Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-07-26 DOI:10.1038/s44319-024-00216-4

Anna Macht, Yiqi Huang, Line S Reinert, Vincent Grass, Kristin Lohmer, Elke Tatjana Aristizabal Prada, Eveline Babel, Alexandra Semmler, Wen Zhang, Andrea Wegner, Eva Lichtenegger-Hartl, Sonja Haas, Günther Hasenpusch, Steffen Meyer, Søren R Paludan, Andreas Pichlmair, Carsten Rudolph, Thomas Langenickel

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引用次数: 0

Abstract

RNA vaccines elicit protective immunity against SARS-CoV-2, but the use of mRNA as an antiviral immunotherapeutic is unexplored. Here, we investigate the activity of lipidoid nanoparticle (LNP)-formulated mRNA encoding human IFNλ1 (ETH47), which is a critical driver of innate immunity at mucosal surfaces protecting from viral infections. IFNλ1 mRNA administration promotes dose-dependent protein translation, induction of interferon-stimulated genes without relevant signs of unspecific immune stimulation, and dose-dependent inhibition of SARS-CoV-2 replication in vitro. Pulmonary administration of IFNλ1 mRNA in mice results in a potent reduction of virus load, virus-induced body weight loss and significantly increased survival. These data support the development of inhaled administration of IFNλ1 mRNA as a potential prophylactic option for individuals exposed to SARS-CoV-2 or at risk suffering from COVID-19. Based on the broad antiviral activity of IFNλ1 regardless of virus or variant, this approach might also be utilized for other respiratory viral infections or pandemic preparedness.

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基于粘膜 IFNλ1 mRNA 的免疫调节可有效降低 SARS-CoV-2 诱导的小鼠死亡率。

RNA 疫苗可引起对 SARS-CoV-2 的保护性免疫，但将 mRNA 用作抗病毒免疫疗法的研究尚属空白。在这里，我们研究了类脂纳米粒子（LNP）制备的编码人类 IFNλ1 (ETH47) 的 mRNA 的活性。IFNλ1 mRNA 的给药促进了剂量依赖性蛋白翻译，诱导了干扰素刺激基因，而没有相关的非特异性免疫刺激迹象，并在体外对 SARS-CoV-2 的复制产生了剂量依赖性抑制作用。通过肺部给小鼠注射 IFNλ1 mRNA 可有效减少病毒载量，减轻病毒引起的体重下降，并显著提高存活率。这些数据支持开发吸入给药 IFNλ1 mRNA，作为暴露于 SARS-CoV-2 或面临 COVID-19 风险的个体的潜在预防选择。基于 IFNλ1 广泛的抗病毒活性，无论病毒或变种如何，这种方法也可用于其他呼吸道病毒感染或大流行的防备。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.