Human Cytomegalovirus-IE2 Affects Embryonic Liver Development and Survival in Transgenic Mouse

Zhang, Xianjuan; Jiang, Shasha; Zhou, Xiaoqiong; Yu, Zhongjie; Han, Shuo; Nan, Fulong; Qiao, Hongye; Niu, Delei; Wang, Zhifei; Niu, Junyun; Zhang, Hong; Liu, Ting; Wang, Yunyang; Wang, Bin

doi:10.1016/j.jcmgh.2022.05.002

Cited by 8 publications

(8 citation statements)

References 36 publications

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“…Albeit, our previous study demonstrated that the presence of HCMV-IE2 can affect the animals’ spatial memory and learning ability in adult mice [ 22 ], which suggests that HCMV-IE2 damage to the nervous system persists. In addition, in another model that IE2 is continuously expressed in liver tissue, we first observed that all IE2-expressing mice died in the late embryonic stage, and secondly, the weight of the liver of the IE2-expressing mice was significantly reduced as compared with the control mice [ 21 ]. Based on these findings, we speculated that newborn microcephaly was produced by long-term steady expression of HCMV-IE2 in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…The Cas9 mRNA, gRNA, and donor vector were microinjected into the single-cell embryos of C57BL/6J mice to obtain F0 generation mice. The positive F0 generation mice identified by PCR amplification and sequencing were breed with C57BL/6J mice to obtain F1 generation mice (Rosa26-LSL-IE2 +/− ) [ 21 ]. Rosa26-LSL-IE2 +/− , Camk2α-Cre mice were generated by crossing Camk2α-Cre mice with F1 mice (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Human Cytomegalovirus IE2 Disrupts Neural Progenitor Development and Induces Microcephaly in Transgenic Mouse

Niu

Zhang

et al. 2023

Mol Neurobiol

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Human cytomegalovirus (HCMV) is a significant contributor to congenital birth defects. Limited by the lack of animal models, the pathogenesis of neurological damage in vivo caused by HCMV infection and the role of individual viral genes remain to be elucidated. Immediate early (IE2) protein may play a function in neurodevelopmental problems caused by HCMV infection. Here, this study intended to investigate IE2’s long-term effects on development of the brain in IE2-expressing transgenic mice (Rosa26-LSL-IE2+/−, Camk2α-Cre) aimed to observe the phenotype of postnatal mice. The expression of IE2 in transgenic mice was confirmed by PCR and Western blot technology. We collected mouse brain tissue at 2, 4, 6, 8, and 10 days postpartum to analyze the developmental process of neural stem cells by immunofluorescence. We discovered that transgenic mice (Rosa26-LSL-IE2+/−, Camk2α-Cre) can reliably produce IE2 in the brain at various postpartum phases. Furthermore, we also observed the symptoms of microcephaly in postnatal transgenic mice, and IE2 can damage the amount of neural stem cells, prevent them from proliferating and differentiating, and activate microglia and astrocytes, creating an unbalanced environment in the brain’s neurons. In conclusion, we demonstrate that long-term expression of HCMV-IE2 can cause microcephaly through molecular mechanisms affecting the differentiation and development of neural stem cells in vivo. This work establishes a theoretical and experimental foundation for elucidating the molecular mechanism of fetal microcephaly brought by HCMV infection in throughout the period of neural development of pregnancy. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Human Cytomegalovirus IE2 Disrupts Neural Progenitor Development and Induces Microcephaly in Transgenic Mouse

Niu

Zhang

et al. 2023

Mol Neurobiol

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“…Following morning, sections were incubated with the secondary antibodies in the incubator 40 min. After washed with distilled water and PBS, then sections were exposed to DAB, 1 min; and hematoxylin, 1 min; differentiate solution, 1 s; and observed after the neutral gum seal 50 .…”

Section: Methodsmentioning

confidence: 99%

Gut microbiota induces hepatic steatosis by modulating the T cells balance in high fructose diet mice

