Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells

Abstract

The immunopathogenesis of dengue haemorrhagic fever and dengue shock syndrome is thought to be mediated by a variety of host factors. Enhancing antibodies are one of the key regulating molecules. These antibodies, via antibody-dependent enhancement (ADE) of infection, are able to facilitate dengue virus (DENV) growth in Fc-bearing host cells. The mechanism of ADE-enhanced DENV production is believed to be mediated through increasing the infected-cell mass. In the present work, the effect of ADE infection was explored further, focusing on the post-entry events of ADE infection. It was hypothesized that the higher virus production in ADE infection compared with DENV infection may be due to the ability of this infection pathway to suppress key antiviral molecules. Therefore, the influence of ADE infection on pro-and anti-inflammatory cytokines, including interleukin-12 (IL-12), gamma interferon (IFN-c), tumour necrosis factor alpha (TNF-a), IL-6 and IL-10, was investigated and it was found that DENV infection via the Fc receptor-mediated pathway was able to suppress the transcription and translation of IL-12, IFN-c and TNF-a. In contrast, infection via this route facilitated expression and synthesis of the anti-inflammatory cytokines IL-6 and IL-10. Moreover, this study demonstrates that the ADE infection pathway also suppresses an innate anti-DENV mediator, nitric oxide radicals, by disrupting the transcription of the iNOS gene transcription factor, IRF-1, and blocking the activation of STAT-1. In conclusion, ADE infection not only facilitates the entry process, but also modifies innate and adaptive intracellular antiviral mechanisms, resulting in unrestricted DENV replication in THP-1 cells. INTRODUCTIONDengue virus (DENV) has become a mosquito-borne virus of immense global health importance, as the disease caused by DENV is now endemic in more than 100 countries, particularly in Asia and Latin America, and about 50 million cases of DENV infection are estimated to occur annually worldwide (Ligon, 2005). DENVs, members of the family Flaviviridae, have positive, single-stranded RNA and belong to four related serotypes, known as DENV-1, -2, -3 and -4. DENV induces a wide range of clinical manifestations and the majority of infected patients experience uncomplicated dengue fever (DF), which is an acute febrile illness typically lasting 3-7 days. Dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) are plasma-leakage syndromes that represent life-threatening manifestations of DENV infection. DHF/DSS can be distinguished from DF by three primary criteria: namely, defects in vascular permeability, haemostatic abnormalities with marked thrombocytopenia and bleeding diathesis (da Fonseca & Fonseca, 2002;Rothman, 2004).Determinants that predispose infected patients to develop DHF have been partially identified (Lei et al., 2001). Various types of cell, such as monocytes and macrophages, dendritic cells, mast cells and hepatocytes, are able to support the replication of DENV (Jindadamrongwech et al., 2004;Kliks e...

Subversion of early innate antiviral responses during antibody-dependent enhancement of Dengue virus infection induces severe disease in immunocompetent mice

“…Denv immunocomplexes activate suppressive antiviral pathways, and the final outcome is a marked decrease in the production of type I IFns as well as the interferon-activated antiviral molecules (e.g., Isgs). Concomitantly, there is upregulation of antiinflammatory mediators, including the cytokine Il-10 [18,19]. similar responses have been observed in samples of DHF patients as compared to DF or dengue-like syndrome individuals [19,20].…”

Dengue: a continuing global threat

“…Secondary dengue infections in adults can produce the classical DSS or severe disease complicated by haemorrhages. The severity of secondary dengue infections has been observed to increase from month-to-month during island outbreaks 43 ; the longer the interval between the first and second infection the more severe is the accompanying disease 44,45 . Tertiary dengue infections can cause severe disease, but only rarely 25 .…”

“…In vitro studies demonstrate that the infection of human monocytes and mature dendritic cells results in increased virus replication as a result of the suppression of the interferon system 45 . Type I interferon-associated genes are less abundantly activated in peripheral blood mononuclear cells taken from patients with severe dengue disease compared with milder disease 46 .…”

Markers of dengue severity: a systematic review of cytokines and chemokines

“…The timing of IL-10 production is dynamic and varies throughout the disease course, exemplified by IL-10 levels peaking around early defervescence in DHF patients, but less so in DF patients (Adikari et al, 2016;Butthep et al, 2012;Libraty et al, 2002a), suggesting that the biggest difference between DF and DHF patients may be observed around the day of early defervescence. Mechanistically, the intrinsic ADE of DENV infections may modulate the severity of dengue via increased IL-10 production and subsequent enhancement of the Suppressor of Cytokine Signalling (SOCS) system (Chareonsirisuthigul et al, 2007;Suhrbier & La Linn, 2003;Ubol et al, 2010). Furthermore, in vitro studies suggest that in ADE-DENV infections, the role of IL-10 changes in the early and later stages of infection from anti-viral to immunoregulation (Halstead et al, 2010;Tsai et al, 2013b).…”

“…Notably, dengue viral titres correlate with disease severity (Endy et al, 2004;Vaughn et al, 2000), but are plausibly influenced by DENV type and infection status (Duyen et al, 2011). Levels of IFNg can be attenuated by IL-10 through SOCS-3 blockage of STAT1-IFNg receptor interaction in intrinsic ADE-DENV infection (Chareonsirisuthigul et al, 2007;Ubol et al, 2010). Indeed, the absence of IFNg in a mouse model of dengue led to primary dengue-infection-induced lethality (Costa et al, 2012).…”