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 11

GCV treatment and neurological functions.

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GCV treatment and neurological functions. (A) GCV treatment and hearing ...
(A) GCV treatment and hearing ability. Hearing ability was determined by ABR test on mice in 4 groups (naive, mock, MCMV, and MCMV+GCV). Examples of 10 ms audiograms of mice from each group over a range of frequencies (clicks) are shown. ABR thresholds were recorded and analyzed by 1-way ANOVA. (B) GCV treatment and short-term learning-memory ability. Short-term learning-memory was assessed by fear conditioning test. Proportion of freezing time and number of freezing events were recorded. Data were analyzed by 1-way ANOVA. (C) GCV treatment and anxiety-like behavior in EPMT. The general anxiety to open spaces was evaluated by the EPMT. 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 of mice were recorded. Data were analyzed by 1-way ANOVA. (D) GCV treatment and anxiety-like behavior in OFT. OFT was performed to assess anxiety-like behavior to open area. 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. Data were analyzed by 1-way ANOVA. (E) GCV treatment and spatial learning-memory. Spatial learning-memory abilities were determined by MWM test. 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 from day 1 to day 6 and the percentages of time in second quadrant on day 8 were recorded. Data were analyzed by 1-way ANOVA at each time point. For all statistical tests, results are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.