Purpose Zika (ZIKV) is a viral inflammatory disease affecting adults, children, and developing fetuses. It is endemic to tropical and sub-tropical countries, resulting in half the global population at risk of infection. Despite this, there are no approved therapies or vaccines against ZIKV disease. Non-invasive imaging biomarkers are potentially valuable tools for studying viral pathogenesis, prognosticating host response to disease, and evaluating in vivo efficacy of experimental therapeutic interventions. In this study, we evaluated [18F]fluorodeoxyglucose ([18F]FDG)-positron emission tomography (PET) as an imaging biomarker of ZIKV disease in a mouse model and correlated metabolic tracer tissue uptake with real-time biochemical, virological, and inflammatory features of tissue infection. Methods [18F]FDG-PET/CT imaging was performed in an acute, lethal ZIKV mouse infection model, at increasing stages of disease severity. [18F]FDG-PET findings were corroborated with ex vivo wholemount-tissue autoradiography and tracer biodistribution studies. Tracer uptake was also correlated with in situ tissue disease status, including viral burden and inflammatory response. Immune profiling of the spleen by flow cytometry was performed to identify the immune cell subsets driving tissue pathology and enhancing tracer uptake in ZIKV disease. Results Foci of increased [18F]FDG uptake were consistently detected in lymphoid tissues—particularly the spleen—of ZIKV-infected animals. Splenic uptake increased with disease severity, and corroborated findings in tissue pathology. Increased splenic uptake also correlated with increased viral replication and elevated expression of pro-inflammatory cytokines within these tissues. ZIKV-infected spleens were characterized by increased infiltration of myeloid cells, as well as increased proliferation of both myeloid and lymphoid cells. The increased cell proliferation correlated with increased tracer uptake in the spleen. Our findings support the use of [18F]FDG as an imaging biomarker to detect and track ZIKV disease in real time and highlight the dependency of affected tissue on the nature of the viral infection. Conclusion [18F]FDG uptake in the spleen is a useful surrogate for interrogating in situ tissue viral burden and inflammation status in this ZIKV murine model.
We report a facile co-precipitation method of synthesizing orthorhombic phase CsNd 2 F 7 and hexagonal phase K 2 NdF 5 nanocrystals, which avoids the use of relatively harsh conditions (e.g., high temperatures and long reaction times in hydrothermal synthesis). By reacting MF (M = Cs and K), Nd(CH 3 CO 2 ) 3 , oleic acid (OA), and 1-octadecene in the presence of sufficient amounts of oleylamine ligands (OAm) to ensure a non-acidic environment, CsNd 2 F 7 and K 2 NdF 5 nanocrystals are formed for reaction temperatures (T r ) ranging between 150 and 300 °C. When OAm is in excess of OA and T r = 300 °C, uniformly distributed CsNd 2 F 7 nanodiscs (∼20 nm in diameter) and sub-10 nm K 2 NdF 5 nanodiscs with an average thickness of 2−3 unit cell layers are formed. When OAm is removed, the acidic mixture produces CsNd 2 F 7 nanocrystals at low T r (150−200 °C); however, a mixture of NdF 3 and Cs-oleate is observed instead when T r is increased. Similarly, in an acidic enviroment, K 2 NdF 5 nanocrystals rapidly decompose into a mixture of K 0.156 Nd 0.142−y F 0.702−3y and y(NdF 3 ) (y < 0.142) at low T r (150−200 °C), while orthorhombic KNdF 4 nanocrystals are synthesized at higher T r (>200 °C). Therefore, the penta-and heptafluoride nanocrystals are thermodynamically stable only in a basic medium when OA is consumed, in part by its condensation reaction with OAm. We further demonstrate that the CsNd 2 F 7 and K 2 NdF 5 nanocrystals display good light-to-heat conversion efficiencies (16−27%) and computed tomography (CT) attenuation, making them promising theranostic photothermal imaging/therapy and CT contrast agents.
Current methods to detect and monitor pathogens in biological systems are largely limited by the tradeoffs between spatial context and temporal detail. A new generation of molecular tracking that provides both information simultaneously involves in situ detection coupled with non-invasive imaging. An example is antisense imaging that uses antisense oligonucleotide probes complementary to a target nucleotide sequence. In this study, we explored the potential of repurposing antisense oligonucleotides initially developed as antiviral therapeutics as molecular probes for imaging of viral infections in vitro and in vivo. We employed nuclease-resistant phosphorodiamidate synthetic oligonucleotides conjugated with cell-penetrating peptides (i.e., PPMOs) previously established as antivirals for dengue virus serotype-2 (DENV2). As proof of concept, and before further development for preclinical testing, we evaluated its validity as in situ molecular imaging probe for tracking cellular DENV2 infection using live-cell fluorescence imaging. Although the PPMO was designed to specifically target the DENV2 genome, it was unsuitable as in situ molecular imaging probe. This study details our evaluation of the PPMOs to assess specific and sensitive molecular imaging of DENV2 infection and tells a cautionary tale for those exploring antisense oligonucleotides as probes for non-invasive imaging and monitoring of pathogen infections in experimental animal models.
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