18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response
Ann-Marie Chacko, … , Jenny G.H. Low, Subhash G. Vasudevan
Ann-Marie Chacko, … , Jenny G.H. Low, Subhash G. Vasudevan
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e93474. https://doi.org/10.1172/jci.insight.93474.
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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 3

Detection of 18F-FDG following nonlethal or lethal infection with DENV2 clinical isolate EDEN2 identifies differences in infection severity and intestinal disease amelioration.

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Detection of 18F-FDG following nonlethal or lethal infection with DENV2 ...
Schematic diagram of experimental setup in (A) nonlethal and (B) lethal ADE infection. (C) Viremia measured in treatment-naive (vehicle control–treated) nonlethal- and lethal-infected mice by PCR assay (n = 3–8 mice/group; gray squares and blue circles, respectively). (D) Survival curves of nonlethal- and lethal-infected mice following treatment with vehicle control (n = 8 mice/group) and lethal-infected mice treated with celgosivir q.i.d. (n = 6 mice/group, orange squares) at day 2 after DENV2. Results are representative of 2 independent experiments. Celgosivir treatment significantly enhanced mouse survival in the lethal model. Kaplan-Meier curves were compared by Mantel-Cox log-rank test; ***P < 0.0001. (E) 18F-FDG uptake (%ID/g) in selected tissues plotted over time after EDEN2 infection (n = 3–8 mice/group). Significant 18F-FDG uptake was observed in the lethal group compared with nonlethal group as early as day 3 after infection, with fold difference indicated between groups above data points. Mean values were compared by 2-way ANOVA with multiple comparisons; *P < 0.05; #P < 0.001. (F and G) Expanded tissue profile of 18F-FDG uptake normalized to 18F-FDG profile in noninfected mice (localization ratio [LR]) and plotted over time in (F) nonlethal and (G) lethal EDEN2-infected mice. For spleen, S.Int., L.Int., and, in one instance, the kidney, significant 18F-FDG uptake is observed relative to naive mice (LR = 1, represented as red dashed line). Mean values were compared by 2-way ANOVA with multiple comparisons; *P < 0.05; **P < 0.01; ***P < 0.0001 (n = 3–8 mice/group). (H and I) Posterior 3D volume rendering of fused 18F-FDG-PET/CT scans of DENV2 progression in mice (H) following lethal EDEN2 infection and (I) after induction of celgosivir therapy 2 days after infection (representative data shown from 1 animal of a cohort of n = 6 treatment naive and n = 3 celgosivir treated). (J) Analysis of in vivo longitudinal 18F-FDG-PET/CT images from individual mice (M1–M9) focused on 18F-FDG gut concentrations (%ID) in treatment-naive (M1–M6, blue squares) and celgosivir-treated (M7–M9, yellow triangles) arms. Mean values were compared by 2-way ANOVA with multiple comparisons; between group means at individual time points, †P < 0.05; #P < 0.0001; over disease time course within group, **P < 0.01; ***P < 0.0001. VC, vehicle control; Rx, treatment.