Transient lymphopenia was observed at the peak of viremia (day 6 p

Transient lymphopenia was observed at the peak of viremia (day 6 p.i.) followed by a very significant increase at day 10 p.i. relevant organs, followed by non-paralytic death of the animals few days after computer virus clearance, similar to the disease kinetic in humans. Spleen damage, liver dysfunction and increased vascular permeability, but no haemorrhage, were observed in moribund animals, suggesting intact vascular integrity, a cardinal feature in DEN shock syndrome. Contamination with D2Y98P thus offers the opportunity Aloe-emodin to further decipher some of the aspects of dengue pathogenesis and provides a new platform for drug and vaccine testing. Author Summary The spread of dengue (DEN) worldwide combined with an increased severity of the DEN-associated clinical outcomes have made this mosquito-borne computer virus of great global public health importance. Contamination with DEN computer virus can be asymptomatic or trigger a wide spectrum of clinical manifestations, ranging from moderate acute febrile illness to classical dengue EGF fever and to severe DEN hemorrhagic fever/DEN Aloe-emodin shock syndrome (DHF/DSS). Progress in understanding DEN disease and in developing effective treatments has been hampered by the lack of a suitable animal model that can reproduce all or part of the disease’s clinical manifestations and outcome. Only a few of the DEN computer virus strains reported so far elicit a virulent phenotype in mice, which results at best in an acute contamination where mice die within few days with no, few or irrelevant disease manifestations. Here we describe a DEN computer virus strain which Aloe-emodin is usually highly virulent in mice and reproduces some of the aspects of severe DEN in humans, including the disease kinetics, organ damage/dysfunction and increased vascular permeability. This DEN computer virus strain thus offers the opportunity to further decipher some of the mechanisms involved in DEN pathogenesis, and provides a new platform for drug and vaccine testing in the mouse model. Introduction Dengue (DEN) computer virus belongs to the family, genus, and is the causative agent of DEN disease, a mosquito-borne illness that is endemic in subtropical and tropical countries [1]. With approximately half of the world’s populace residing in DEN endemic regions [2] and more than 50 million new infections projected to occur annually [3], DEN certainly poses as a global economic and health threat. Infection with one of the four DEN serotypes can be asymptomatic or trigger a wide spectrum of clinical manifestations, ranging from moderate acute febrile illness to classical dengue fever (DF), and to severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), characterized by fever, hemorrhagic tendency, thrombocytopenia, and capillary leakage according to the WHO guidelines [4]. Despite the increasing attention and research efforts devoted to DEN in recent years, the cellular and molecular mechanisms responsible for DEN pathogenesis remain largely unknown. Current hypotheses for the development of severe DEN that involve dysfunction of the host immune system include enhancing mechanisms induced by sub-neutralizing cross-reactive antibodies and memory T cells [3], [5]. Other non-enhancing mechanisms implicating the immune system include auto-immune responses against cross-reactive viral components, such as DEN non-structural 1 (NS1) protein [6], [7]. Platelet lysis, nitric oxide-mediated apoptosis of endothelial cells and complement activation have also been proposed to mediate thrombocytopenia and vascular leakage [8]. In addition, host genetic predisposition [9]C[11] and computer virus virulence [12], [13] were reported as risk factors for the development of severe DEN. No effective drugs or vaccines against DEN are currently available on the market [14]. Undeniably, progress in deciphering the mechanisms responsible for DEN pathogenesis and in developing effective prophylactic and/or therapeutic treatments has been impeded by the lack of suitable animal models [15]. Humans and mosquitoes represent so far the only natural hosts for DEN computer virus. nonhuman primates have been reported to be permissive to DEN contamination but no apparent clinical symptoms of the disease were observed [16], [17], although a recent study reported indicators of hemorrhage in rhesus macaques intravenously infected with a high dose of a DEN2 computer virus strain [18]. In addition, since the infected animals develop transient viremia and antibody responses, they have been useful for evaluating the efficacy of vaccine and antiviral candidates prior to clinical.