Chen Shiqi, Zhang Yi, Ashuo Asha, Song Shu, Yuan Lunzhi, Wang Weixia, Wang Cong, Du Zunguo, Wu Yangtao, Tan Dan, Huang Chenlu, Chen Jingna, Li Yaming, Bai Jinjin, Guo Huilin, Huang Zehong, Guan Yi, Xia Ningshao, Yuan Zhenghong, Zhang Jiming, Yuan Quan, Fang Zhong
Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China.
EBioMedicine. 2025 Jan;111:105517. doi: 10.1016/j.ebiom.2024.105517. Epub 2024 Dec 21.
Liver involvement is a common complication of coronavirus disease 2019 (COVID-19), especially in hospitalized patients. However, the underlying mechanisms involved are not fully understood.
Immunohistochemistry (IHC) staining of SARS-CoV-2 spike (S) and nucleocapsid (N) proteins was conducted on liver tissues from six patients with COVID-19. The 10x Genomics Visium CytAssist Spatial Gene Assay was designed to analyze liver transcriptomics. TCR CDR3 sequences were analyzed in DNA from liver tissues. Liver function indicators were retrospectively studied in 650 hospitalized patients with COVID-19.
SARS-CoV-2 proteins were initially detected in the livers of naturally infected golden (Syrian) hamsters, prompting us to investigate the situation in clinical cases. Thus, we collected liver tissues from patients with abnormal liver biochemical values. Viral S and N proteins were detected in the livers of severe and deceased patients but not in those of moderate patients. We further demonstrated that hepatocytes and erythroid cells in hepatic sinusoids are major cells targeted by SARS-CoV-2. Immune cells, especially T cells, were enriched in surviving severe patients, characterized by enhanced CDR3α clonality and novel CDR3β recombination of the T-cell receptor. In contrast, hepatocyte apoptosis was triggered, and the transcription of albumin (ALB) was obviously impaired in the deceased patients. We then performed a retrospective study including patients with COVID-19. Serum aspartate aminotransferase (AST) and ALB levels at baseline significantly differed in the deceased cohort. However, AST regression did not decrease the risk of death. ALB recovery indicated clinical improvement, and declining or low serum ALB concentrations were associated with death.
This study provides clinical evidence for liver infection with SARS-CoV-2, insight into the impact of SARS-CoV-2 on the liver, and a potential way to evaluate the risk of death via assessing serum ALB concentration fluctuations in patients with COVID-19.
National Key R&D Program of China (2021YFC2300602), National Natural Science Foundation of China (92369110), National Natural Science Foundation of China (U23A20474), Shanghai Municipal Science and Technology Major Project (ZD2021CY001), Shanghai Jinshan District Medical and Health Technology Innovation Fund Project (2023-WS-31).
肝脏受累是2019冠状病毒病（COVID-19）的常见并发症，尤其是在住院患者中。然而，其潜在机制尚未完全明确。
对6例COVID-19患者的肝脏组织进行严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突（S）蛋白和核衣壳（N）蛋白的免疫组织化学（IHC）染色。采用10x基因组学Visium CytAssist空间基因检测法分析肝脏转录组学。对肝脏组织DNA中的T细胞受体（TCR）互补决定区3（CDR3）序列进行分析。对650例住院COVID-19患者的肝功能指标进行回顾性研究。
最初在自然感染的金黄地鼠（叙利亚仓鼠）肝脏中检测到SARS-CoV-2蛋白，这促使我们研究临床病例中的情况。因此，我们收集了肝生化值异常患者的肝脏组织。在重症和死亡患者的肝脏中检测到病毒S蛋白和N蛋白，而中度患者肝脏中未检测到。我们进一步证明，肝血窦中的肝细胞和红细胞是SARS-CoV-2的主要靶细胞。免疫细胞，尤其是T细胞，在存活的重症患者中富集，其特征为T细胞受体的CDR3α克隆性增强和新的CDR3β重组。相比之下，死亡患者肝细胞发生凋亡，白蛋白（ALB）转录明显受损。然后我们进行了一项纳入COVID-19患者的回顾性研究。死亡队列患者基线时血清天冬氨酸转氨酶（AST）和ALB水平存在显著差异。然而，AST水平下降并未降低死亡风险。ALB恢复表明临床改善，血清ALB浓度下降或降低与死亡相关。
本研究为SARS-CoV-2肝脏感染提供了临床证据，深入了解了SARS-CoV-2对肝脏的影响，并提供了一种通过评估COVID-19患者血清ALB浓度波动来评估死亡风险的潜在方法。
国家重点研发计划（2021YFC2300602）、国家自然科学基金（92369110）、国家自然科学基金（U23A20474）、上海市科技重大专项（ZD2021CY001）、上海市金山区医疗卫生科技创新基金项目（2023-WS-31）。
