Novel mechanisms regulating immunity to respiratory virus infection

调节呼吸道病毒感染免疫力的新机制

• 批准号: 10753849
• 负责人: Silke Paust
• 金额: --
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2023-08-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10753849
• 关键词: Acute; Acute Respiratory Distress Syndrome; Address; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Response; B-Lymphocytes; Bacterial Infections; Bacterial Pneumonia; CD80 gene; Cell physiology; Cells; Cessation of life; Cytotoxic T-Lymphocytes; Data; Disease; Epidemic; Granzyme; Health; Human; Hyperimmunoglobulin M Syndrome; Hypoxia; Immune; Immune response; Immunity; In Vitro; Infection; Inflammation; Influenza; Influenza A virus; Interferon Type II; Interleukin-10; Knockout Mice; Knowledge; Ligands; Lung; Lymphocyte; Lymphocyte Function; Malignant Neoplasms; Mediating; Morbidity - disease rate; Multiple Organ Failure; Mus; Mutate; Natural Killer Cells; Outcome; PDL1 pathway; Pathway interactions; Persons; Phenotype; Population; Public Health; Pulmonary Pathology; RNA Viruses; Rag1 Mouse; Role; Seasons; Severity of illness; Signal Pathway; Signal Transduction; Slice; Structure of parenchyma of lung; Suspensions; T cell regulation; T-Lymphocyte; Therapeutic; Viral; Viral Pneumonia; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; Work; antiviral immunity; cell type; chronic infection; cytokine; exhaustion; fighting; humoral immunity deficiency; immune cell infiltrate; immunopathology; immunoregulation; improved; influenza infection; influenzavirus; interleukin-10 receptor; mast cell; mortality; neutralizing antibody; novel; novel therapeutics; pandemic potential; pharmacologic; prevent; programmed cell death ligand 1; programmed cell death protein 1; respiratory infection virus; response; therapeutic target; tumor; vaccination outcome; viral resistance

Influenza viruses are rapidly mutating RNA viruses and are the causative agent of about one billion annual respiratory virus infections and 500,000 deaths worldwide. Influenza-related deaths are generally attributable to viral or bacterial pneumonia (from secondary bacterial infections); excessive inflammation resulting in acute respiratory distress syndrome; and severe lung immunopathology, leading to hypoxia and multi-organ failure. Influenza viruses have significant pandemic potential, seasonal epidemics burden the human population, and viral resistance has developed to all available treatment options. Much emphasis is placed on the humoral immune response to influenza, as neutralizing antibodies are the desired vaccine outcome. However, B cell- deficient mice and humans with hyper-IgM syndrome clear influenza virus infections, while T cell-deficient mice do not. Thus, B cell-independent mechanisms protect against influenza virus-related mortality. However, the immune response to influenza virus infection remains poorly understood, and much-needed therapeutics augmenting the antiviral immune response while preventing harmful immunopathology remain to be developed. To address this knowledge gap, we recently generated novel and compelling evidence that Influenza A virus (IAV) infection triggers lung mast cells (MCs) to produce the anti-inflammatory cytokine IL-10 (MC-IL-10). In wild- type (WT) and T- and B-cell deficient (Rag1-KO) mice, IAV/MC-IL-10 induces the expression of the IL-10 receptor (IL-10R) and programmed cell death ligand 1 (PD-L1) on Natural Killer (NK) cells. Notably, in Rag1-KO mice, where NK cells are the sole virus-fighting lymphocytes, PD-L1 blockade, but not PD-1, PD-L2, or CD80 blockade, significantly reduces IAV-related lethality. The IAV/MC-IL10/NK-PD-L1 pathway is also conserved in humans, at least in vitro: IAV infection of human-lung tissue-derived single-primary-cell suspensions or intact human lung tissue slices elicit MC-IL-10 and NK cell-expressed IL-10R and PD-L1. In mice and humans, T cells also upregulate the IL-10R, PD-1, and PD-L1 upon IAV infection. Further, IAV-infected IL-10-KO/Rag-WT mice, whose NK and T cells do not upregulate IL-10R, PD-1, PD-L1, or PD-L2, and IAV-infected WT mice in which PD-L1 is blocked, develop prolonged immune infiltration and immunopathology after IAV clearance. Our findings are novel and surprising. The induction of the PD/PD-L pathway is generally associated with lymphocyte exhaustion (via T cell-expressed PD-1) in cancer or chronic infection rather than the modulation of lymphocyte function in response to an acute viral illness. We hypothesize that influenza virus-induced MC-IL-10 balances helpful antiviral responses with harmful immunopathology through PDL1 signaling in NK cells, and PD-1 and/or PD-L1 signaling in T cells. We propose identifying the mechanisms of IAV/MC/IL-10/PD-L1-mediated NK cell and IAV/MC/IL-10/PD-1 and/or PD-L1-mediated T cell regulation and each pathway's contribution to viral clearance vs. lung tissue damage. Our proposal is highly significant to human health, as it has great potential to identify therapeutic targets for alleviating IAV immunopathology-associated mortality and morbidity.

