. Glycoconj J 2009;26:1197–1212 [CrossRef]
    [Google Scholar]
  27. Srikiatkhachorn A, Mathew A, Rothman AL. Immune-Mediated cytokine storm and its role in severe dengue. Semin Immunopathol 2017;39:563–574 [CrossRef]
    [Google Scholar]
  28. Espinosa DA, Beatty PR, Reiner GL, Sivick KE, Hix Glickman L et al. Cyclic dinucleotide-adjuvanted dengue virus nonstructural protein 1 induces protective antibody and T cell responses. J Immunol 2019;202:1153–1162 [CrossRef]
    [Google Scholar]
  29. Connolly-Andersen AM, Thunberg T, Ahlm C. Endothelial activation and repair during hantavirus infection: association with disease outcome. Open Forum Infect Dis 2014;1:ofu027 [CrossRef]
    [Google Scholar]
  30. Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 2007;9:121–167 [CrossRef]
    [Google Scholar]
  31. Pahakis MY, Kosky JR, Dull RO, Tarbell JM. The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress. Biochem Biophys Res Commun 2007;355:228–233 [CrossRef]
    [Google Scholar]
  32. Wu C, Xia L, Liu L, Qu F, Li G et al. A novel, sensitive and convenient method for determination of sialic acids in human serum utilizing ultrasonic-assisted closed in-syringe hydrolysis and derivatization prior to high performance liquid chromatography. Analytical Methods 2016;8:554–563 [CrossRef]
    [Google Scholar]
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