Abstract
Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in severe cases, patients can deteriorate and develop life-threatening vascular leakage, bleeding, and multi-organ failure. DF is the most prevalent mosquito-borne disease affecting more than 390 million people per year with a mortality rate close to 1% in the general population but especially high among children. There is no specific treatment and there is only one licensed vaccine with restricted application. Clinical and experimental evidence advocate the role of the humoral and T-cell responses in protection against DF, as well as a role in the disease pathogenesis. A lot of pro-inflammatory factors induced during the infectious process are involved in increased severity in dengue disease. The advances in DF research have been hampered by the lack of an animal model that recreates all the characteristics of this disease. Experiments in nonhuman primates (NHP) had failed to reproduce all clinical signs of DF disease and during the past decade, humanized mouse models have demonstrated several benefits in the study of viral diseases affecting humans. In DENV studies, some of these models recapitulate specific signs of disease that are useful to test drugs or vaccine candidates. However, there is still a need for a more complete model mimicking the full spectrum of DENV. This review focuses on describing the advances in this area of research.
Highlights
IntroductionDengue virus (DENV) is a member of the Flavivirus genus of the Flaviviridae family with approximately 11,000 nucleotides single-stranded RNA positive-sense genome that encodes three structural proteins (envelope or E; pre-membrane/membrane or pre-M/M; and the capsid, C) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5)
Dengue virus (DENV) is a member of the Flavivirus genus of the Flaviviridae family with approximately 11,000 nucleotides single-stranded RNA positive-sense genome that encodes three structural proteins and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5)
The fact that these animals replicate virus locally, get sick, die after infection, and develop immune responses after vaccination, allowed investigators to use this route of inoculation to test DENV vaccine safety and efficacy in different strains of juvenile mice, among them Albino Swiss mice, BALB/CJ, Swiss CD1, BALB/c, and severe combined immunodeficiency (SCID) mice transplanted with human liver cells [123,126,127,128,129]
Summary
Dengue virus (DENV) is a member of the Flavivirus genus of the Flaviviridae family with approximately 11,000 nucleotides single-stranded RNA positive-sense genome that encodes three structural proteins (envelope or E; pre-membrane/membrane or pre-M/M; and the capsid, C) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). Epidemiologic evidence points to the fact that more severe dengue occur at higher frequency during a second infection with a different DENV serotype [14,15] This led to the hypothesis that preformed antibodies do not neutralize the second serotype, but after recognizing the virus, direct virus-antibody complexes to Fc-receptors in monocytes and macrophages increasing the number of infected cells and viremia, enhancing the ability to cause an exacerbated disease as evidenced by higher viral load in people with severe dengue. These severe DENV cases are associated with an extensive T-cell activation and an aberrant humoral response that affects the endothelium structure and function [16]. The presence of homologous neutralizing antibodies titers were initially considered to be associated with protection, recent vaccine trials found that some participants with neutralizing antibodies developed dengue [20,21]
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