Construction and validation of a mouse model for studying severe human adenovirus infections

Dingbin Chen; Yuqian Yan; Ting Mei; Peipei Yang; Siqi Deng; Yiqiang Li; Tie Zhao; Ning Xin; Biyan Duan; Weifeng Liang; Yuemei Yang; Wei Zhao; Donald Seto; Junxian Ou; Qiwei Zhang

doi:10.1016/j.virs.2024.11.001

December 2024

. doi: 10.1016/j.virs.2024.11.001

Citation: Dingbin Chen, Yuqian Yan, Ting Mei, Peipei Yang, Siqi Deng, Yiqiang Li, Tie Zhao, Ning Xin, Biyan Duan, Weifeng Liang, Yuemei Yang, Wei Zhao, Donald Seto, Junxian Ou, Qiwei Zhang. Construction and validation of a mouse model for studying severe human adenovirus infections .VIROLOGICA SINICA, 2024, 39(6) : 963-973. http://dx.doi.org/10.1016/j.virs.2024.11.001

人腺病毒重症感染小鼠模型的构建与验证

Dingbin Chen ^a ,
Yuqian Yan ^b,c ,
Ting Mei ^a ,
Peipei Yang ^a ,
Siqi Deng ^a ,
Yiqiang Li ^a ,
Tie Zhao ^a ,
Ning Xin ^a ,
Biyan Duan ^a ,
Weifeng Liang ^a ,
Yuemei Yang ^d ,
Wei Zhao ^b ,
Donald Seto ^e ,
Junxian Ou ^a,f,g,, ,
Qiwei Zhang ^a,g,,

cstr: 32224.14.j.virs.2024.11.001

a. 暨南大学生命科学技术学院免疫学与微生物学系, 病原微生物研究院, 广州 510632;
b. 南方医科大学公共卫生学院, BSL-3实验室, 广东省热带病研究重点实验室, 广州 510515;
c. 广州医科大学附属广州市妇女儿童医疗中心检验科, 广州 510620;
d. 云南省蒙自市红河州第一人民医院, 云南 661100;
e. 乔治梅森大学系统生物学学院生物信息学与计算生物学组, 美国弗吉尼亚州马纳萨斯 20110;
f 暨南大学附属广东省第二人民医院, 广州 510310;
g 暨南大学病毒致病及防控教育部重点实验室, 广州 510632

通讯作者： Junxian Ou, junxianou1993@jnu.edu.cn; Qiwei Zhang, zhangqw@jnu.edu.cn
收稿日期： 2024-08-03
录用日期： 2024-10-29

摘要

人类腺病毒（HAdVs）是一种高度传染性的病原体，其不同基因型可引起急性呼吸道疾病（ARD），并与死亡相关，尤其是在免疫功能低下的患者、幼儿和新兵中。目前，尚未批准任何针对HAdVs的疫苗或特效药物用于临床。腺病毒的宿主具有严格的物种特异性，这大大限制了针对HAdVs的疫苗和药物的发展。在这项研究中，免疫功能正常的BALB/c小鼠通过尾静脉注射不同剂量的人腺病毒5型（HAdV-5）进行感染。所有注射高剂量HAdV-5（3.2×10¹⁰ TCID₅₀/kg）的小鼠在3至5天内死亡，而接受低剂量HAdV-5（8×10⁹ 或4×10⁹ TCID₅₀/kg）的小鼠存活下来。有趣的是，在注射中等剂量HAdV-5（1.6×10¹⁰⁹ TCID₅₀/kg）的小鼠中，60%（n=3/5）的雄性小鼠死亡，而所有雌性小鼠存活下来。这表明雄性小鼠可能比雌性小鼠更容易感染HAdV-5，这与儿童感染腺病毒的临床发现一致。HAdV-5的DNA主要分布在肝脏，其次是脾脏和肺部。在肺、肝和脾脏中观察到了病理变化，且其严重程度与病毒剂量呈正相关。对肝脏的转录组和qPCR分析表明，雄性小鼠中H2-Aa、H2-Ea-ps、CD74和H2-Eb1基因的表达下调，以及雌性小鼠中AHR基因的表达下调，可能与观察到的雄性小鼠感染腺病毒引起更高的死亡率有关。因此，这种有效、可行且低成本的小鼠模型可以作为HAdV疫苗和抗腺病毒疗法评估的候选模型。
- 人5型腺病毒
- , 动物模型
- , BALB/c小鼠
- , 人腺病毒重症感染

Construction and validation of a mouse model for studying severe human adenovirus infections

Dingbin Chen ^a ,
Yuqian Yan ^b,c ,
Ting Mei ^a ,
Peipei Yang ^a ,
Siqi Deng ^a ,
Yiqiang Li ^a ,
Tie Zhao ^a ,
Ning Xin ^a ,
Biyan Duan ^a ,
Weifeng Liang ^a ,
Yuemei Yang ^d ,
Wei Zhao ^b ,
Donald Seto ^e ,
Junxian Ou ^a,f,g,, ,
Qiwei Zhang ^a,g,,

a. Institute of Medical Microbiology, Department of Immunology and Microbiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China;
b. BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China;
c. Department of Clinical Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510620, China;
d. South Yunnan Central Hospital (Honghe First People's Hospital), Mengzi, Yunnan, 661100, China;
e. Bioinformatics and Computational Biology Program, School of Systems Biology, George Mason University, Manassas, VA, 20110, USA;
f. The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510310, China;
g. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China

Corresponding author: Junxian Ou, junxianou1993@jnu.edu.cn Qiwei Zhang, zhangqw@jnu.edu.cn
Received Date: 03 August 2024
Accepted Date: 29 October 2024

Abstract

Human adenoviruses (HAdVs) are highly contagious pathogens with various genotypes implicated in acute respiratory disease (ARD) and linked to fatality, especially in immunosuppressed patients, young children, and military recruits. Currently, no vaccines or specific drugs are approved for clinical use. The hosts of adenoviruses are strictly species-specific, which strongly limits the development of vaccines and drugs against HAdVs. In this study, immunocompetent BALB/c mice were challenged with different doses of human adenovirus type 5 (HAdV-5) via tail intravenous injection (i.v.). All mice challenged with a high dose of HAdV-5 (3.2 × 10¹⁰ TCID₅₀/kg) died within 3–5 days, while those receiving a low dose of HAdV-5 (8 × 10⁹ or 4 × 10⁹ TCID₅₀/kg) survived. Interestingly, among the mice receiving a medium dose of HAdV-5 (1.6 × 10¹⁰ TCID₅₀/kg), 60% (n = 3/5) of male mice died, while all female mice survived. This suggests that male mice may be more susceptible to HAdV-5 infection than female mice, consistent with clinical findings in children. HAdV-5 DNA was mainly distributed in the liver, followed by the spleen and lung. Pathological changes were observed in the lung, liver, and spleen, with severity increasing in correlation with the virus challenge dosage. Transcriptome and qPCR analyses of the liver indicated that the down-regulated expression of the H2-Aa, H2-Ea-ps, CD74, and H2-Eb1 genes in male mice, as well as the AHR gene in female mice, may contribute to the observed higher mortality rates in male mice. Therefore, this effective, feasible, and cost-efficient mouse model could serve as a candidate for evaluating HAdV vaccines and anti-adenovirus therapeutics.
- Human adenovirus type 5 (HAdV-5)
- , Animal model
- , BALB/c mice
- , Severe human adenovirus infections

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