A congenital CMV infection model for follow-up studies of neurodevelopmental disorders, neuroimaging abnormalities, and treatment
Yue-Peng Zhou, Meng-Jie Mei, Xian-Zhang Wang, Sheng-Nan Huang, Lin Chen, Ming Zhang, Xin-Yan Li, Hai-Bin Qin, Xiao Dong, Shuang Cheng, Le Wen, Bo Yang, Xue-Fang An, Ao-Di He, Bing Zhang, Wen-Bo Zeng, Xiao-Jun Li, Youming Lu, Hong-Chuang Li, Haidong Li, Wei-Guo Zou, Alec J. Redwood, Simon Rayner, Han Cheng, Michael A. McVoy, Qiyi Tang, William J. Britt, Xin Zhou, Xuan Jiang, Min-Hua Luo
Yue-Peng Zhou, Meng-Jie Mei, Xian-Zhang Wang, Sheng-Nan Huang, Lin Chen, Ming Zhang, Xin-Yan Li, Hai-Bin Qin, Xiao Dong, Shuang Cheng, Le Wen, Bo Yang, Xue-Fang An, Ao-Di He, Bing Zhang, Wen-Bo Zeng, Xiao-Jun Li, Youming Lu, Hong-Chuang Li, Haidong Li, Wei-Guo Zou, Alec J. Redwood, Simon Rayner, Han Cheng, Michael A. McVoy, Qiyi Tang, William J. Britt, Xin Zhou, Xuan Jiang, Min-Hua Luo
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Research Article Infectious disease Virology

A congenital CMV infection model for follow-up studies of neurodevelopmental disorders, neuroimaging abnormalities, and treatment

Abstract

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.

Authors

Yue-Peng Zhou, Meng-Jie Mei, Xian-Zhang Wang, Sheng-Nan Huang, Lin Chen, Ming Zhang, Xin-Yan Li, Hai-Bin Qin, Xiao Dong, Shuang Cheng, Le Wen, Bo Yang, Xue-Fang An, Ao-Di He, Bing Zhang, Wen-Bo Zeng, Xiao-Jun Li, Youming Lu, Hong-Chuang Li, Haidong Li, Wei-Guo Zou, Alec J. Redwood, Simon Rayner, Han Cheng, Michael A. McVoy, Qiyi Tang, William J. Britt, Xin Zhou, Xuan Jiang, Min-Hua Luo

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Figure 2

cMCMV infection induces auditory and behavioral abnormalities.

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cMCMV infection induces auditory and behavioral abnormalities. (A) Audit...
(A) Auditory function. ABR was determined in naive and mock- or MCMV-infected mice at W7–8. Representative audiograms in 10 ms from naive and mock- or MCMV-infected pups tested over a range of frequencies (clicks). ABR thresholds are shown on the right. (B) Short-term learning-memory ability. Short-term learning-memory ability was assessed by fear conditioning test at W12–13, and proportions of freezing time and number of freezing events were recorded. (C) Anxiety-like behavior in EPMT. General anxiety to open spaces was evaluated at W12–13. Representative heatmaps of mouse movement tracks and durations are shown. Time spent in the open arms (indicated by white dashed line), percentage of entries to the open arms versus total counts, and number of rearing events were recorded. (D) Anxiety-like behavior in OFT. OFT was performed to assess anxiety-like behavior to open areas. Representative heatmaps of movement tracks and durations are shown. Total traveled distance, percentage of time traveled in the center, and number of rearing events were measured. (E) Spatial learning-memory. Spatial learning-memory abilities were determined by MWM test during W13–14. All mice were trained in the maze for 6 days and tested on the eighth day. Representative heatmaps of movement tracks and durations are shown. Total time of finding the target platform (indicated as a circle in the heatmap) from day 1 to day 6 and proportions of time in the second quadrant on day 8 were recorded. All data were analyzed by 1-way ANOVA test and results are presented as means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Sample size n for each group is indicated.