Serotype-associated immune response and network immunoclusters in children and adults during acute Dengue virus infection

Abstract

The present study was designed as an exploratory investigation to characterize the overall profile of chemokines, growth factors, and pro-inflammatory/regulatory cytokines during acute DENV infection according to DENV-1, DENV-2, DENV-4 serotypes and age: children: <1–10-year-old (yo); adolescents:11–20 yo; adults 21–40 yo; and older adults: 41–75 yo. The levels of soluble immunemediators were measured in serum by high-throughput microbeads array in 636 subjects including 317 DENV-infected and 319 age-matching non-infected control (NI). Overall, most soluble mediators were increased in DENV-infected patients as compared to NI group regardless of age and DENV serotype, with high magnitude order of increase for CCL2, CXCL10, IL-1β, IFN-γ, IL1-Ra (fold change >3x), except PDGF in which no fold change was observed. Moreover, despite the age ranges, DENV-1 and DENV-4 presented increased levels of VEGF, IL-6, and TNF-α in serum but decreased levels of PDGF, while DENV-2 exhibited increased levels of CXCL8, CCL4, and IL-12. Noteworthy was that DENV-2 showed increased levels of IL-12, IL-15, IL-17, IL-4, IL-9, and IL-13, and maintained an unaltered levels of PDGF at younger ages (<1–10 yo and 11–20 yo), whereas in older ages (21–40 yo and 41–75 yo), the results showed increased levels of CCL2, IL-6, and TNF-α, but lower levels of PDGF. In general, DENV infection at younger age groups exhibited more complex network immunoclusters as compared to older age groups. Multivariate analysis revealed a clustering of DENV cases according to age for a set of soluble mediators especially in subjects infected with DENV-2 serotype. Altogether, our findings demonstrate that the profile of circulating soluble mediators differs substantially in acute DENV according to age and DENV serotypes suggesting the participation of serotype-associated immune response, which may represent a potential target for development of therapeutics and could be used to assist medical directive for precise clinical management of severe cases.