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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 09-11-2022 | Zika Virus | Original Article

TSPO expression in a Zika virus murine infection model as an imaging target for acute infection-induced neuroinflammation

Authors: Carla Bianca Luena Victorio, Rasha Msallam, Wisna Novera, Joanne Ong, Tham Jing Yang, Arun Ganasarajah, Jenny Low, Satoru Watanabe, Ann-Marie Chacko

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2023

Abstract

Introduction

Zika virus (ZIKV) is a neurotropic human pathogen that causes neuroinflammation, whose hallmark is elevated translocator protein (TSPO) expression in the brain. This study investigates ZIKV-associated changes in adult brain TSPO expression, evaluates the effectiveness of TSPO radioligands in detecting TSPO expression, and identifies cells that drive brain TSPO expression in a mouse infection model.

Methods

The interferon-deficient AG129 mouse infected with ZIKV was used as neuroinflammation model. TSPO expression was evaluated by tissue immunostaining. TSPO radioligands, [³H]PK11195 and [¹⁸F]FEPPA, were used for in vitro and ex vivo detection of TSPO in infected brains. [¹⁸F]FEPPA-PET was used for in vivo detection of TSPO expression. Cell subsets that contribute to TSPO expression were identified by flow cytometry.

Results

Brain TSPO expression increased with ZIKV disease severity. This increase was contributed by TSPO-positive microglia and infiltrating monocytes; and by influx of TSPO-expressing immune cells into the brain. [³H]PK11195 and [¹⁸F]FEPPA distinguish ZIKV-infected brains from normal controls in vitro and ex vivo. [¹⁸F]FEPPA brain uptake by PET imaging correlated with disease severity and neuroinflammation. However, TSPO expression by immune cells contributed to significant blood pool [¹⁸F]FEPPA activity which could confound [¹⁸F]FEPPA-PET imaging results.

Conclusions

TSPO is a biologically relevant imaging target for ZIKV neuroinflammation. Brain [¹⁸F]FEPPA uptake can be a surrogate marker for ZIKV disease and may be a potential PET imaging marker for ZIKV-induced neuroinflammation. Future TSPO-PET/SPECT studies on viral neuroinflammation and related encephalitis should assess the contribution of immune cells on TSPO expression and employ appropriate image correction methods to subtract blood pool activity.

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Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46:509–20. https://doi.org/10.1016/0035-9203(52)90042-4.

Li H, Saucedo-Cuevas L, Shresta S, Gleeson JG. The neurobiology of Zika virus. Neuron. 2016;92:949–58. https://doi.org/10.1016/j.neuron.2016.11.031.CrossRef

Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360:2536–43. https://doi.org/10.1056/NEJMoa0805715.CrossRef

Araujo AQ, Silva MT, Araujo AP. Zika virus-associated neurological disorders: a review. Brain. 2016;139:2122–30. https://doi.org/10.1093/brain/aww158.CrossRef

Mecharles S, Herrmann C, Poullain P, Tran TH, Deschamps N, Mathon G, et al. Acute myelitis due to Zika virus infection. Lancet. 2016;387:1481. https://doi.org/10.1016/S0140-6736(16)00644-9.CrossRef

Neri VC, Xavier MF, Barros PO, Melo Bento C, Marignier R, Papais AR. Case report: acute transverse myelitis after Zika virus infection. Am J Trop Med Hyg. 2018;99:1419–21. https://doi.org/10.4269/ajtmh.17-0938.CrossRef

Anaya JM, Rodriguez Y, Monsalve DM, Vega D, Ojeda E, Gonzalez-Bravo D, et al. A comprehensive analysis and immunobiology of autoimmune neurological syndromes during the Zika virus outbreak in Cucuta. Colombia J Autoimmun. 2017;77:123–38. https://doi.org/10.1016/j.jaut.2016.12.007.CrossRef

Roth W, Tyshkov C, Thakur K, Vargas W. Encephalomyelitis following definitive Zika virus infection. Neurol Neuroimmunol Neuroinflamm. 2017;4: e349. https://doi.org/10.1212/NXI.0000000000000349.CrossRef

Siu R, Bukhari W, Todd A, Gunn W, Huang QS, Timmings P. Acute Zika infection with concurrent onset of Guillain-Barre syndrome. Neurology. 2016;87:1623–4. https://doi.org/10.1212/WNL.0000000000003038.CrossRef

10.

