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

Abstract

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.

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

“…Furthermore, a significant temporal trend in 18 F-FDG uptake was seen in intestines and selected tissues over the time course of infection. Notably, 18 F-FDG uptake and visualization by PET robustly differentiated treatment-naive groups from drug-treated groups as well as nonlethal from lethal infections with a clinical strain of DENV2. Thus, 18 F-FDG may serve as a novel DENV infection-associated inflammation biomarker for assessing treatment response during therapeutic intervention trials.…”

“…18 F-FDG uptake was most prominent in the intestines and correlated with increased virus load and proinflammatory cytokines. Furthermore, a significant temporal trend in 18 F-FDG uptake was seen in intestines and selected tissues over the time course of infection. Notably, 18 F-FDG uptake and visualization by PET robustly differentiated treatment-naive groups from drug-treated groups as well as nonlethal from lethal infections with a clinical strain of DENV2.…”

“…A comprehensive review comparing preclinical animal models used in dengue pathogenesis research has been recently compiled (15). The AG129 mouse model, which is deficient in IFN-α, -β, and -γ, has been used extensively to recapitulate some of the salient features of lethal human diseases, such as high viremia level, elevated cytokine levels, vascular leakage, and thrombocytopenia (16)(17)(18)(19). We recently showed that the infection of AG129 mice with mouse-adapted S221 DENV2/anti-DENV envelope glycoprotein monoclonal antibody immune complexes resulted in a tissueDevelopment of antiviral therapy against acute viral diseases, such as dengue virus (DENV), suffers from the narrow window of viral load detection in serum during onset and clearance of infection and fever.…”

“…We recently showed that the infection of AG129 mice with mouse-adapted S221 DENV2/anti-DENV envelope glycoprotein monoclonal antibody immune complexes resulted in a tissueDevelopment of antiviral therapy against acute viral diseases, such as dengue virus (DENV), suffers from the narrow window of viral load detection in serum during onset and clearance of infection and fever. We explored a biomarker approach using 18 F-fluorodeoxyglucose ( 18 F-FDG) PET in established mouse models for primary and antibody-dependent enhancement infection with DENV. 18 F-FDG uptake was most prominent in the intestines and correlated with increased virus load and proinflammatory cytokines.…”

“…We explored a biomarker approach using 18 F-fluorodeoxyglucose ( 18 F-FDG) PET in established mouse models for primary and antibody-dependent enhancement infection with DENV. 18 F-FDG uptake was most prominent in the intestines and correlated with increased virus load and proinflammatory cytokines. Furthermore, a significant temporal trend in 18 F-FDG uptake was seen in intestines and selected tissues over the time course of infection.…”