Differential Expression of Toll-like Receptors in Dendritic Cells of Patients with Dengue during Early and Late Acute Phases of the Disease

Abstract

BackgroundDengue hemorrhagic fever (DHF) is observed in individuals that have pre-existing heterotypic dengue antibodies and is associated with increased viral load and high levels of pro-inflammatory cytokines early in infection. Interestingly, a recent study showed that dengue virus infection in the presence of antibodies resulted in poor stimulation of Toll-like receptors (TLRs), thereby facilitating virus particle production, and also suggesting that TLRs may contribute to disease pathogenesis.Methodology/Principal FindingsWe evaluated the expression levels of TLR2, 3, 4 and 9 and the co-stimulatory molecules CD80 and CD86 by flow cytometry. This was evaluated in monocytes, in myeloid and plasmacytoid dendritic cells (mDCs and pDCs) from 30 dengue patients with different clinical outcomes and in 20 healthy controls. Increased expression of TLR3 and TLR9 in DCs of patients with dengue fever (DF) early in infection was detected. In DCs from patients with severe manifestations, poor stimulation of TLR3 and TLR9 was observed. In addition, we found a lower expression of TLR2 in patients with DF compared to DHF. Expression levels of TLR4 were not affected. Furthermore, the expression of CD80 and CD86 was altered in mDCs and CD86 in pDCs of severe dengue cases. We show that interferon alpha production decreased in the presence of dengue virus after stimulation of PBMCs with the TLR9 agonist (CpG A). This suggests that the virus can affect the interferon response through this signaling pathway.Conclusions/SignificanceThese results show that during dengue disease progression, the expression profile of TLRs changes depending on the severity of the disease. Changes in TLRs expression could play a central role in DC activation, thereby influencing the innate immune response.

Fc receptors in antibody‐dependent enhancement of viral infections

“…Thus, RNA virus infection of conventional DCs or macrophages isolated from RIG‐1‐ and MDA5‐deficient mice fails to induce IFN, whereas IFN production is still observed in plasmacytoid DC . Upregulation of these RNA sensors has been reported following DENV infection in monocytic THP‐1 , HUH‐7 (human hepatoma‐derived cell line) , and primary DCs ( Fig. ).…”

“…As mentioned above, the hallmark of ADE, especially in vitro , is increased infectivity or viral load. Under normal conditions, there are several intracellular RNA sensors, including endosomal Toll‐like receptor (TLR)‐3 and TLR‐7/8, which recognize double‐stranded RNA (dsRNA) and single‐stranded RNA, respectively ( Fig. ).…”

Blood dendritic cells: “canary in the coal mine” to predict chronic inflammatory disease?

“…For example, infections with P. falciparum , dengue virus, or influenza virus typically trigger a rise in circulating blood mDCs which may favor pathogen dissemination and chronic inflammation (Aldridge et al, 2009; Cao et al, 2012; Ibitokou et al, 2012; Torres et al, 2013). During sepsis and shock, rapid elevations of mDCs occur through differentiation of precursors in blood (Faivre et al, 2007, 2012).…”

Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer

“…However, human monocyte-derived DCs have been shown to express moderate (Bauer et al 2001;Hornung et al 2002;Meixlsperger et al 2013;Semnani et al 2008) to high (Hoene et al 2006;Ito et al 2002) levels of TLR7 and TLR9, which are upregulated in response to viral and bacterial infection (Saikh et al 2004;Torres et al 2013). In addition, human DCs have been reported to respond to TLR7 and TLR9 agonists (Hellman and Eriksson 2007;Krug et al 2003;Montoya et al 2006).…”