Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.

IF 7.1 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2025-01-03 DOI:10.1016/j.jcmgh.2024.101447
Marianne R Spalinger, Golshid Sanati, Pritha Chatterjee, Rong Hai, Jiang Li, Alina N Santos, Tara M Nordgren, Michel L Tremblay, Lars Eckmann, Elaine Hanson, Michael Scharl, Xiwei Wu, Brigid S Boland, Declan F McCole
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Abstract

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.

Methods: 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.

Results: 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.

Conclusion: 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.

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托法替尼减轻PTPN2基因中IBD风险变异引起的SARS-CoV-2感染易感性增加
背景:由SARS-CoV-2引起的冠状病毒病(COVID-19)引发了全球大流行,造成了严重的医疗和社会经济后果。虽然老年人和有潜在合并症的人的死亡率较高,但人们对促进对SARS-CoV-2感染和严重疾病易感性的宿主因素知之甚少。尽管患有某些自身免疫性/炎症性疾病的个体对病毒感染的易感性增加,但对这些疾病中SARS-CoV-2易感性的了解尚不完整。本研究的目的是调查自身免疫风险基因PTPN2是否影响对SARS-CoV-2病毒摄取的易感性,PTPN2也会增加患炎症性肠病(IBD)的风险。方法:利用PTPN2基因型IBD患者、PTPN2缺陷小鼠和人肠道和肺上皮细胞系的样本,研究PTPN2如何影响SARS-CoV-2受体ACE2的表达,以及表达SARS-CoV2刺突蛋白和活SARS-CoV-2病毒样颗粒的摄取。结果:我们报道了自身免疫性PTPN2功能丧失风险变异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进入。ACE2表达升高和病毒进入是由JAK- stat信号传导增加介导的,并被JAK抑制剂托法替尼逆转。总之,我们的研究结果揭示了SARS-CoV-2受体表达增加和病毒进入的一种新的风险生物标志物,并确定了一种临床批准的治疗剂来降低这一风险。
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来源期刊
CiteScore
13.00
自引率
2.80%
发文量
246
审稿时长
42 days
期刊介绍: "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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