[18F]DPA-714 PET Imaging Reveals Global Neuroinflammation in Zika Virus-Infected Mice

Kuszpit, Kyle; Hollidge, Bradley S.; Zeng, Xiankun; Stafford, Robert G.; Daye, Sharon P.; Zhang, Xiang; Basuli, Falguni; Golden, Joseph W.; Swenson, Rolf E.; Smith, Darci R.; Bocan, T. M. A.

doi:10.1007/s11307-017-1118-2

Cited by 17 publications

(21 citation statements)

References 33 publications

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“…2E). Consistent with our previous findings that 5A3 treatment alone does not increase inflammation in mice (26,32), 5A3 treatment of uninfected mice did not result in increased liver inflammation compared to that in untreated mice ( Fig. 2E and data not shown).…”

Section: Resultssupporting

confidence: 92%

Exploring Crimean-Congo Hemorrhagic Fever Virus-Induced Hepatic Injury Using Antibody-Mediated Type I Interferon Blockade in Mice

Lindquist

Zeng

Altamura

et al. 2018

J Virol

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Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe hepatic injury in humans. However, the mechanism(s) causing this damage is poorly characterized. CCHFV produces an acute disease, including liver damage, in mice lacking type I interferon (IFN-I) signaling due to either STAT-1 gene deletion or disruption of the IFN-I receptor 1 gene. Here, we explored CCHFV-induced liver pathogenesis in mice using an antibody to disrupt IFN-I signaling. When IFN-I blockade was induced within 24 h postexposure to CCHFV, mice developed severe disease with greater than 95% mortality by 6 days postexposure. In addition, we observed increased proinflammatory cytokines, chemoattractants, and liver enzymes in these mice. Extensive liver damage was evident by 4 days postexposure and was characterized by hepatocyte necrosis and the loss of CLEC4F-positive Kupffer cells. Similar experiments in CCHFV-exposed NOD-SCID-γ (NSG), Rag2-deficient, and perforin-deficient mice also demonstrated liver injury, suggesting that cytotoxic immune cells are dispensable for hepatic damage. Some apoptotic liver cells contained viral RNA, while other apoptotic liver cells were negative, suggesting that cell death occurred by both intrinsic and extrinsic mechanisms. Protein and transcriptional analysis of livers revealed that activation of tumor necrosis factor superfamily members occurred by day 4 postexposure, implicating these molecules as factors in liver cell death. These data provide insights into CCHFV-induced hepatic injury and demonstrate the utility of antibody-mediated IFN-I blockade in the study of CCHFV pathogenesis in mice. IMPORTANCE CCHFV is an important human pathogen that is both endemic and emerging throughout Asia, Africa, and Europe. A common feature of acute disease is liver injury ranging from mild to fulminant hepatic failure. The processes through which CCHFV induces severe liver injury are unclear, mostly due to the limitations of existing small-animal systems. The only small-animal model in which CCHFV consistently produces severe liver damage is mice lacking IFN-I signaling. In this study, we used antibody-mediated blockade of IFN-I signaling in mice to study CCHFV liver pathogenesis in various transgenic mouse systems. We found that liver injury did not depend on cytotoxic immune cells and observed extensive activation of death receptor signaling pathways in the liver during acute disease. Furthermore, acute CCHFV infection resulted in a nearly complete loss of Kupffer cells. Our model system provides insight into both the molecular and the cellular features of CCHFV hepatic injury.

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Section: Resultssupporting

confidence: 92%

Exploring Crimean-Congo Hemorrhagic Fever Virus-Induced Hepatic Injury Using Antibody-Mediated Type I Interferon Blockade in Mice

Lindquist

Zeng

Altamura

et al. 2018

J Virol

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“…We recently described the ability and sensitivity of PET imaging using [ 18 F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, to detect and quantify neuroinflammation in ZIKV-infected mice [4]. Our results demonstrated that global neuroinflammation plays an important role in the progression of ZIKV infection in a transiently immunosuppressed mouse model [5].…”

mentioning

confidence: 87%

“…An in vivo imaging approach is particularly advantageous to study progression of ZIKV-induced neurological sequelae because the development of neuropathology and congenital defects is a dynamic process. While molecular imaging has been used to characterize disease progression and evaluate drugs in the areas of neuroscience, cardiovascular, inflammation and oncology, application of imaging in infectious disease is limited [3].We recently described the ability and sensitivity of PET imaging using [ 18 F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, to detect and quantify neuroinflammation in ZIKV-infected mice [4]. Our results demonstrated that global neuroinflammation plays an important role in the progression of ZIKV infection in a transiently immunosuppressed mouse model [5].…”

mentioning

confidence: 99%

Could Pet Imaging Provide Insights Into Zika Virus Neurological Sequelae progression?

Smith

Bocan

2018

Future Virol.

