Since the uptake of virus–antibody complexes is more efficient than the entry of free virus through host cell receptor,

DENV infection is enhanced.[2, 29] It is not well understood how a greater viral load emerges from ADE-infected cells and how a greater viral load would provoke severe disease, especially because increased viral load alone is not the direct cause of plasma leakage.[1, 16] The final interpretation of ADE in terms of mechanisms and real impact on disease remains to be further explored. There is no perfect buy Staurosporine animal model to the study of DENV infection pathogenesis. A great part of these studies was performed using patient samples (plasma or peripheral blood mononuclear cells). These studies were descriptive and a link between systemic and local immune responses in the course of infection is frequently not possible to address. Non-human primates have been extensively used to study ADE and to test the efficacy and safety of pre-clinical vaccines.[39] However, there is an intense debate in terms of cost and accessibility of these models to answer precise questions about disease pathogenesis. In the face learn more of those limitations, a genetically appropriate mouse model would be essential

to determine how different immune system components regulate a protective immune response, and to investigate how T cells and other leucocytes, endothelial cells and cytokines contribute to severe disease during primary and secondary heterologous infection. not Initial attempts to develop a mouse model for dengue in immunocompetent mice with high titre viral infection were unable to recapitulate several important aspects of human DENV infection, including replication in peripheral tissues and development of the hallmark symptoms of DENV disease.[19, 40] Immune-competent mouse models have been shown to be resistant to DENV infections, because of the ability of their innate immune system to respond efficiently with total viral clearance, though success has been seen with mouse-adapted viruses

and/or artificial infection routes such as intracranial and intraperitoneal injection. In vivo studies have shown that DENV inhibits type I IFN production and that lack of type I IFN response renders mice susceptible, indicating that this mechanism of immune response subversion is critical for DENV success and so affects transmission.[41, 42] In addition, others have shown that downstream protein expression induced by type I IFN and the Janus kinase/STAT pathway play important roles in DENV infection control.[42, 43] Sabin and Schlesinger showed in 1945 that DENV can be propagated by intracerebral inoculation in mice.[44] Even if the initial adaptation to the mouse seemed to be a tedious and difficult process, 16 consecutive passages have been achieved and the virus propagated in mice produced dengue in human volunteers, but was not pathogenic for cotton rats, hamsters, guinea-pigs or rabbits.