Vitamin D-Regulated MicroRNAs: Are They Protective Factors against Dengue Virus Infection?

Vitamin D-Regulated MicroRNAs: Are They Protective Factors against Dengue Virus Infection? John F. Arboleda and Silvio Urcuqui-Inchima Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia (UdeA), Calle 70 No. 52-51, Medellín, Colombia Received 22 December 2015; Revised 7 April 2016; Accepted 20 April 2016 Academic Editor: Subhash C. Verma Copyright © 2016 John F. Arboleda and Silvio Urcuqui-Inchima. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Over the last few years, an increasing body of evidence has highlighted the critical participation of vitamin D in the regulation of proinflammatory responses and protection against many infectious pathogens, including viruses. The activity of vitamin D is associated with microRNAs, which are fine tuners of immune activation pathways and provide novel mechanisms to avoid the damage that arises from excessive inflammatory responses. Severe symptoms of an ongoing dengue virus infection and disease are strongly related to highly altered production of proinflammatory mediators, suggesting impairment in homeostatic mechanisms that control the host’s immune response. Here, we discuss the possible implications of emerging studies anticipating the biological effects of vitamin D and microRNAs during the inflammatory response, and we attempt to extrapolate these findings to dengue virus infection and to their potential use for disease management strategies. 1. Introduction Activation of innate immune cells results in the release of proinflammatory mediators to initiate a protective local response against invading pathogens [1]. However, overactivated inflammatory activity could be detrimental since it can cause tissue damage and even death of the host. Therefore, negative feedback mechanisms are required to control the duration and intensity of the inflammatory response [1, 2]. Although little is known about the molecular mechanisms occurring during dengue virus (DENV) infection/disease, it has been suggested that the immune response initiated against the virus greatly contributes to pathogenesis. Indeed, several symptoms of the disease are tightly related to imbalanced immune responses, particularly to high production of proinflammatory cytokines [3, 4] suggesting an impairment of homeostatic mechanisms that control inflammation. Interestingly, vitamin D has been described as an important modulator of immune responses to several pathogens and as a key factor enhancing immunoregulatory mechanisms that avoid the damage that arises from excessive inflammatory responses [5, 6], as in dengue disease [7]. Mounting evidence obtained from human populations and experimental in vitro studies has suggested that this hormone can play a key role in the immune system’s response to several viruses [8–14], thereby becoming a potential target of intervention to combat DENV infection and disease progression. Among several mechanisms, vitamin D activity has been associated with the expression of certain microRNAs (miRs) [15] that are one of the main regulatory switches operating at the translational level [16]. miRs constitute approximately 1% of the human genome and their sequences can be found within introns of other genes or can be encoded independently and transcribed in a similar fashion to mRNAs encoded by protein-coding genes [16]. A typical mature miR of 18–23 base pairs associates with the RNA-induced silencing complex (RISC) and moves towards the target mRNA [17]. Once there, the miR binds to the complementary sequence in the 3′untranslated region (3′UTR) of the mRNA, thereby inducing gene silencing through mRNA cleavage, translational repression, or deadenylation [16]. A single miR may directly regulate the expression of hundreds of mRNAs at once and several miRs can also target the same mRNA resulting in enhanced translation inhibition [18]. Targeting of specific genes involved in modulation of immune response pathways by miRs provides a finely tuned regulatory mechanism for the restoration of the host’s resting inflammation state [19–21]. Since the association between vitamin D and miR activity may play a relevant role in ongoing DENV infections, here we provide an overview of DENV-induced inflammatory responses and the early evidence anticipating a possible participation of the vitamin D and miR interplay regulating antiviral and inflammatory responses during DENV infection/disease. 2. DENV and the Immune Response DENV is an icosahedral-enveloped virus with a positive sense single-stranded RNA (ssRNA) genome that belongs to the family Flaviviridae, genus Flavivirus. There are four phylogenetically related but antigenically distinct viral serotypes (DENV 1–4) able to cause the full spectrum of the disease [22]. In addition, a sylvatic serotype (DENV-5), with no evidence regarding its ability to infect humans, has been recently reported [23]. DENV is transmitted by Aedes mosquitoes in tropical and subtropical areas where the disease has become a major public health threat and one of the most rapidly spreading vector-borne diseases in the world, with an increasing incidence of 30-fold in the past 50 years [24, 25]. An estimated 3.6 billion people live in high risk areas worldwide and it is estimated that over 390 million cases occur every year, of which 96 million suffer from dengue fever [26–28]. Although only a minor number of cases may progress to the severe forms of the disease, 21.000 deaths are reported annually [27]. Guidelines of the World Health Organization (WHO) recognize dengue as a clinical continuum from dengue fever (DF), a nonspecific febrile illness, to dengue with or without warning signs that can progress to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) [3]. These severe forms of the disease are characterized by a wide spectrum of symptoms, including the development of vascular permeability, plasma leakage, thrombocytopenia, focal or generalized hemorrhages, and tissue and/or organ damage that may lead to shock and death [29, 30]. Besides ecoepidemiology, host genetic variations, and virus virulence, the risk factor is increased mainly by secondary infections with different dengue serotypes, presumably through a mechanism known as antibody-dependent immune enhancement (ADE), whereby nonneutralizing antibodies from previous heterotypic infections enhance virus entry via receptors for immunoglobulins or Fc receptors (FcRs) [29, 31, 32]. Skin is the first barrier for the invading DENV and the site where innate immunity exerts the first line of defense [33]. Following the bite by an infected mosquito, local tissue resident dendritic cells (DCs) and macrophages are the main targets of the virus [34, 35]. The viral structural E protein binds to cellular receptors, such as DC-SIGN (Dendritic Cell-Specific Intercellul (...truncated)