Infection and Drug Resistance (Jul 2019)
Antiviral and immunomodulatory effects of polyphenols on macrophages infected with dengue virus serotypes 2 and 3 enhanced or not with antibodies
Abstract
Carolina Jasso-Miranda,1,2 Irma Herrera-Camacho,2 Lilian Karem Flores-Mendoza,3 Fabiola Dominguez,1 Veronica Vallejo-Ruiz,1 Gilma Guadalupe Sanchez-Burgos,4 Victoria Pando-Robles,5 Gerardo Santos-Lopez,1 Julio Reyes-Leyva11Laboratory of Immunology and Virology, East Biomedical Research Center, Mexican Institute of Social Security (IMSS), CP 74360 Metepec, Puebla, México; 2Laboratory of Biochemistry and Molecular Biology, Center of Chemistry, Institute of Sciences, Meritorious Autonomous University of Puebla, CP 72570 San Manuel, Puebla, Mexico; 3Department of Chemical, Biologic and Agricultural Sciences, Science and Enginery Division, University of Sonora, CP 85880 Navojoa, Sonora, Mexico; 4Yucatan’s Medical Research Unit, Mexican Institute of Social Security (IMSS), CP 97150 Merida, Yucatan, Mexico; 5Infectious Disease Research Center, National Institute of Public Health, CP 62100 Cuernavaca, Morelos, MexicoBackground: There is a lack of specific antiviral therapy against dengue virus (DENV) in current use. Therefore, a great proportion of dengue cases progress to severe clinical forms due to a complex interplay between virus and host immune response. It has been hypothesized that heterotypic non-neutralizing antibodies enhance DENV infection in phagocytic cells, and this induces an inflammatory response that is involved in the pathogenesis of severe dengue.Purpose: To identify the antiviral and immunomodulatory effects of polyphenols on dengue virus infection.Methods: Human U937-DC-SIGN macrophages were infected with DENV serotypes 2 or 3 in the presence or not of enhancing antibody 4G2. Viral titers and the secretion of tumor necrosis factor-alpha, IL-6, IL-10 and interferon-alpha were analyzed timely.Results: DENV infection alone induced high production of IL-6 and TNF-α, but in the presence of 4G2 antibody, viral titers and TNF-α secretion were potentiated. Based on anti-inflammatory antecedents, the polyphenols curcumin, fisetin, resveratrol, apigenin, quercetin and rutin were tested for antiviral and immunomodulatory properties. Only quercetin and fisetin inhibited DENV-2 and DENV-3 infection in the absence or presence of enhancing antibody (>90%, p<0.001); they also inhibited TNF-α and IL-6 secretion (p<0.001).Conclusion: Quercetin and fisetin down-regulate the production of proinflammatory cytokines induced by DENV infection enhanced by antibodies a mechanism involved in severe dengue.Keywords: dengue, proinflammatory cytokines, TNF-α, enhancing antibody, immunopathogenesis
