Dengue Virus Control of Type I IFN Responses: A History of Manipulation and Control

Abstract

The arthropod-borne diseases caused by dengue virus (DENV) are a major and emerging problem of public health worldwide. Infection with DENV causes a series of clinical manifestations ranging from mild flu syndrome to severe diseases that include hemorrhage and shock. It has been demonstrated that the innate immune response plays a key role in DENV pathogenesis. However, in recent years, it was shown that DENV evades the innate immune response by blocking type I interferon (IFN-I). It has been demonstrated that DENV can inhibit both the production and the signaling of IFN-I. The viral proteins, NS2A and NS3, inhibit IFN-I production by degrading cellular signaling molecules. In addition, the viral proteins, NS2A, NS4A, NS4B, and NS5, can inhibit IFN-I signaling by blocking the phosphorylation of the STAT1 and STAT2 molecules. Finally, NS5 mediates the degradation of STAT2 using the proteasome machinery. In this study, we briefly review the most recent insights regarding the IFN-I response to DENV infection and its implication for pathogenesis.

FIG. 1.

Dengue virus (DENV) blocks type I interferon (IFN-I) production. The innate immune system senses the pathogen microorganism through pattern recognition receptors (PRRs) that recognize patterns present in microorganisms known as pathogen-associated molecular patterns (PAMPs). (A) The PRRs involved in DENV recognition are the Toll-like receptors (TLRs), 3, 7, and 8, and also the RNA helicase-type receptors, such as retinoic acid-inducible-associated protein I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5). TLR3 senses double-stranded RNA (dsRNA) produced in DENV replication, and TLR7 and TLR8 sense single-stranded RNA (ssRNA). TLR7 and TLR8 are endosomal receptors associated with the adaptor protein MyD88. Activation of these TLRs, together with MyD88, recruits the IRAK1 and IRAK4 kinases, which associate with TNF-receptor-associated factor 6 (TRAF6), leading to its ubiquitination. TRAF6 promotes phosphorylation of the interferon regulatory factor (IRF)-7 that finally leads to transcription of IFN-α. On the other hand, phosphorylation of IRF-3 is mediated by TLR3, which is associated with the adaptor molecule TRIF and leads to the activation of TRAF3, to finally induce transcription of IFN-β. The cytoplasmic receptors, RIG-I and MDA-5, activate the mitochondria-related adaptor molecule IPS-I (also known as MAVS, CARDIF, and VISA), which in turn activates TRAF3 leading to the phosphorylation of the transcription factors, IRF-3 and IRF-7. (B) DENV inhibits IFN-I production avoiding PRR recognition through the formation of intracellular vesicles, in which the replication process is concentrated and hidden from the host innate immunity. The viral protease NS2B/NS3 degrades the signaling molecule stimulator of IFN genes (STING) involved in TRAF3 and TANK-binding kinase 1 (TBK1) activation. Finally, microRNA (miRNA)-146a induced by DENV downregulates the expression of TRAF6.

FIG. 2.

DENV inhibits IFN-I signaling. IFN-α/β binding to its receptors, known as IFANR, leads to the activation of the tyrosine kinases, Janus kinase 1 (Jak1) and Tyrosine kinase 2 (Tyk2), which once activated form a heterodimer that binds to the DNA-binding protein IRF-9 to finally form the transcription factor, IFN-stimulated gene factor 3 (ISGF-3). This transcription factor translocates to the nucleus where it stimulates the expression of hundreds of IFN-I-stimulated genes (ISGs). DENV inhibits Tyk2 activation and also STAT1 phosphorylation through its proteins, NS2A, NS4A, and NS4B. DENV also downregulates the expression of STAT2 and its NS5 protein blocks STAT2 phosphorylation. Finally, NS5 degrades STAT2 through a proteosoma-dependent mechanism, binding to the cellular protein ubiquitin protein ligase E3 component recognin 4 (UBR4).