The Role of IFI35 in Innate Immunity and Influenza Pathogenesis

IFI35 在先天免疫和流感发病机制中的作用

• 批准号: 9913449
• 负责人: Adrianus CM Boon
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-10 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913449
• 关键词: Affect; Agonist; Binding Proteins; Biological Models; Bone Marrow; CSF3 gene; Cell Nucleus; Cells; Cessation of life; Chemotactic Factors; Chimera organism; Data; Dendritic Cells; Development; Disease; Disease Outcome; Follow-Up Studies; Genes; Genetic Polymorphism; Hematopoietic; Human; Immune; Immune response; Immune signaling; Immunologics; Immunotherapy; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Innate Immune Response; Integration Host Factors; Interferons; Kinetics; Knockout Mice; Life; Link; Lung; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; NOS2A gene; Natural Immunity; Nitric Oxide; Pathogenesis; Pathogenicity; Predisposition; Production; Proteins; Recombinants; Reporter; Role; Shapes; Structure of parenchyma of lung; TLR3 gene; Testing; Tissues; Viral; Virus; Virus Diseases; Wild Type Mouse; adaptive immune response; chemokine; congenic; cytokine; design; gene function; human pathogen; immunopathology; in vivo; inflammatory milieu; influenzavirus; innovation; insight; lung injury; macrophage; microbial disease; novel; prevent; protein expression; recruit; response; therapeutic development; trafficking; transcription factor

PROJECT SUMMARY Influenza virus is an important human pathogen that can cause severe disease and death in humans. Highly pathogenic influenza viruses, such as H5N1, induce excessive host responses associated with pro- inflammatory cytokine production, recruitment of innate immune cells and a diminished adaptive immune response. The host proteins involved in this pathogenic response are largely unknown. This information is important and will provide a framework for the rational design of new treatments against pathogenic influenza infection. We have previously identified interferon induced protein 35 (IFI35) as a host gene associated with susceptibility to highly pathogenic H5N1 influenza A virus (2, 3). We now present data showing a direct link between murine IFI35 and exacerbation of influenza-virus induced disease. IFI35 knockout mice infected with the highly pathogenic H5N1 influenza virus recovered more rapidly compared to congenic wild type mice, producing less pro-inflammatory cytokines, such as IL12p40, G-CSF and KC. Correspondingly, bone marrow macrophages derived from IFI35 knockout mice produced significantly less IL12p40 following stimulation with a TLR3 agonist. The IL12p40 is produced as a homodimer (IL12p402) which is a chemo attractant and pre- inflammatory cytokine. In summary, IFI35 appears to be a key regulator of the inflammatory response following viral infection. This proposal is aimed at characterizing how IFI35 protein modulates IL12p40 and IL12p402 production after influenza virus infection and investigating mechanistically how IFI35 shapes the inflammatory environment and disease outcome.

项目概要 流感病毒是一种重要的人类病原体，可导致人类严重疾病和死亡。 致病性流感病毒，例如 H5N1，会诱导与亲流感相关的过度宿主反应。 炎症细胞因子的产生、先天免疫细胞的募集和适应性免疫系统的减弱 参与这种致病反应的宿主蛋白在很大程度上是未知的。 很重要，将为合理设计针对致病性流感的新疗法提供框架 感染。 我们之前已经鉴定出干扰素诱导蛋白 35 (IFI35) 作为与 对高致病性 H5N1 甲型流感病毒的易感性 (2, 3) 我们现在提供的数据显示了直接联系。 小鼠 IFI35 与流感病毒感染的 IFI35 敲除小鼠的疾病恶化之间的关系。 与同源野生型小鼠相比，高致病性 H5N1 流感病毒恢复得更快， 产生较少的促炎细胞因子，例如 IL12p40、G-CSF 和相应的 KC。 来自 IFI35 敲除小鼠的巨噬细胞在用 TLR3 激动剂以同型二聚体 (IL12p402) 形式产生，它是一种化学引诱剂和前体。 炎症细胞因子。​总而言之，IFI35 似乎是炎症反应的关键调节因子 该提案旨在描述 IFI35 蛋白如何调节 IL12p40 和 IL12p402。 流感病毒感染后的产生并从机制上研究 IFI35 如何塑造炎症 环境和疾病结果。

项目成果

A potently neutralizing SARS-CoV-2 antibody inhibits variants of concern by utilizing unique binding residues in a highly conserved epitope.

• DOI: 10.1016/j.immuni.2021.08.016
• 发表时间: 2021-10-12
• 期刊: Immunity
• 影响因子: 32.4
• 作者: VanBlargan LA;Adams LJ;Liu Z;Chen RE;Gilchuk P;Raju S;Smith BK;Zhao H;Case JB;Winkler ES;Whitener BM;Droit L;Aziati ID;Bricker TL;Joshi A;Shi PY;Creanga A;Pegu A;Handley SA;Wang D;Boon ACM;Crowe JE Jr;Whelan SPJ;Fremont DH;Diamond MS
• 通讯作者: Diamond MS

Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection.

• DOI: 10.1084/jem.20180118
• 发表时间: 2018-04-02
• 期刊: The Journal of experimental medicine
• 作者: Nair S;Huynh JP;Lampropoulou V;Loginicheva E;Esaulova E;Gounder AP;Boon ACM;Schwarzkopf EA;Bradstreet TR;Edelson BT;Artyomov MN;Stallings CL;Diamond MS
• 通讯作者: Diamond MS