Abstract
The involvement of the immune system in the protection and pathology of natural dengue virus (DENV) has been extensively studied. However, despite studies that have referred to activation of neutrophils in DENV infections, the exact roles of neutrophils remain elusive. Here, we explored the phenotypic and functional responses of neutrophils in a cohort of adult dengue patients. Results indicated that during an acute DENV infection, neutrophils up-regulate CD66b expression, and produce a more robust respiratory response as compared with that in convalescent or healthy individuals; this confirmed in vivo neutrophil activation during DENV infection. Spontaneous decondensation of nuclei, an early event of neutrophil extracellular trap (NET) formation, was also markedly increased in cells isolated from DENV-infected patients during the acute phase of the infection. In vitro incubation of NETs with DENV-2 virus significantly decreased DENV infectivity. Interestingly, increased levels of NET components were found in the serum of patients with more severe disease form—dengue hemorrhagic fever (DHF), but not uncomplicated dengue fever, during the acute phase of the infection. Levels of pro-inflammatory cytokines IL-8 and TNFα were also increased in DHF patients as compared with those in healthy and DF subjects. This suggested that NETs may play dual roles during DENV infection. The increased ability for NET formation during acute DENV infection appeared to be independent of PAD4-mediated histone H3 hyper-citrullination. Our study suggests that neutrophils are involved in immunological responses to DENV infection.
Highlights
The dengue virus (DENV) is a growing public health concern worldwide
Evidences of excessive inflammation during DENV infection suggested that activation of neutrophils and formation of neutrophil extracellular trap (NET) may be involved in disease pathogenesis [33]
We showed that neutrophils were primed in vivo (Figures 6i–iii), and were prone spontaneous delobulation
Summary
The dengue virus (DENV) is a growing public health concern worldwide. There are four DENV serotypes, which cause a multitude of clinical outcomes that range from self-limiting febrile illness, dengue fever (DF), and dengue hemorrhagic fever (DHF) to life-threatening dengue shock syndrome (DSS) [1]. The mechanisms underlying the pathogenesis of the disease and immune responses to DENV infection are not completely understood; these are likely the result of complex interplays between viral factors such as viral load, serotypes, and viral proteins [2, 3] and host factors, such as pre-existing immune responses and changes in endothelial cell composition [4,5,6]. The roles of neutrophils during viral infections have been re-evaluated following the discovery of neutrophil extracellular traps (NETs). The roles of NETs in viral infections vary greatly from virus to virus. Beneficial roles of NETs in trapping (HIV) [9] and inhibiting viral dissemination (murine pox virus) [10] have been reported. Inhibition of NET formation did not affect infection outcomes [12]. The mechanisms underlying NET formation and the factors that dictate the role of NETs during viral infections remain largely unknown
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