流感病毒是一种快速变异的 RNA 病毒，每年约 10 亿人感染流感病毒。 全球有呼吸道病毒感染和 50 万人死亡。流感相关死亡通常归因于 病毒性或细菌性肺炎（继发性细菌感染）；过度炎症导致急性 呼吸窘迫综合征；以及严重的肺部免疫病理学，导致缺氧和多器官衰竭。 流感病毒具有巨大的大流行潜力，季节性流行病给人类带来负担，并且 病毒对所有可用的治疗方案都产生了耐药性。非常注重幽默感 对流感的免疫反应，因为中和抗体是理想的疫苗结果。然而，B 细胞—— 缺陷小鼠和患有高 IgM 综合征的人类可以清除流感病毒感染，而 T 细胞缺陷小鼠 不要。因此，B 细胞独立机制可防止流感病毒相关的死亡。然而， 对流感病毒感染的免疫反应仍知之甚少，急需治疗方法 增强抗病毒免疫反应，同时预防有害的免疫病理学仍有待开发。 为了解决这一知识差距，我们最近生成了新颖且令人信服的证据，表明甲型流感病毒 (IAV) 感染会触发肺肥大细胞 (MC) 产生抗炎细胞因子 IL-10 (MC-IL-10)。在野外—— 型 (WT) 和 T 细胞和 B 细胞缺陷 (Rag1-KO) 小鼠，IAV/MC-IL-10 诱导 IL-10 受体的表达 (IL-10R) 和自然杀伤 (NK) 细胞上的程序性细胞死亡配体 1 (PD-L1)。值得注意的是，在 Rag1-KO 小鼠中， 其中 NK 细胞是唯一的抗病毒淋巴细胞，PD-L1 阻断，但不是 PD-1、PD-L2 或 CD80 阻断， 显着降低 IAV 相关致死率。 IAV/MC-IL10/NK-PD-L1 通路在人类中也是保守的， 至少在体外：人肺组织来源的单原代细胞悬浮液或完整人肺的 IAV 感染 组织切片诱导 MC-IL-10 和 NK 细胞表达的 IL-10R 和 PD-L1。在小鼠和人类中，T 细胞也 IAV 感染后上调 IL-10R、PD-1 和 PD-L1。此外，IAV感染的IL-10-KO/Rag-WT小鼠， NK 和 T 细胞不上调 IL-10R、PD-1、PD-L1 或 PD-L2 的小鼠，以及 IAV 感染的 WT 小鼠 PD-L1 被阻断，在 IAV 清除后形成长期的免疫浸润和免疫病理学。我们的发现 新颖且令人惊讶。 PD/PD-L途径的诱导一般与淋巴细胞相关 癌症或慢性感染中的耗竭（通过 T 细胞表达的 PD-1）而不是淋巴细胞的调节 发挥应对急性病毒性疾病的功能。我们假设流感病毒诱导的 MC-IL-10 平衡 通过 NK 细胞中的 PDL1 信号传导以及 PD-1 和/或，产生有益的抗病毒反应和有害的免疫病理学 T 细胞中的 PD-L1 信号传导。我们建议鉴定 IAV/MC/IL-10/PD-L1 介导的 NK 细胞的机制 和 IAV/MC/IL-10/PD-1 和/或 PD-L1 介导的 T 细胞调节以及每个途径对病毒的贡献 间隙与肺组织损伤。我们的建议对人类健康非常重要，因为它具有巨大的潜力 确定减轻 IAV 免疫病理学相关死亡率和发病率的治疗靶点。