Abstract
Dengue is a mosquito-borne disease of global public health significance that is caused by four serologically and genetically related viruses (DENV-1 to DENV-4). Most human DENV infections are asymptomatic, but clinical cases can range in severity from a relatively mild self-limiting illness to a severe life-threatening disease. Infection with one serotype of DENV results in life-long homotypic immunity but only short term heterotypic protection. There are no licensed vaccines or antivirals for dengue due in part to difficulty in developing small animal models that mimic the systemic disease seen in humans. Consequently, an important advance was the description of models of DENV-2 infection in AG129 mice (deficient in interferon alpha/beta and gamma receptor signaling) that resemble human disease. However, the need for well characterized models of disease due to DENV-1, -3, and -4 still remains. Here we describe a new AG129 mouse model utilizing a non-mouse-adapted Thai human DENV-4 strain 703-4. Following intraperitoneal challenge, animals experience a rapidly progressive lethal infection without developing neurologic clinical signs of disease. High virus titers are seen in multiple visceral tissues including the liver, spleen and large intestine, and the infected animals develop vascular leakage and thrombocytopenia, hallmarks of human dengue. Taken together, our studies demonstrate that this model is an important addition to the field of dengue research particularly in understanding similarities and differences in the pathologic basis of the disease caused by different DENV serotypes and in determining comparative efficacy of putative vaccines and antivirals.
Highlights
The genus Flavivirus within the family Flaviviridae contains viruses that cause a number of important mosquito-borne diseases including yellow fever, Japanese encephalitis, West NilePLOS ONE | DOI:10.1371/journal.pone.0125476 May 4, 2015Lethal DENV-4 Model in AG129 Mice encephalitis and most importantly dengue, which is caused by four serologically distinct but genetically related viruses (DENV-1 to DENV-4)
The World Health Organization (WHO) estimates that approximately 3 billion people currently live in areas where they are at risk of DENV infection and that there are approximately 100 million clinical DENV infections annually worldwide [1, 2]
DENV-4 703–4 produces a lethal infection in AG129 mice
Summary
The genus Flavivirus within the family Flaviviridae contains viruses that cause a number of important mosquito-borne diseases including yellow fever, Japanese encephalitis, West Nile. Lethal DENV-4 Model in AG129 Mice encephalitis and most importantly dengue, which is caused by four serologically distinct but genetically related viruses (DENV-1 to DENV-4). The World Health Organization (WHO) estimates that approximately 3 billion people currently live in areas where they are at risk of DENV infection and that there are approximately 100 million clinical DENV infections annually worldwide [1, 2]. Multiple factors are believed to contribute to the increasing public health importance of dengue including expansion of the geographical distribution of two of its principal vectors (Aedes aegypti and Aedes albopictus), increases in both urbanization and population size in endemic countries, and growth in international trade and travel
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