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" An in vivo imaging approach is particularly advantageous to study progression of ZIKV-induced neurological sequelae because the development of neuropathology and congenital defects is a dynamic process. "First draft submitted: 9 November 2017; Accepted for publication: 21 November 2017; Published online: 10 January 2018Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged since 2007 causing human outbreaks in Africa, Asia, Oceania and most recently in the Americas. Mortality is not a common feature of human ZIKV infection, which is generally asymptomatic and self-limiting in most individuals. However, during the recent epidemics in Asia and the Americas, more severe clinical complications have been reported. Severe disease is characterized by neurological complications, which in adults include Guillain-Barré syndrome or in a few cases, encephalopathy, meningoencephalitis and acute myelitis [1]. ZIKV infection in pregnant women is a major global public health concern due to its link to congenital abnormalities including microcephaly, spontaneous abortion and intrauterine growth restriction [2], now referred to as congenital Zika syndrome.The unexpectedly frequent and severe clinical complications of ZIKV infection have prompted intense research on host-virus interactions, which remains a high priority research area. It is crucial that we characterize the neuropathogenesis and causative roles of ZIKV infection in the etiology of fetal microcephaly and other congenital malformations during pregnancy. Appropriate use of animal models is needed to address some of these key unanswered questions regarding the pathogenesis of ZIKV and to evaluate candidate medical countermeasures. Current approaches to study viral pathogenesis involve reduced mortality or extended time-to-death as the efficacy end point, viremia as an index of infection and serial necropsies to establish the pathological consequences of infection. New technology in the form of molecular imaging tools shifts the classical paradigm of serial necropsies and offers less invasive alternatives capable of providing a dynamic assessment of pathogen infection in real time. An in vivo imaging approach is particularly advantageous to study progression of ZIKV-induced neurological sequelae because the development of neuropathology and congenital defects is a dynamic process. While molecular imaging has been used to characterize disease progression and evaluate drugs in the areas of neuroscience, cardiovascular, inflammation and oncology, application of imaging in infectious disease is limited [3].We recently described the ability and sensitivity of PET imaging using [ 18 F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, to detect and quantify neuroinflammation in ZIKV-infected mice [4]. Our results demonstrated that global neuroinflammation plays an important role in the progression of ZIKV infection in a transiently immunosuppressed mouse model [5]. Importantly, the use of [18 F]DPA-714 PET imaging was more sensitive compared with standard...

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“…Kuszpit et al demonstrated that [ 18 F]DPA-714 (38) is a sensitive tool for the detection of neuroinflammation, induced by Zika virus (ZIKV) infection, using a mice model of ZIKV neurological disease. Moreover, the evaluation of therapeutics being developed for the treatment of the disease is also possible by [ 18 F]DPA-714 (38) imaging [80].…”

Section: Translocator Protein Receptor Ligandsmentioning

confidence: 99%

“…[ 11 C]PK11195(36) and pyrazolopyrimidine-derived radiotracers 37-41 for translocator protein (TSPO) PET imaging[72][73][74][75][76][77][78][79][80][81][82].…”

mentioning

confidence: 99%

Pyrazoles as Key Scaffolds for the Development of Fluorine-18-Labeled Radiotracers for Positron Emission Tomography (PET)

Gomes

Silva

2020

Molecules

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The need for increasingly personalized medicine solutions (precision medicine) and quality medical treatments, has led to a growing demand and research for image-guided therapeutic solutions. Positron emission tomography (PET) is a powerful imaging technique that can be established using complementary imaging systems and selective imaging agents—chemical probes or radiotracers—which are drugs labeled with a radionuclide, also called radiopharmaceuticals. PET has two complementary purposes: selective imaging for diagnosis and monitoring of disease progression and response to treatment. The development of selective imaging agents is a growing research area, with a high number of diverse drugs, labeled with different radionuclides, being reported nowadays. This review article is focused on the use of pyrazoles as suitable scaffolds for the development of 18F-labeled radiotracers for PET imaging. A brief introduction to PET and pyrazoles, as key scaffolds in medicinal chemistry, is presented, followed by a description of the most important [18F]pyrazole-derived radiotracers (PET tracers) that have been developed in the last 20 years for selective PET imaging, grouped according to their specific targets.

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[18F]DPA-714 PET Imaging Reveals Global Neuroinflammation in Zika Virus-Infected Mice

Cited by 17 publications

References 33 publications

Exploring Crimean-Congo Hemorrhagic Fever Virus-Induced Hepatic Injury Using Antibody-Mediated Type I Interferon Blockade in Mice

Exploring Crimean-Congo Hemorrhagic Fever Virus-Induced Hepatic Injury Using Antibody-Mediated Type I Interferon Blockade in Mice

Could Pet Imaging Provide Insights Into Zika Virus Neurological Sequelae progression?

Pyrazoles as Key Scaffolds for the Development of Fluorine-18-Labeled Radiotracers for Positron Emission Tomography (PET)

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