Evaluation of antiviral therapies in respiratory and neurological disease models of Enterovirus D68 infection in mice

Hurst, Brett L.; Evans, W. Joseph; Smee, Donald F.; Wettere, Arnaud J. Van; Tarbet, E. Bart

doi:10.1016/j.virol.2018.10.014

Cited by 31 publications

(42 citation statements)

References 53 publications

(45 reference statements)

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“…In addition, future studies will determine if treatment regimens that reduce or prevent viremia can also prevent the onset of neurological signs following EV-D68 infection, as a concurrent manuscript describes the neurological model following intraperitoneal infection of mouse-adapted EV-D68 in 10-day-old AG129 mice (Hurst et al, 2019). In addition, sequence analyses of mouse-passaged virus has been initiated and will be published upon completion.…”

Section: Discussionmentioning

confidence: 99%

Development of a respiratory disease model for enterovirus D68 in 4-week-old mice for evaluation of antiviral therapies

et al. 2019

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Enterovirus D68 (EV-D68) is a non-polio enterovirus that affects the respiratory system and can cause serious complications, especially in children and older people with weakened immune systems. As an emerging virus, there are no current antiviral therapies or vaccines available. Our goal was to develop a mouse model of human EV-D68 infection that mimicked the disease observed in humans and could be used for evaluation of experimental therapeutics. This is the first report of a respiratory disease model for EV-D68 infection in mice. We adapted the virus by 30 serial passages in AG129 mice, which are deficient in IFN-α/β and-γ receptors. Despite a lack of weight loss or mortality in mice, lung function measured by plethysmography, showed an increase in enhanced pause (Penh) on days 6 and 7 post-infection. In addition, as virus adapted to mice, virus titer in the lungs increased 320-fold, and the pro-inflammatory cytokines MCP-1 and RANTES increased 15-fold and 2-fold in the lung, respectively. In addition, a time course of mouse-adapted EV-D68 infection was determined in lung, blood, liver, kidney, spleen, leg muscle, spinal cord and brain. Virus in the lung replicated rapidly after intranasal inoculation of adapted virus, 10 6 CCID 50 /mL by 4 hours and 10 8.3 CCID 50 /mL by 24 hours. Virus then spread to the blood and other tissues, including spinal cord and brain. This mouse model for EV-D68 infection includes enhanced pause (Penh) as an indicator of morbidity, and viremia, virus titers and proinflammatory cytokines in the lung, and lung histopathology as indicators of disease. Our mouse-adapted virus has a similar antiviral profile to the original isolate as well as another respiratory picornavirus, rhinovirus-14. This model will be valuable in evaluating experimental therapies in the future.

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Section: Discussionmentioning

confidence: 99%

Development of a respiratory disease model for enterovirus D68 in 4-week-old mice for evaluation of antiviral therapies

et al. 2019

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“…Dosing was performed intranasally using SeV or EV-D68 in 30 ml of PBS or an equivalent amount of UV-inactivated virus (as a control for viral replication) or PBS alone under ketamine/ xylazine anesthesia at 6-9 wk of age for SeV or 4 wk of age for EV-D68. Mouse age for SeV was based on previous work (27)(28)(29)(30) and for EV-D68 was aimed at using younger but still adult mice to potentially increase susceptibility to infection just as was done in other recent reports (51)(52)(53). Our approach thereby enables direct comparison across publications.…”

Section: Virus Preparation and Infectionmentioning

confidence: 99%

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

Zhang

Mao

Keeler

et al. 2019

The Journal of Immunology

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Epithelial barrier cells are proposed to be critical for host defense, and airway epithelial cell capacity for IFN signal transduction is presumed to protect against respiratory viral infection. However, it has been difficult to fully test these concepts given the absence of tools to analyze IFN signaling specific to airway epithelial cells in vivo. To address these issues, we generated a new line of transgenic mice with Cre-driver genes (Foxj1 and Scgb1a1) for a floxed-Stat1 allele (designated Foxj1-Scgb1a1-Cre-Stat1f/f mice) to target the master IFN signal regulator STAT1 in airway epithelial cells and tested these mice for control of infection because of mouse parainfluenza (Sendai) virus and human enterovirus D68 (EV-D68). Indeed, both types of infections showed increases in viral titers and severity of acute illness in Foxj1-Scgb1a1-Cre-Stat1f/f mice and conventional Stat1−/− mice compared with wild-type mice. In concert, the chronic lung disease that develops after Sendai virus infection was also increased in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1–/– mice, marked by airway and adjacent parenchymal immune cell infiltration and mucus production for at least 7 wk postinfection. Unexpectedly, relatively mild EV-D68 infection also progressed to chronic lung disease in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1−/− mice but was limited (like viral replication) to airways. The results thereby provide proof-of-concept for a critical role of barrier epithelial cells in protection from acute illness and chronic disease after viral infection and suggest a specific role for airway epithelial cells given the limitation of EV-D68 replication and acute and chronic manifestations of disease primarily to airway tissue.

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“…However, radiological images of EV-D68-infected patients have identified lesions within the brain stem, specifically the cranial nerve motor nuclei (18, 30–32, 36, 37). In a second model, mice lacking the alpha/beta/gamma interferon (IFN-α/β/γ) response inoculated intraperitoneally or intranasally develop limb paralysis (38, 39), yet evidence of viral replication is absent.…”

Section: Introductionmentioning

confidence: 99%

Neurotropism of Enterovirus D68 Isolates Is Independent of Sialic Acid and Is Not a Recently Acquired Phenotype

Rosenfeld

Warren

Racaniello

2019

mBio

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Since 2014, numerous outbreaks of childhood infections with enterovirus D68 (EV-D68) have occurred worldwide. Most infections are associated with flu-like symptoms, but paralysis may develop in young children. It has been suggested that infection only with recent viral isolates can cause paralysis. To address the hypothesis that EV-D68 has recently acquired neurotropism, murine organotypic brain slice cultures, induced human motor neurons and astrocytes, and mice lacking the alpha/beta interferon receptor were infected with multiple virus isolates. All EV-D68 isolates, from 1962 to the present, can infect neural cells, astrocytes, and neurons. Furthermore, our results show that sialic acid binding does not play a role in EV-D68 neuropathogenesis. The study of EV-D68 infection in organotypic brain slice cultures, induced motor neurons, and astrocytes will allow for the elucidation of the mechanism by which the virus infection causes disease.

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Evaluation of antiviral therapies in respiratory and neurological disease models of Enterovirus D68 infection in mice

Cited by 31 publications

References 53 publications

Development of a respiratory disease model for enterovirus D68 in 4-week-old mice for evaluation of antiviral therapies

Development of a respiratory disease model for enterovirus D68 in 4-week-old mice for evaluation of antiviral therapies

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

Neurotropism of Enterovirus D68 Isolates Is Independent of Sialic Acid and Is Not a Recently Acquired Phenotype

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