The On Dengue Virus

The drastic increase in the dengue infection could be partly attributed to geographic expansion of the vector due to increasing urbanization, unavailability of specific antiviral therapies, licensed dengue vaccine, and poor understanding of the host immune responses. It has been reported that the immune-dominant envelope protein (E protein) domain III region (EDIII) is one of the most potent vaccine candidate because of its ability to trigger host immunity by inducing production of protective neutralizing antibodies. However, its role in the modulation of innate inflammatory responses hitherto remains unexplored.

Herein, we demonstrate that EDIII protein of DENV induces pro-inflammatory signatures by inducing enhanced production of inflammatory cytokines such as IL-1β and TNF-α in THP-1 cells, which is dependent on NF-κB pathway.

Also, we observed increase in the maturation of IL-1β, which was found to be associated with ROS production and potassium efflux. Further, our findings reveal that the IL-1β activation by EDIII protein was indeed dependent on the Caspase-1 and NLRP3 activation.

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In conclusion this study unearths the role of DENV EDIII protein in modulating innate inflammatory responses, which might provide possible mechanism of pathogenesis and open-up new avenues for the development of therapeutics against DENV. Keywords DENV, Inflammasomes, EDIII, Potassium efflux, NF-κB, IL-1β 1. Introduction Dengue is a common viral infection prevalent worldwide, which has shown an increase in the spread as well as epidemic incidences over the past few decades.

This is evident from the numbers reported in the WHO report, which clearly indicates that there has been a gradual upsurge in the Dengue cases globally from less than a thousand cases in 1950 to around three million cases annually in 2015.

Dengue is a mosquito-borne viral disease that is transmitted by the bites of female mosquitoes, mainly of the species Aedes aegypti, and Aedes albopictus in a few cases. It is primarily caused by four different but quite related Dengue virus (DENV) serotypes, namely, DENV-1,DENV-2, DENV-3,and DENV-4. The presence of four different causative serotypes of the virus that lead to cross-reactivity and hence, additional risk on subsequent dengue infections.

Clinically, dengue infection is characterised by a plethora of symptoms ranging from asymptomatic mild flu called as Dengue fever (DF), to the more severe condition, which includes coagulopathy, enhanced vascular fragility and thrombocytopenia known as Dengue Haemorrhagic fever (DHF), which may lead to hypovolemic shock called Dengue Shock Syndrome. Dengue virus (DENV) is an enveloped virus with positive-sense single stranded RNA genome that codes for seven non-structural and three structural proteins. The non-structural proteins (NSPs) (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) play a role in replication of viral RNA and assembly as well as regulation of the host cellular and immunological responses.

DENV NS1 protein acts as immunogen during severe phase of infection and elicits a potent anti-NS1 response [11]. Emerging evidences highlight a vital role of NS1 in the activation of immune complement system during infection. NSPs like NS2A, NS2B, NS4B and NS5 have been reported to modulate type I interferon (IFN) signaling while simultaneously NS5 and NS4B proteins induce production of chemokines and proinflammatory mediators. DENV structural proteins such as envelope glycoprotein (E) is a major component of the envelope of viral membrane, which helps the virus attachment to the host cell and subsequent fusion to the cellular membrane during the endosomal-mediated virus internalization.

The E protein is constituted of three structural domains, namely, EDI, EDII and EDIII, held by a helical stem region hitched to virus membrane by trans-membrane anchor. EDIII is an Ig-like domain involved in the in binding of the virus, which makes it to be an imperative target for the humoral immune response during infection. The EDIII is the region which has the highest variability amongst the four serotypes, congruently, the highly specific antibodies generated against this particular region are the ones with a high neutralising ability.

The innate immune responses mediated by host plays a primary role in limiting Dengue infection, however the immunological mechanisms exploited by the dengue virus to trick the host immune response still needs to be explored. Dengue virus has been known to escape from host immune responses through multiple routes and triggering of inflammation associated with host tissue damage is one such approach. It is also evident from the studies which report that the DENV-infected cells produce a significantly enhanced levels of the proinflammatory cytokines, tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 12p70, as well as prostaglandin E2.

Moreover, higher levels of pro-IL-1β, pro-IL-18, and NLRP3 in association with caspase-1 activation has also been observed in DENV-infected macrophages. Hence, identifying the DENV component which triggers such response would enable in the design of antiviral therapies. The DENV EDIII region has been investigated as a potential candidate for DENV vaccine development owing to its ability to trigger potent antibody response, nevertheless its role in the modulation of host innate inflammatory responses is not yet completely investigated. Therefore, in the present study, we have investigated the role of domain III of Dengue envelope protein (DENV EDIII) in tailoring innate immune responses in the differentiated human monocyte cell line (THP-1).