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.

流感病毒正在迅速突变RNA病毒，是每年约十亿的病毒药物 全球呼吸道病毒感染和500,000例死亡。与流感相关的死亡通常归因于 病毒或细菌性肺炎（来自继发细菌感染）；过度炎症导致急性 呼吸窘迫综合征；和严重的肺免疫病理学，导致缺氧和多器官衰竭。 流感病毒具有巨大的流行潜力，季节性流行病负担人口，以及 病毒抗性已发展为所有可用的治疗选择。非常重点放在幽默上 作为中和抗体的免疫反应是所需的疫苗结果。但是，B细胞 - 缺乏高IGM综合征的小鼠和人类清除流感病毒感染，而T细胞缺陷小鼠 不要。因此，B细胞独立的机制可以预防与流感病毒相关的死亡率。但是， 对流感病毒感染的免疫反应仍然很少了解，并且急需的治疗剂 在预防有害免疫病理学的同时增加抗病毒免疫反应仍有待发展。 为了解决这一知识差距，我们最近产生了新颖而令人信服的证据，这些证据使流感病毒 （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 类型（WT）以及T-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）和编程细胞死亡配体1（PD-L1）在天然杀伤（NK）细胞上。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阻滞，而不是PD-1，PD-L2或CD80阻断， 显着降低了与IAV相关的致死性。 IAV/MC-IL10/NK-PD-L1途径在人类中也是保守的 体外最少：人肺组织衍生的单核细胞悬浮液或完整的人肺的IAV感染 组织切片引起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， 其NK和T细胞不会上调IL-10R，PD-1，PD-L1或PD-L2和IAV感染的WT小鼠，其中 PD-L1被阻断，在IAV清除后会产生长时间的免疫浸润和免疫病理学。我们的发现 是新颖而令人惊讶的。 PD/PD-L途径的诱导通常与淋巴细胞有关 癌症或慢性感染中的疲惫（通过T细胞表达的PD-1），而不是调节淋巴细胞 响应急性病毒疾病的作用。我们假设流感病毒诱导的MC-IL-10余额 通过NK细胞中的PDL1信号传导以及PD-1和/或 T细胞中的PD-L1信号传导。我们建议识别IAV/MC/IL-10/PD-L1介导的NK细胞的机制 IAV/MC/IL-10/PD-1和/或PD-L1介导的T细胞调节以及每种途径对病毒的贡献 清除与肺组织损伤。我们的建议对人类健康非常重要，因为它具有很大的潜力 确定可以减轻IAV免疫病理学相关的死亡率和发病率的治疗靶标。