18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response
Ann-Marie Chacko, Satoru Watanabe, Keira J. Herr, Shirin Kalimuddin, Jing Yang Tham, Joanne Ong, Marie Reolo, Raymond M.F. Serrano, Yin Bun Cheung, Jenny G.H. Low, Subhash G. Vasudevan
Ann-Marie Chacko, Satoru Watanabe, Keira J. Herr, Shirin Kalimuddin, Jing Yang Tham, Joanne Ong, Marie Reolo, Raymond M.F. Serrano, Yin Bun Cheung, Jenny G.H. Low, Subhash G. Vasudevan
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Research Article Infectious disease Inflammation

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

Abstract

Development 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 18F-fluorodeoxyglucose (18F-FDG) PET in established mouse models for primary and antibody-dependent enhancement infection with DENV. 18F-FDG uptake was most prominent in the intestines and correlated with increased virus load and proinflammatory cytokines. Furthermore, a significant temporal trend in 18F-FDG uptake was seen in intestines and selected tissues over the time course of infection. Notably, 18F-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, 18F-FDG may serve as a novel DENV infection–associated inflammation biomarker for assessing treatment response during therapeutic intervention trials.

Authors

Ann-Marie Chacko, Satoru Watanabe, Keira J. Herr, Shirin Kalimuddin, Jing Yang Tham, Joanne Ong, Marie Reolo, Raymond M.F. Serrano, Yin Bun Cheung, Jenny G.H. Low, Subhash G. Vasudevan

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Figure 2

18F-FDG-PET/CT imaging to monitor the response to antiviral treatment following lethal infection with mouse-adapted S221 DENV2.

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18F-FDG-PET/CT imaging to monitor the response to antiviral treatment f...
(A) Schematic representation of the antiviral treatment regimen for celgosivir 4 times daily (q.i.d.) at day 2 after initiation of lethal S221 DENV2 infection. Treatment time course is indicated by blue arrows. Biomarkers (DENV2/cytokines, 18F-FDG tissue biodistribution (BioD), and 18F-FDG-PET/CT) were sampled over course of treatment. (B) Survival curves of lethal-infected mice following treatment with vehicle control (i.e., treatment naive; n = 12 mice/group, blue circles) and celgosivir q.i.d. (n = 6 mice/group, orange squares) at day 2 after DENV2. Results are representative of 2 independent experiments. Kaplan-Meier curves were compared by Mantel-Cox log-rank test; ***P = 0.045. (C) Celgosivir-treated mice showed significant differences in viremia versus the treatment-naive group at day 4 after infection by PCR assay (n = 6–12 mice/group). Mean values were compared by 2-way ANOVA with multiple comparisons; ***P = 0.03. (D) Terminal 18F-FDG uptake by BioD in selected tissues plotted over time after infection. Significant 18F-FDG uptake was observed in the treatment group compared with the treatment-naive group at day 4 after infection, with fold reduction indicated above data points. Mean values were compared by 2-way ANOVA with multiple comparisons; ***P < 0.001. (E) 18F-FDG-PET/CT images before and during antiviral treatment with celgosivir showing dramatically lower 18F-FDG uptake in the gut region as compared with treatment-naive mice (far right panel) (representative data shown from 1 animal of a cohort of n = 3). VC, vehicle control; Rx, treatment.