Understanding evasion of cell intrinsic innate immunity in viral populations with high rates of replicative failure

了解复制失败率高的病毒群体中细胞内在先天免疫的逃避

• 批准号: 10667630
• 负责人: Alistair B Russell
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667630
• 关键词: Address; Cells; Cessation of life; Data; Defect; Detection; Disease; Evolution; Failure; Genomic Segment; Human; Immune; Individual; Influenza; Influenza A virus; Interferons; Life Cycle Stages; Ligands; Modeling; Molecular Virology; Natural Immunity; Oncolytic; Pathology; Pathway interactions; Polymerase; Population; Production; Property; Rest; Route; Signaling Protein; Structure; Therapeutic; Variant; Viral; Virion; Virus; Virus Diseases; acute infection; antagonist; high risk; improved; insight; member; mutation screening; new therapeutic target; novel therapeutics; particle; pathogen; pathogenic virus; pressure; respiratory infection virus; response; success; vaccine candidate; viral detection

Cell intrinsic innate immunity is a barrier that all viral pathogens must overcome or otherwise subvert in order to successfully complete their infectious lifecycle. Collectively, these pathways detect non-self or danger associated molecules, and, in response, produce signaling proteins called interferons that induce both local and systemic anti-pathogen responses. These responses ultimately drive the clearance of most acute infections, although they also lead to much of the observed pathology. Most, if not all, viral pathogens encode antagonists of these pathways; frequently at the level of interferon production. One such pathogen, human influenza A virus, is so successful that only around 0.5% of infected cells successfully detect viral infection at early timepoints. Nevertheless, that small fraction of responders is crucial to the course of disease—individuals with defects in interferon pathways are often at extremely high risk of complications or death following infection by respiratory viruses, including influenza. Paradoxically, while most viral populations maintain stringent suppression of host detection, they replicate with relatively low fidelity. For influenza, only about 10% of viral particles can successfully complete the viral lifecycle. The rest of the particles are capable of entering cells and exposing potential innate immune ligands, but nevertheless fail at some step to produce infectious progeny. Regardless, the vast majority of virions, even those which cannot complete the viral lifecycle, still go undetected. What mechanisms, then, allow viral populations to remain undetected by host cells despite failing so frequently at replication? As a starting point to this ambitious line of inquiry, we are focusing on several discrete mechanisms in influenza A virus for which we already possess either preliminary data or the capacity to readily procure such data: 1) How the structure of the segmented genome of influenza A virus influences the range of potential immunostimulatory failure 2) How the multifunctionality of influenza’s predominant innate immune antagonist, NS1, influences rates of viral detection, and 3) How polymerase error rate may be subject to innate immune pressure. To address these questions my group will use a combination of variant analysis, deep mutational scanning, and more classical molecular virology. By profiling the challenges viral populations must overcome to evade innate immunity, and the mechanisms by which they do so, it is our hope to better inform models of viral evolution and potentially even identify novel therapeutic routes exploiting those challenges. viral Critically, our approaches have already identified key components of the viral lifecycle that are subject to surveillance, and have identified viral variants with desirable properties as potential vaccine candidates or oncolytic therapeutics.

细胞固有的先天免疫是所有病毒病原体必须克服或以其他方式颠覆的障碍 为了成功完成其感染生命周期，这些途径共同检测非自我或危险。 相关分子，并作为响应，产生称为干扰素的信号蛋白，诱导局部 和全身抗病原体反应这些反应最终推动了最急性的清除。 感染，尽管它们也会导致许多观察到的病理学，大多数（如果不是全部）病毒病原体都编码。 这些途径的拮抗剂；通常是在干扰素产生的水平上。 甲型流感病毒非常成功，以至于只有大约 0.5% 的受感染细胞能够成功检测到病毒感染 然而，一小部分响应者对于整个过程至关重要。 疾病——存在干扰素途径缺陷的个体通常面临极高的并发症或并发症风险 感染呼吸道病毒（包括流感）后死亡。 矛盾的是，虽然大多数病毒种群保持着对宿主检测的严格抑制，但它们 对于流感病毒，只有大约10%的病毒颗粒能够成功完成复制。 病毒生命周期的其余部分能够进入细胞并暴露潜在的先天免疫。 配体，但无论如何，绝大多数都无法产生感染性后代。 病毒体，即使是那些无法完成病毒生命周期的病毒体，仍然未被发现，那么，什么机制呢？ 尽管病毒复制如此频繁地失败，但仍能让病毒群体不被宿主细胞检测到吗？ 作为这一雄心勃勃的调查路线的起点，我们重点关注以下几个离散机制： 我们已经掌握了甲型流感病毒的初步数据或有能力轻易获得此类病毒 数据：1）甲型流感病毒分段基因组结构如何影响潜在范围 免疫刺激失败 2) 流感主要先天免疫拮抗剂的多功能性如何， NS1，影响病毒检测率，以及 3) 聚合酶错误率如何受到先天免疫的影响 为了解决这些问题，我的团队将结合使用变异分析和深度突变。 通过分析病毒群体必须克服的挑战，进行扫描和更经典的分子病毒学。 为了逃避先天免疫，以及它们这样做的机制，我们希望更好地为模型提供信息 病毒进化，甚至有可能利用这些挑战确定新的治疗途径。 病毒性的 关键的是，我们的 方法已经确定了受监测的病毒生命周期的关键组成部分，并且 已鉴定出具有理想特性的病毒变体作为潜在的候选疫苗或溶瘤病毒 疗法。

项目成果

The use of single-cell RNA-seq to study heterogeneity at varying levels of virus-host interactions.

使用单细胞 RNA-seq 研究不同水平的病毒-宿主相互作用的异质性。

• 发表时间: 2024-01
• 影响因子: 6.7
• 作者: Swaminath, Sharmada;Russell, Alistair B
• 通讯作者: Russell, Alistair B