NON-INVASIVE IMAGING OF DISEASE AMELIORATION IN AG129 MOUSE MODEL OF DENGUE VIRUS INFECTION

Objectives Dengue virus (DENV) is emerging as a global public health threat affecting almost half of the world’s population. To date, no effective vaccine or anti-viral therapeutic is available. The study of the pathogenic properties of DENV infection is hampered by the lack of clear mapping of target tissues involved in the acute phase of the illness. We assessed the utility of FDG PET as a novel approach to detecting DENV-associated inflammation and disease amelioration in preclinical mouse models.

Methods The robust AG129 mouse model for dengue infection (deficient in interferon α, β, and γ receptors), was inoculated with a mouse-adapted strain of DENV serotype 2 (DENV2). FDG biodistribution and FDG PET imaging were performed both during disease progression and after a single dose of a neutralizing antibody to tumor necrosis factor-alpha (anti-TNFα) on Day 3 post infection (n=6-12 per cohort). In parallel, organ cytokine production and viral replication analysis was performed through the course of disease and drug treatment for correlation of FDG uptake with known markers of inflammation and infection/viral load.

Results DENV infected mice showed dramatic increase in gastrointestinal tissue uptake (stomach/intestines/spleen) over disease progression as early as Day 1 post infection. Significantly high FDG was observed specifically in the small intestine at Day 4 post infection (38.3±8.2 %ID/g). This uptake dropped precipitously to 20.1±4.8 %ID/g and 7.5±2.5 %ID/g one and two days following anti-TNFα treatment, respectively (P<0.0001). Similar drops in FDG uptake in response to treatment were also seen in spleen (P<0.0001) and large intestine (P<0.001). Treatment naïve mice all died by Day 5 of infection, whereas 100% of the anti-TNFα-treated group survived. FDG uptake tracked closely with inflammatory tissue cytokine levels.

Conclusions Non-invasive molecular imaging in DENV is innovative, and to our knowledge, such research is not being pursued elsewhere. The diagnostic and prognostic value of FDG PET for identifying key inflammatory foci and response to therapy early in the course of disease will have important implications in dengue patient management and outcome. Research Support: Duke-NUS Khoo Pilot Award to SK; NMRC/MOHIAFCat1/0008/2014 to SGV; Duke-NUS Start-up grant and NRF Lab@AU Programme (AG/CIVGC70-C/NRF/2013/2) to AMC.

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