Notch4调节性T细胞和SARS-CoV-2病毒血症决定了COVID19的存活结果。

IF 12.6 1区 医学 Q1 ALLERGY Allergy Pub Date : 2024-10-03 DOI:10.1111/all.16333
Mehdi Benamar, Peggy S Lai, Ching-Ying Huang, Qian Chen, Fatma Betul Oktelik, Paola Contini, Muyun Wang, Daniel Okin, Elena Crestani, Jason Fong, Tsz Man Chan Fion, Merve Nida Gokbak, Hani Harb, Wanda Phipatanakul, Luca Marri, Chiara Vassallo, Andrea Guastalla, Minsik Kim, Hui-Yu Sui, Lorenzo Berra, Marcia B Goldberg, Claudia Angelini, Raffaele De Palma, Talal A Chatila
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引用次数: 0

摘要

背景:免疫失调和SARS-CoV-2血浆病毒血症与致命的COVID-19疾病有关。然而,这两个因素是如何相互作用形成疾病结果的还不清楚:我们对 2020 年 6 月 1 日至 2022 年 2 月 8 日期间在马萨诸塞州波士顿和意大利热那亚的急诊医院就诊的 280 名 COVID-19 患者的前瞻性队列进行了病毒和免疫表型分析。对疾病严重程度、死亡率、血浆病毒血症和免疫失调进行了评估。利用致死性甲型 H1N1 流感小鼠感染模型分析了 Notch4 和热蛋白抑制在疾病结局中的治疗潜力:结果:根据Notch4+ Treg细胞百分比和/或血浆病毒血症的存在对患者进行分层,发现了四个具有不同临床轨迹和免疫表型的亚组。与其他组别相比,同时具有高Notch4+ Treg细胞%和病毒血症的患者病情最严重,90天死亡率最高,即使在调整了基线合并症后也是如此。Notch4和血浆病毒血症的增加影响了SARS-CoV-2感染中免疫反应的不同环节。Notch4的增加与Treg细胞两性胰岛素表达和抑制功能的降低有关,而血浆病毒血症则与单核细胞热解增加有关。在小鼠致死性甲型 H1N1 流感感染模型中,使用 Notch4 阻断和热蛋白沉积抑制的组合疗法可逐步降低死亡率:结论:COVID-19住院患者的临床轨迹和生存结果取决于疾病发病机制中的两个主要因素:病毒血症和Notch4+ Treg细胞。通过拮抗Notch4和嗜热细胞,重置COVID-19免疫失调的干预策略可能对严重的病毒性肺部感染有效。
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Notch4 regulatory T cells and SARS-CoV-2 viremia shape COVID19 survival outcome.

Background: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear.

Methods: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome.

Results: Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection.

Conclusions: The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.

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来源期刊
Allergy
Allergy 医学-过敏
CiteScore
26.10
自引率
9.70%
发文量
393
审稿时长
2 months
期刊介绍: Allergy is an international and multidisciplinary journal that aims to advance, impact, and communicate all aspects of the discipline of Allergy/Immunology. It publishes original articles, reviews, position papers, guidelines, editorials, news and commentaries, letters to the editors, and correspondences. The journal accepts articles based on their scientific merit and quality. Allergy seeks to maintain contact between basic and clinical Allergy/Immunology and encourages contributions from contributors and readers from all countries. In addition to its publication, Allergy also provides abstracting and indexing information. Some of the databases that include Allergy abstracts are Abstracts on Hygiene & Communicable Disease, Academic Search Alumni Edition, AgBiotech News & Information, AGRICOLA Database, Biological Abstracts, PubMed Dietary Supplement Subset, and Global Health, among others.
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