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破坏的屏障， 才能顺利完成它们的传染性生命周期总的来说，这些通路检测非自我或危险 相关的分子，并作为回应，产生称为干扰素的信号蛋白， 和系统性抗病原体反应。这些反应最终会清除大多数急性 感染，虽然它们也导致许多观察到的病理。大多数，如果不是全部，病毒病原体编码 这些途径的拮抗剂;经常在干扰素生产水平。其中一种病原体，人类 甲型流感病毒是如此成功，以至于只有大约0.5%的感染细胞成功检测到病毒感染， 早期时间点尽管如此，这一小部分反应者对治疗过程至关重要。 疾病-干扰素途径有缺陷的个体通常处于并发症或 呼吸道病毒感染后死亡，包括流感。 奇怪的是，虽然大多数病毒群体保持严格抑制宿主检测，但它们 以相对较低的保真度复制。对于流感来说，只有大约10%的病毒颗粒能够成功完成 病毒的生命周期其余的颗粒能够进入细胞并暴露潜在的先天免疫 配体，但在某些步骤不能产生感染性后代。不管怎样，绝大多数 病毒粒子，甚至那些不能完成病毒生命周期的病毒粒子，仍然未被发现。那么， 允许病毒群体保持不被宿主细胞检测到，尽管在复制时如此频繁地失败？ 作为这一雄心勃勃的调查路线的起点，我们将重点放在几个独立的机制上， 甲型流感病毒，我们已经拥有初步数据或有能力随时获得这些数据， 数据：1）甲型流感病毒分段基因组的结构如何影响潜在的 2）流感的主要先天免疫拮抗剂的多功能性， NS 1，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 压力为了解决这些问题，我的团队将使用变异分析、深度突变分析和基因组测序相结合的方法。 扫描和更经典的分子病毒学。通过分析病毒种群必须克服的挑战， 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，甚至有可能确定利用这些挑战的新治疗途径。 病毒 关键是，我们 这些方法已经确定了受监测的病毒生命周期的关键组成部分， 已经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疫苗， 治疗学

项目成果

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

• DOI: 10.1371/journal.ppat.1011898
• 发表时间: 2024-01
• 期刊: PLoS pathogens
• 影响因子: 6.7