Spalinger Marianne R, Sanati Golshid, Chatterjee Pritha, Hai Rong, Li Jiang, Santos Alina N, Nordgren Tara M, Tremblay Michel L, Eckmann Lars, Hanson Elaine, Scharl Michael, Wu Xiwei, Boland Brigid S, McCole Declan F
Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California; Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.
Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California.
Cell Mol Gastroenterol Hepatol. 2025;19(5):101447. doi: 10.1016/j.jcmgh.2024.101447. Epub 2025 Jan 3.
BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake.
Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus.
We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib.
Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的冠状病毒病（COVID-19）引发了一场全球大流行，带来了严重的医学和社会经济后果。尽管老年人和有基础合并症的人死亡率更高，但促进对SARS-CoV-2感染和严重疾病易感性的宿主因素仍知之甚少。虽然患有某些自身免疫/炎症性疾病的个体对病毒感染的易感性增加，但对于这些疾病中SARS-CoV-2的易感性了解并不完整。我们研究的目的是调查自身免疫风险基因PTPN2（该基因也会增加患炎症性肠病的风险）是否会影响对SARS-CoV-2病毒摄取的易感性。
我们使用来自已进行PTPN2基因分型的炎症性肠病患者的样本、PTPN2缺陷小鼠以及人肠道和肺上皮细胞系，研究PTPN2如何影响SARS-CoV-2受体血管紧张素转换酶2（ACE2）的表达，以及表达SARS-CoV-2刺突蛋白的病毒样颗粒和活SARS-CoV-2病毒的摄取。
我们报告，自身免疫性PTPN2功能丧失风险变体rs1893217促进SARS-CoV-2受体ACE2的表达，并增加SARS-CoV-2刺突蛋白和活病毒的细胞内进入。ACE2表达升高和病毒进入是由Janus激酶-信号转导子和转录激活子信号增加介导的，并且被Janus激酶抑制剂托法替布逆转。
总的来说，我们的研究结果揭示了一种新的SARS-CoV-2受体表达增加和病毒进入的风险生物标志物，并确定了一种临床批准的治疗药物来减轻这种风险。
