@article {Victorio221, author = {Carla Bianca Victorio and Joanne Ong and Marie Jennifer Reolo and Muhammad Haziq bin Razeli and Satoru Watanabe and Jenny Low and Subhash Vasudevan and Ann-Marie Chacko}, title = {Detection of Zika virus (ZIKV)-induced neuroinflammation in a murine infection model with translocator protein (TSPO) ligand 3H-PK11195}, volume = {60}, number = {supplement 1}, pages = {221--221}, year = {2019}, publisher = {Society of Nuclear Medicine}, abstract = {221Objectives: Viruses that infect the central nervous system (CNS){\textemdash}i.e. neurotropic viruses{\textemdash}are emerging pathogens of public health significance due to their impact on human health and their economic burden to society. Infection with neurotropic viruses such as Zika Virus (ZIKV) causes immediate and delayed neuropathology, as exemplified by fetal microcephaly and adult Guillain-Barr{\'e} syndrome. The common early hallmark of virus-driven neuropathology is neuroinflammation. Activation of the 18-kDa translocator protein (TSPO) is a biomarker for neuroinflammation, and other groups have already validated it in the context of neurological diseases such as Alzheimer{\textquoteright}s. In this study, we assessed the suitability of TSPO as an imaging biomarker of neuroinflammation in the context of acute and protracted ZIKV-induced neurological disease in a murine model. Methods: All animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Duke-NUS Medical School. AG129 mice (deficient in interferon (IFN) α/β and γ receptors) were infected with lethal doses of ZIKV Paraiba01/Brazil or Uganda MR766 strain. Neurological examinations and general health examinations were conducted daily post-infection. Moribund mice were sacrificed, and the brains were harvested. Brain cryosections (10 {\textmu}m) were incubated with TSPO ligand 3H-PK11195 (0.1nM) and digital autoradiography (DAR) performed. Images were compared with contiguous tissue sections immunohistochemically (IHC) stained with antibody binding to TSPO. Contiguous tissue sections were also subjected to histopathological examination with hematoxylin \& eosin, as well as IHC stained with antibodies that detect ZIKV RNA and envelope protein to confirm tissue viral infection. Results: The ZIKV Paraiba01/Brazil induced acute disease (median survival of 9 days) with mild to moderate neurological deficits such as ataxia and limb paresis, while Uganda MR766 strain induced protracted disease (median survival of 19 days) with mild neurological deficits. ZIKV was found to aggressively replicate in the infected brain (p\<0.0001) and induce overexpression of IL-6 pro-inflammatory cytokine (6.8-fold increase; p=0.0144) compared to mock-infected mice. DAR studies with 3H-PK11195 revealed widespread neuroinflammation in both mice infected with ZIKV Paraiba01/Brazil strain (1.5-fold increase; p=0.0009) and Uganda MR766 strain (1.6-fold increase; p=0.0008). The rostral region of the infected brain{\textemdash}particularly the cerebral cortex, cerebral nuclei, and hippocampal formation{\textemdash}consistently bound more 3H-PK11195 compared to the same region in mock-infected brains (Paraiba01/Brazil vs. Mock, 2.6-fold-change; Uganda MR766 vs. Mock, 2.5-fold change). The 3H-PK11195 signals coincided with TSPO upregulated expression as determined by IHC staining, histopathological lesions of neuroinflammation (i.e. glial infiltration, glial nodule formation, and perivascular cuffing) assessed by H\&E staining, and IHC staining with antibodies that detect ZIKV dsRNA and envelope protein. Conclusions: ZIKV infection induces neuroinflammation in the AG129 mouse model, and TSPO is a suitable biomarker to detect neuroinflammation. Future studies will include the use of PET/SPECT TSPO imaging in ZIKV-infected mice to validate the in vitro and ex vivo findings. In vivo imaging will also be employed to assess temporal patterns of ZIKV-induced neuroinflammation and evaluate various candidate ZIKV inhibitors for in vivo efficacy.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/60/supplement_1/221}, eprint = {https://jnm.snmjournals.org/content}, journal = {Journal of Nuclear Medicine} }