Niemeyer B, Niemeyer R, Borges R, Marchiori E. Acute disseminated encephalomyelitis following Zika virus infection. Eur Neurol. 2017;77:45–6. https://doi.org/10.1159/000453396.CrossRef

11.

Pradhan F, Burns JD, Agameya A, Patel A, Alfaqih M, Small JE, et al. Case report: Zika virus meningoencephalitis and myelitis and associated magnetic resonance imaging findings. Am J Trop Med Hyg. 2017;97:340–3. https://doi.org/10.4269/ajtmh.16-0921.CrossRef

12.

Betlazar C, Harrison-Brown M, Middleton RJ, Banati R, Liu GJ. Cellular sources and regional variations in the expression of the neuroinflammatory marker translocator protein (TSPO) in the normal brain. Int J Mol Sci. 2018;19. https://doi.org/10.3390/ijms19092707.

13.

Israel I, Ohsiek A, Al-Momani E, Albert-Weissenberger C, Stetter C, Mencl S, et al. Combined [¹⁸F]DPA-714 micro-positron emission tomography and autoradiography imaging of microglia activation after closed head injury in mice. J Neuroinflammation. 2016;13:140. https://doi.org/10.1186/s12974-016-0604-9.CrossRef

14.

Keller T, Lopez-Picon FR, Krzyczmonik A, Forsback S, Kirjavainen AK, Takkinen JS, et al. [¹⁸F]-DPA for the detection of activated microglia in a mouse model of Alzheimer’s disease. Nucl Med Biol. 2018;67:1–9. https://doi.org/10.1016/j.nucmedbio.2018.09.001.CrossRef

15.

Mirzaei N, Tang SP, Ashworth S, Coello C, Plisson C, Passchier J, et al. In vivo imaging of microglial activation by positron emission tomography with [¹¹C]PBR28 in the 5XFAD model of Alzheimer’s disease. Glia. 2016;64:993–1006. https://doi.org/10.1002/glia.22978.CrossRef

16.

Van Camp N, Lavisse S, Roost P, Gubinelli F, Hillmer A, Boutin H. TSPO imaging in animal models of brain diseases. Eur J Nucl Med Mol Imaging. 2021;49:77–109. https://doi.org/10.1007/s00259-021-05379-z.CrossRef

17.

Bocan TM, Stafford RG, Brown JL, Akuoku Frimpong J, Basuli F, Hollidge BS, et al. Characterization of brain inflammation, apoptosis, hypoxia, blood-brain barrier integrity and metabolism in Venezuelan equine encephalitis virus (VEEV TC-83) exposed mice by in vivo positron emission tomography imaging. Viruses. 2019;11. https://doi.org/10.3390/v11111052.

18.

Doorduin J, Klein HC, de Jong JR, Dierckx RA, de Vries EF. Evaluation of [¹¹C]-DAA1106 for imaging and quantification of neuroinflammation in a rat model of herpes encephalitis. Nucl Med Biol. 2010;37:9–15. https://doi.org/10.1016/j.nucmedbio.2009.09.002.CrossRef

19.

Hammoud DA, Sinharay S, Shah S, Schreiber-Stainthorp W, Maric D, Muthusamy S, et al. Neuroinflammatory changes in relation to cerebrospinal fluid viral load in Simian immunodeficiency virus encephalitis. mBio. 2019;10. https://doi.org/10.1128/mBio.00970-19.

20.

Kuszpit K, Hollidge BS, Zeng X, Stafford RG, Daye S, Zhang X, et al. [¹⁸F]DPA-714 PET imaging reveals global neuroinflammation in Zika virus-infected mice. Mol Imaging Biol. 2018;20:275–83. https://doi.org/10.1007/s11307-017-1118-2.CrossRef

21.

Guilarte TR, Rodichkin AN, McGlothan JL, Acanda De La Rocha AM, Azzam DJ. Imaging neuroinflammation with TSPO: a new perspective on the cellular sources and subcellular localization. Pharmacol Ther. 2022;234:108048. https://doi.org/10.1016/j.pharmthera.2021.108048.

