Viral Immune Evasion in Dengue: Toward Evidence-Based Revisions of Clinical Practice Guidelines

Abstract

Dengue, a leading cause of illness and death in the tropics and subtropics since the 1950׳s, is fast spreading in the Western hemisphere. Over 30% of the world׳s population is at risk for the mosquitoes that transmit any one of four related Dengue viruses (DENV). Infection induces lifetime protection to a particular serotype, but successive exposure to a different DENV increases the likelihood of severe form of dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). Prompt supportive treatment lowers the risk of developing the severe spectrum of Dengue-associated physiopathology. Vaccines are not available, and the most effective protective measure is to prevent mosquito bites. Here, we discuss selected aspects of the syndemic nature of Dengue, including its potential for pathologies of the central nervous system (CNS). We examine the fundamental mechanisms of cell-mediated and humoral immunity to viral infection in general, and the specific implications of these processes in the regulatory control of DENV infection, including DENV evasion from immune surveillance. In line with the emerging model of translational science in health care, which integrates translational research (viz., going from the patient to the bench and back to the patient) and translational effectiveness (viz., integrating and utilizing the best available evidence in clinical settings), we examine novel and timely evidence-based revisions of clinical practice guidelines critical in optimizing the management of DENV infection and Dengue pathologies. We examine the role of tele-medicine and stakeholder engagement in the contemporary model of patient centered, effectiveness-focused and evidence-based health care.AbbreviationsBBB - blood-brain barrier, CNS - central nervous system, DAMP - damage-associated molecular patterns, DENV - dengue virus, DF - dengue fever, DHF - dengue hemorrhagic fever, DSS - dengue shock syndrome, DALYs - isability adjusted life years, IFN-g - interferon-gamma, ILX - interleukinX, JAK/STAT - janus kinase (JAK) / Signal transducer and activator of transcription (STAT), LT - Escherichia coli heat-labile enterotoxin formulations deficient in GM1 binding by mutation (LT[G33D]), MCP-1 - monocyte chemotactic protein 1, M-CSF - macrophage colony-stimulating fact, MHC - major histocompatibility complex, MIF - macrophage migration inhibitory factor, [MIP-1]-α / -β - macrophage inflammatory protein-1 alpha and beta, mAb - monoclonal antibody, NS1 - non-structural protein 1 of dengue virus, NK - natural killer cells, PAMP - pathogen-associated molecular patterns, PBMC - peripheral blood mononuclear cells, TBF-b - transforming growth factor-beta, TNF-α - tumor necrosis-alpha, VHFs - virus hemorrhagic fevers, WHO - World Health Organization.

Dengue virus-1 NS5 genetic variant associated with a severe clinical infection: Possible reduction of the innate immune response by inhibition of interferon type 1 and the Janus kinase-signal transducer and activator of transcription signaling pathway

“…The response of interferon or cytokines to dengue infection was part of the innate immunity initiated at day 0-1 following dENV infection, and declines 3-4 days thereafter. The upregulation of these early innate immune responses coincides, as it should from an immune surveillance perspective, with a drop in dENV viral replication during days 0-3 of the fever (35). A variation in the impairment of the function of type 1 interferon, either at the level of its receptor or by interfering with its signaling pathway (JAK-STAT) may cause variations in the clinical course of the disease.…”

Hypothalamus-Pituitary-Adrenal cell mediated Immunity Regulation in the Immune Restoration Inflammatory Syndrome (IRIS)

“…It is possible and even probable that this hypothetical model will also contribute to the elucidation of the pathological mechanisms that underlie Zika virus infection. Proof of principle is given in our recent discussion of neuroendocrineimmune interactions in Dengue [ 29 ]. Zika and Dengue are members of the genus Flavivirus, which also includes the West Nile virus, the tick-borne encephalitis virus, the Chikungunya virus, the Yellow Fever virus, and contribute to the incidence of and morbidity of encephalitis, among other pathologies.…”

“…In brief, the inflammatory response is composed of two phases: the first, triggered and sustained by myeloid CD45+CD14+ cells (some of which are CD4+dim) that produce interleukin (IL)6, IL1b and tumor necrosis factor (TNF)a in addition to prostaglandins and other non-cytokines that favor inflammatory processes - this is a rather sharp and short-lived response; and the second, triggered by lymphoid CD45+CD14- cells (many of which are CD4+high) that engender a TH17 response (i.e., predominant cytokines: IL17 and IL23), which is finely regulated by IL9 and other TH9 cytokines representatives - this, by contrast, is a sustained inflammation, such as that we observe in inflammatory diseases (e.g., inflammatory bowel disease). Both arms are subject to fine regulation brought up in part by regulatory T cells (CD4+CD25+FoxP3+) [ 12 , 13 ]. One important gap in knowledge in the immuno-pathology of IRIS is the characterization, within the fast rising CD4 cell population, of which subpopulation of CD4+ cell is fast proliferating, and of whether or not the rise in cell number corresponds to increased specific functional responses.…”

Bioinformation Informs the Allostasiome: Translational Environmental Restoration (TER) for the Climate Crisis Medical Emergency

“…With that expansion of the tropical zones, mosquito-borne diseases spread wider and faster into heavily inhabited cities. Novel infectious diseases, including Ebola [ 6 ], Zika [ 7 ] and others [ 8 ] pose new challenges to public health and health care in Western societies. When making the case for patient-centered care [ 1 ] in this context, it behooves us to take into serious consideration the important role of the individual allostatic responses of each individual patient to the climatic macroenvironmental stressors discussed above.…”