Abstract
BackgroundSeveral experimental animal models have been used to study the pathogenesis of dengue disease; however, most of the studies used laboratory-adapted viruses, which lack the virulence of viruses circulating in humans. The aim of this study was to analyze the ability of clinical Dengue virus (DENV) isolates (D2/BR/RP/RMB/09 and D3/BR/SL3/02) to infect immunocompetent C57BL/6 mice.MethodsTwo strategies of intraperitoneal infection, which were based on the concept of the antibody dependent enhancement phenomenon, were used. In one strategy, the animals were inoculated with macrophages infected in vitro with dengue viruses, which were incubated with enhancing antibodies, and in the other strategy, the animals were inoculated with a complex of enhancing antibodies and dengue viruses.ResultsThe D3/BR/SL3/08 isolate showed a higher ability of infection (virus RNA was more frequently detected in the serum and in several organs) in the experimental model compared to both the D2/BR/RP/RMB/2009 isolate and a laboratory adapted DENV-1 strain (Mochizuki strain), regardless of the infection strategy used. The main features of the D3/BR/SL3/08 isolate were its neuroinvasiveness and the induction of an extended period of viremia. Enhancing antibodies did not influence on the infection of animals when macrophages were used, but the level of viremia was increased when they were used as a complex with a D3/BR/SL3/02 isolate.DiscussionWe showed that DENV isolates could infect immunocompetent C57BL/6 mice, which have has been previously used to study some aspect of dengue disease when infected with laboratory adapted strains. DENV genome was detected in the same organs found in humans when autopsy and biopsy samples were analyzed, showing that C57BL/6 mice reproduce some aspects of the DENV tropism observed in humans. The main difference observed between the D3/BR/SL3/02 and D2/BR/RP/RMB/2009 clinical isolates was the neuroinvasive ability of the first one. Neuroinvasiveness has been described in some DENV infected cases and is common for other members of the Flavivirus genus.ConclusionsThese results suggest that C57BL/6 mice can be used as an experimental model to evaluate virulence differences among DENV clinical isolates.
Highlights
Several experimental animal models have been used to study the pathogenesis of dengue disease; most of the studies used laboratory-adapted viruses, which lack the virulence of viruses circulating in humans
These results suggest that C57BL/6 mice can be used as an experimental model to evaluate virulence differences among Dengue virus (DENV) clinical isolates
DENV infect C57BL/6 peritoneal macrophages To determine the susceptibility of C57BL/6 macrophages to infection by DENV, peritoneal macrophages were incubated in vitro with laboratory-adapted (DENV-1, Mochizuki strain) and clinical DENV isolates (DENV-2, D2/BR/RP/RMB/2009 and DENV-3, D3/BR/SL3/02)
Summary
Several experimental animal models have been used to study the pathogenesis of dengue disease; most of the studies used laboratory-adapted viruses, which lack the virulence of viruses circulating in humans. Epidemiological studies have shown that a secondary infection with a different virus subtype is highly associated with the severe form of the disease [7]. Several experimental animal models have been used to study the pathogenesis of the disease [8]; most studies used laboratory adapted viruses, which lack the virulence of viruses that circulate in humans. We demonstrated a differential ability of infection of clinical DENV isolates in C57BL/6 mice, suggesting that this experimental model can be used to study virulence differences among clinical isolates
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