55型人腺病毒致hDSG2转基因小鼠肺感染动物模型的建立及意义

周恩禄; 孙军平; 张明月; 韩欣洁; 王浚宇; 汪建新

doi:10.12435/j.issn.2095-5227.2023.005

55型人腺病毒致hDSG2转基因小鼠肺感染动物模型的建立及意义

Establishment and significance of hDSG2 transgenic mice lung infection model induced by human adenovirus type 55

摘要

摘要:
背景 55型人腺病毒(human adenovirus type 55，HAdV-B55)可引起呼吸道感染，严重者可发展为病毒性肺炎甚至危及生命。理想的HAdV-B55感染模型对发病机制、药物治疗以及多价疫苗的研制有重要价值。
目的建立HAdV-B55人源化受体桥粒芯糖蛋白2(humanized receptor desmoglein-2，hDSG2)转基因小鼠肺感染动物模型。
方法雄性hDSG2转基因小鼠、野生型C57BL/6(C57)小鼠各25只，按感染后3 d、5 d、7 d、14 d和PBS对照随机分为5组，每组5只，感染小鼠用HAdV-B55(10⁸ TCID50)滴鼻进行感染，对照组用相同剂量的PBS滴鼻，每日称重并观察小鼠活动情况，分别于感染后3 d、5 d、7 d、14 d取材，对照组滴鼻后14 d取材。测定各组的肺系数、肺组织病理、肺组织内HAdV-B55基因拷贝量、白细胞介素-6(interleukin-6，IL-6)和γ干扰素表达水平以及血清中IL-6浓度水平。
结果 hDSG2转基因小鼠感染HAdV-B55病毒后一般状况较C57小鼠恢复慢，体质量增长较慢(P＜0.01)，且表现出活动减少、蜷缩抱团等急性感染症状；hDSG2转基因小鼠的肺组织病理表现较C57小鼠重，主要为肺泡壁增厚和炎性细胞浸润，同时肺系数增高显著(P＜0.05)，肺组织内HAdV-B55基因拷贝量显著增多(P＜0.05)，肺组织内IL-6表达水平(P＜0.05)与血清中IL-6浓度显著升高(P＜0.01)。
结论采用经鼻滴入HAdV-B55方法，可以建立hDSG2转基因小鼠肺感染的动物模型，该模型稳定性和持续致病性较好，具有进一步深入研究的价值。

Abstract:
Background Human adenovirus type 55 (HAdV-B55) can cause respiratory tract infection, which may evolve into viral pneumonia and even life-threatening in severe cases. An appropriate model of HAdV-B55 infection would be of great importance for exploring the pathogenesis and the development of drug therapies and multivalent vaccines.
Objective To establish an animal model of humanized receptor desmoglein-2 (hDSG2) transgenic mouse with pulmonary infection of HAdV-B55.
Methods Totally 25 male hDSG2 transgenic mice and 25 male wild-type C57BL/6 (C57) mice were randomly divided into five groups (5 mice in each group), including 3, 5, 7, 14 days after infection groups and PBS control group. Mice in the infection groups were infected with HAdV-B55 (10⁸ TCID50) by nasal instillation. Mice in the control group were treated with PBS at the same dose by nasal instillation. Animals were weighed daily and their activities were observed. Samples were separately taken on 3, 5, 7 and 14 days after infection, and mice in the control group were killed at 14 days after nasal instillation. Lung coefficient, lung tissue pathology, copy number of HAdV-B55 gene in lung tissues, expression levels of IL-6 and IFN-γ, and sera concentration of IL-6 were detected for each group.
Results After infection with HAdV-B55, the hDSG2 transgenic mice recovered slowly and gained weight more slowly than C57 mice (P<0.01), and they developed the symptoms of acute infection such as reduced activity, hunching and huddling. The pathological manifestations in lung tissues of hDSG2 transgenic mice were more severe than those in lung tissues of C57 mice, which included alveolar wall thickening and inflammatory cell infiltration, along with significantly increased lung coefficient (P<0.05), significantly increased copy number of HAdV-B55 gene in lung tissues (P<0.05), and significantly increased expression of IL-6 in lung tissues (P<0.05) and serum IL-6 concentrations (P<0.01).
Conclusion An animal model of hDSG2 transgenic mice lung infection is established by using nasal instillation of HAdV-B55. The model features with high stability and persistent pathogenicity, which is useful for further scientific research.

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