22.

Nutma E, Ceyzériat K, Amor S, Tsartsalis S, Millet P, Owen DR, et al. Cellular sources of TSPO expression in healthy and diseased brain. Eur J Nucl Med Mol Imaging. 2021;49:146–63. https://doi.org/10.1007/s00259-020-05166-2.CrossRef

23.

Sumathy K, Kulkarni B, Gondu RK, Ponnuru SK, Bonguram N, Eligeti R, et al. Protective efficacy of Zika vaccine in AG129 mouse model. Sci Rep. 2017;7:46375. https://doi.org/10.1038/srep46375.CrossRef

24.

Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, Osorio JE. Characterization of lethal Zika virus infection in AG129 mice. PLoS Negl Trop Dis. 2016;10: e0004682. https://doi.org/10.1371/journal.pntd.0004682.CrossRef

25.

Rossi SL, Tesh RB, Azar SR, Muruato AE, Hanley KA, Auguste AJ, et al. Characterization of a novel murine model to study Zika virus. Am J Trop Med Hyg. 2016;94:1362–9. https://doi.org/10.4269/ajtmh.16-0111.CrossRef

26.

Tang WW, Young MP, Mamidi A, Regla-Nava JA, Kim K, Shresta S. A mouse model of Zika virus sexual transmission and vaginal viral replication. Cell Rep. 2016;17:3091–8. https://doi.org/10.1016/j.celrep.2016.11.070.CrossRef

27.

Victorio CBL, Ong J, Tham JY, Reolo MJ, Novera W, Msallam R, et al. Preclinical evaluation of [¹⁸F]FDG-PET as a biomarker of lymphoid tissue disease and inflammation in Zika virus infection. Eur J Nucl Med Mol Imaging. 2022. https://doi.org/10.1007/s00259-022-05892-9.CrossRef

28.

Schoggins JW. Interferon-stimulated genes: what do they all do? Annu Rev Virol. 2019;6:567–84. https://doi.org/10.1146/annurev-virology-092818-015756.CrossRef

29.

Miorin L, Maestre AM, Fernandez-Sesma A, Garcia-Sastre A. Antagonism of type I interferon by flaviviruses. Biochem Biophys Res Commun. 2017;492:587–96. https://doi.org/10.1016/j.bbrc.2017.05.146.CrossRef

30.

Morrison TE, Diamond MS. Animal models of Zika virus infection, pathogenesis, and immunity. J Virol. 2017;91. https://doi.org/10.1128/JVI.00009-17.

31.

Watanabe S, Tan NWW, Chan KWK, Vasudevan SG. Dengue virus and Zika virus serological cross-reactivity and their impact on pathogenesis in mice. J Infect Dis. 2019;219:223–33. https://doi.org/10.1093/infdis/jiy482.CrossRef

32.

Victorio CB, Xu Y, Ng Q, Chua BH, Alonso S, Chow VT, et al. A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema. Sci Rep. 2016;6:28876. https://doi.org/10.1038/srep28876.CrossRef

33.

Victorio CBL, Novera W, Tham JY, Watanabe S, Vasudevan SG, Chacko AM. Peptide-conjugated phosphorodiamidate morpholino oligomers for in situ live-cell molecular imaging of dengue virus replication. Int J Mol Sci. 2020;21. https://doi.org/10.3390/ijms21239260.

34.

Chiu K, Lau WM, Lau HT, So KF, Chang RC. Micro-dissection of rat brain for RNA or protein extraction from specific brain region. J Vis Exp. 2007:269. https://doi.org/10.3791/269.

35.

Chacko AM, Watanabe S, Herr KJ, Kalimuddin S, Tham JY, Ong J, et al. [¹⁸F]FDG as an inflammation biomarker for imaging dengue virus infection and treatment response. JCI Insight. 2017;2. https://doi.org/10.1172/jci.insight.93474.

36.

Msallam R, Balla J, Rathore APS, Kared H, Malleret B, Saron WAA, et al. Fetal mast cells mediate postnatal allergic responses dependent on maternal IgE. Science. 2020;370:941–50. https://doi.org/10.1126/science.aba0864.CrossRef

37.

Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Madrid F, Mittelbrunn M. Analysis of microRNA and protein transfer by exosomes during an immune synapse. Methods Mol Biol. 2013;1024:41–51. https://doi.org/10.1007/978-1-62703-453-1_4.CrossRef

38.

Victorio CB, Ong J, Reolo MJ, bin Razeli MH, Watanabe S, Low J, et al. Detection of Zika virus (ZIKV)-induced neuroinflammation in a murine infection model with translocator protein (TSPO) ligand [³H]PK11195. Journal of Nuclear Medicine. 2019;60:221.

39.

Guilarte TR, Rodichkin AN, McGlothan JL, Acanda De La Rocha AM, Azzam DJ. Imaging neuroinflammation with TSPO: a new perspective on the cellular sources and subcellular localization. Pharmacol Ther. 2021:108048. https://doi.org/10.1016/j.pharmthera.2021.108048.

40.

Manangeeswaran M, Ireland DD, Verthelyi D. Zika (PRVABC59) Infection is associated with T cell infiltration and neurodegeneration in CNS of immunocompetent neonatal C57Bl/6 mice. PLoS Pathog. 2016;12: e1006004. https://doi.org/10.1371/journal.ppat.1006004.CrossRef

41.

Michlmayr D, Andrade P, Gonzalez K, Balmaseda A, Harris E. CD14⁺CD16⁺ monocytes are the main target of Zika virus infection in peripheral blood mononuclear cells in a paediatric study in Nicaragua. Nat Microbiol. 2017;2:1462–70. https://doi.org/10.1038/s41564-017-0035-0.CrossRef

42.

Li C, Xu D, Ye Q, Hong S, Jiang Y, Liu X, et al. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell. 2016;19:120–6. https://doi.org/10.1016/j.stem.2016.04.017.CrossRef

43.

Smith DR, Hollidge B, Daye S, Zeng X, Blancett C, Kuszpit K, et al. Neuropathogenesis of Zika virus in a highly susceptible immunocompetent mouse model after antibody blockade of type I interferon. PLoS Negl Trop Dis. 2017;11: e0005296. https://doi.org/10.1371/journal.pntd.0005296.CrossRef

44.

Sun X, Hua S, Chen HR, Ouyang Z, Einkauf K, Tse S, et al. Transcriptional changes during naturally acquired Zika virus infection render dendritic cells highly conducive to viral replication. Cell Rep. 2017;21:3471–82. https://doi.org/10.1016/j.celrep.2017.11.087.CrossRef

45.

Park T, Kang MG, Baek SH, Lee CH, Park D. Zika virus infection differentially affects genome-wide transcription in neuronal cells and myeloid dendritic cells. PLoS ONE. 2020;15: e0231049. https://doi.org/10.1371/journal.pone.0231049.CrossRef

46.

Hayashida E, Ling ZL, Ashhurst TM, Viengkhou B, Jung SR, Songkhunawej P, et al. Zika virus encephalitis in immunocompetent mice is dominated by innate immune cells and does not require T or B cells. J Neuroinflammation. 2019;16:177. https://doi.org/10.1186/s12974-019-1566-5.CrossRef

47.

Nettis MA, Veronese M, Nikkheslat N, Mariani N, Lombardo G, Sforzini L, et al. PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers. Transl Psychiatry. 2020;10:89. https://doi.org/10.1038/s41398-020-0768-z.CrossRef

Title: TSPO expression in a Zika virus murine infection model as an imaging target for acute infection-induced neuroinflammation
Authors: Carla Bianca Luena Victorio
Rasha Msallam
Wisna Novera
Joanne Ong
Tham Jing Yang
Arun Ganasarajah
Jenny Low
Satoru Watanabe
Ann-Marie Chacko
Publication date: 09-11-2022
Publisher: Springer Berlin Heidelberg
Keywords: Zika Virus
Positron Emission Tomography
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2023
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-06019-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

TSPO expression in a Zika virus murine infection model as an imaging target for acute infection-induced neuroinflammation

Abstract

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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