Elevated Dengue Virus Nonstructural Protein 1 Serum Levels and Altered Toll-Like Receptor 4 Expression, Nitric Oxide, and Tumor Necrosis Factor Alpha Production in Dengue Hemorrhagic Fever Patients

Abstract

Background. During dengue virus (DV) infection, monocytes produce tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) which might be critical to immunopathogenesis. Since intensity of DV replication may determine clinical outcomes, it is important to know the effects of viral nonstructural protein 1 (NS1) on innate immune parameters of infected patients. The present study investigates the relationships between dengue virus nonstructural protein 1 (NS1) serum levels and innate immune response (TLR4 expression and TNF-α/NO production) of DV infected patients presenting different clinical outcomes. Methodology/Principal Findings. We evaluated NO, NS1 serum levels (ELISA), TNF-α production by peripheral blood mononuclear cells (PBMCs), and TLR4 expression on CD14+ cells from 37 dengue patients and 20 healthy controls. Early in infection, increased expression of TLR4 in monocytes of patients with dengue fever (DF) was detected compared to patients with dengue hemorrhagic fever (DHF). Moreover, PBMCs of DHF patients showed higher NS1 and lower NO serum levels during the acute febrile phase and a reduced response to TLR4 stimulation by LPS (with a reduced TNF-α production) when compared to DF patients. Conclusions/Significance. During DV infection in humans, some innate immune parameters change, depending on the NS1 serum levels, and phase and severity of the disease which may contribute to development of different clinical outcomes.

Prior Exposure to Zika Virus Significantly Enhances Peak Dengue-2 Viremia in Rhesus Macaques

“…Our results showed that the expression of TLR-4 was significantly upregulated on both CD14 + CD16 − and CD14 + CD16 + monocyte subsets, and on CD14 − CD16 − subsets of macrophages in ZIKV immune animals at day 63 post-ZIKV infection (day 7 post-DENV-2) as compared to day 0 and 56 post-ZIKV infection (time points prior to DENV-2 infection) suggesting that DENV-2 infection was accompanied by a significant activation of inflammatory subsets of monocyte/macrophages. Previous studies have reported that TLR-4 expressing CD14 + cells significantly increased in DENV patients 27 , 29 , and DENV directly activated human macrophages via TLR-4 leading to the induction and release of pro-inflammatory cytokines, and this effect was inhibited with TLR-4 antagonists, and anti-TLR-4 antibody 30 . Others have shown that non-classical monocytes (CD14 + CD16 + ) produce significant levels for pro-inflammatory cytokines 31 .…”

Fc receptors in antibody‐dependent enhancement of viral infections

“…In contrast to TNF and IL‐6, which are higher in ADE of DENV, production of NO in THP‐1 cells was significantly reduced . Lower serum NO levels were also observed in DHF patients who had higher NS1 levels during the acute febrile phase, compared with patients with mild dengue fever , suggesting that DENV can suppress NO. However, the data on NO in DENV infection are conflicting.…”

Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents

“…Several inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon-γ, and IL-6, are reported to be highly released in patients with DHF, which is a clinical characteristic of DHF3334. Although aberrant activation of COX-2 is associated with severe inflammation and viral pathogenesis, the role of COX-2 in the pathogenesis of DHF remains unclear.…”