Zhou

Zhang

Niu

et al. 2023

Sci Rep

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Metabolic diseases are often associated with high fructose (HF) consumption. HF has also been found to alter the gut microbiota, which then favors the development of nonalcoholic fatty liver disease. However, the mechanisms underlying of the gut microbiota on this metabolic disturbance are yet to be determined. Thus, in this study, we further explored the effect the gut microbiota concerning the T cells balance in an HF diet mouse model. We fed mice 60% fructose-enriched diet for 12 weeks. At 4 weeks, HF diet did not affect the liver, but it caused injury to the intestine and adipose tissues. After 12 weeks, the lipid droplet aggregation was markedly increased in the liver of HF-fed mice. Further analysis of the gut microbial composition showed that HF decreased the Bacteroidetes/Firmicutes ratio and increased the levels of Blautia, Lachnoclostridium, and Oscillibacter. In addition, HF can increase the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in the serum. T helper type 1 cells were significantly increased, and regulatory T(Treg) cells were markedly decreased in the mesenteric lymph nodes of the HF-fed mice. Furthermore, fecal microbiota transplantation alleviates systemic metabolic disorder by maintaining liver and intestinal immune homeostasis. Overall, our data indicated that intestinal structure injury and intestinal inflammation might be early, and liver inflammation and hepatic steatosis may be a subsequent effect following HF diets. Gut microbiota disorders impairing the intestinal barrier function and triggering immune homeostasis imbalance may be an importantly responsible for long-term HF diets induced hepatic steatosis.

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“…Immunohistochemistry procedures were performed as what a former report depicted with minor modifications ( Zhang et al., 2022 ). Briefly, after deparaffinization and rehydration, the lung sections were immersed in 1× sodium citrate buffer at 98°C for 15 min to repair antigen, then treated with 3% hydrogen peroxide for 10 min at room temperature to inactivate endogenous peroxidase.…”

Section: Methodsmentioning

confidence: 99%

Pyroptosis, apoptosis, and autophagy are involved in infection induced by two clinical Klebsiella pneumoniae isolates with different virulence

Wang

Xin

et al. 2023

Front. Cell. Infect. Microbiol.

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Klebsiella pneumoniae can cause widespread infections and is an important factor of hospital- and community-acquired pneumonia. The emergence of hypervirulent K. pneumoniae poses a serious clinical therapeutic challenge and is associated with a high mortality. The goal of this work was to investigate the influence of K. pneumoniae infection on host cells, particularly pyroptosis, apoptosis, and autophagy in the context of host–pathogen interactions to better understand the pathogenic mechanism of K. pneumoniae. Two clinical K. pneumoniae isolates, one classical K. pneumoniae isolate and one hypervirulent K. pneumoniae isolate, were used to infect RAW264.7 cells to establish an in vitro infection model. We first examined the phagocytosis of macrophages infected with K. pneumoniae. Lactate dehydrogenase (LDH) release test, and calcein-AM/PI double staining was conducted to determine the viability of macrophages. The inflammatory response was evaluated by measuring the pro-inflammatory cytokines and reactive oxygen species (ROS) production. The occurrence of pyroptosis, apoptosis, and autophagy was assessed by detecting the mRNA and protein levels of the corresponding biochemical markers. In addition, mouse pneumonia models were constructed by intratracheal instillation of K. pneumoniae for in vivo validation experiments. As for results, hypervirulent K. pneumoniae was much more resistant to macrophage-mediated phagocytosis but caused more severe cellular damage and lung tissues damage compared with classical K. pneumoniae. Moreover, we found increased expression of NLRP3, ASC, caspase-1, and GSDMD associated with pyroptosis in macrophages and lung tissues, and the levels were much higher following hypervirulent K. pneumoniae challenge. Both strains induced apoptosis in vitro and in vivo; the higher apoptosis proportion was observed in infection caused by hypervirulent K. pneumoniae. Furthermore, classical K. pneumoniae strongly triggered autophagy, while hypervirulent K. pneumoniae weakly activated this process. These findings provide novel insights into the pathogenesis of K. pneumoniae and may form the foundation for the future design of treatments for K. pneumoniae infection.

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Human Cytomegalovirus-IE2 Affects Embryonic Liver Development and Survival in Transgenic Mouse

Cited by 8 publications

References 36 publications

Human Cytomegalovirus IE2 Disrupts Neural Progenitor Development and Induces Microcephaly in Transgenic Mouse

Human Cytomegalovirus IE2 Disrupts Neural Progenitor Development and Induces Microcephaly in Transgenic Mouse

Gut microbiota induces hepatic steatosis by modulating the T cells balance in high fructose diet mice

Pyroptosis, apoptosis, and autophagy are involved in infection induced by two clinical Klebsiella pneumoniae isolates with different virulence

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