A Non Mouse-Adapted Dengue Virus Strain as a New Model of Severe Dengue Infection in AG129 Mice

Autor: George W. Yip, Jowin K. W. Ng, Wouter Schul, Grace K. Tan, Scott L. Trasti, Sylvie Alonso
Rok vydání: 2010
Předmět:
Zdroj: PLoS Neglected Tropical Diseases, Vol 4, Iss 4, p e672 (2010)
PLoS Neglected Tropical Diseases
ISSN: 1935-2735
DOI: 10.1371/journal.pntd.0000672
Popis: The spread of dengue (DEN) worldwide combined with an increased severity of the DEN-associated clinical outcomes have made this mosquito-borne virus of great global public health importance. Progress in understanding DEN pathogenesis and in developing effective treatments has been hampered by the lack of a suitable small animal model. Most of the DEN clinical isolates and cell culture-passaged DEN virus strains reported so far require either host adaptation, inoculation with a high dose and/or intravenous administration to elicit a virulent phenotype in mice which results, at best, in a productive infection with no, few, or irrelevant disease manifestations, and with mice dying within few days at the peak of viremia. Here we describe a non-mouse-adapted DEN2 virus strain (D2Y98P) that is highly infectious in AG129 mice (lacking interferon-α/β and -γ receptors) upon intraperitoneal administration. Infection with a high dose of D2Y98P induced cytokine storm, massive organ damage, and severe vascular leakage, leading to haemorrhage and rapid death of the animals at the peak of viremia. In contrast, very interestingly and uniquely, infection with a low dose of D2Y98P led to asymptomatic viral dissemination and replication in relevant organs, followed by non-paralytic death of the animals few days after 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. Infection with D2Y98P thus offers the opportunity 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 virus of great global public health importance. Infection with DEN virus can be asymptomatic or trigger a wide spectrum of clinical manifestations, ranging from mild acute febrile illness to classical dengue fever and to severe DEN hemorrhagic fever/DEN 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 virus strains reported so far elicit a virulent phenotype in mice, which results at best in an acute infection where mice die within few days with no, few or irrelevant disease manifestations. Here we describe a DEN virus strain which is 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 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.
Databáze: OpenAIRE
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