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.

流感病毒是快速突变的RNA病毒，并且是每年约10亿人死亡的病原体。 呼吸道病毒感染和全球50万人死亡。流感相关死亡通常可归因于 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;以及严重的肺免疫病理学，导致缺氧和多器官衰竭。 流感病毒具有显著的大流行潜力，季节性流行给人类带来负担， 病毒对所有可用的治疗方案都产生了抗药性。许多重点放在体液 疫苗的作用是增强对流感的免疫应答，因为中和抗体是所需的疫苗结果。但是，B细胞- 缺乏T细胞的小鼠和患有高IgM综合征的人清除流感病毒感染，而T细胞缺乏的小鼠 不要。因此，不依赖于B细胞的机制可防止流感病毒相关死亡。但 对流感病毒感染的免疫应答仍然知之甚少， 增强抗病毒免疫应答同时防止有害的免疫病理学仍有待开发。 为了弥补这一知识缺口，我们最近获得了新的令人信服的证据， (IAV)感染触发肺肥大细胞（MC）产生抗炎细胞因子IL-10（MC-IL-10）。在野外- 型（WT）和T-和B-细胞缺陷型（Rag 1-KO）小鼠，IAV/MC-IL-10诱导IL-10受体的表达 （IL-10 R）和程序性细胞死亡配体1（PD-L1）对自然杀伤（NK）细胞的作用。特别是，在Rag 1-KO小鼠中， 其中NK细胞是唯一的抗病毒淋巴细胞，PD-L1阻断，但不阻断PD-1、PD-L2或CD 80， 显著降低了IAV相关的致死率。IAV/MC-IL 10/NK-PD-L1通路在人类中也是保守的， 体外最少：人肺组织来源的单原代细胞悬液或完整人肺的IAV感染 组织切片引发MC-IL-10和NK细胞表达的IL-10 R和PD-L1。在小鼠和人类中，T细胞也 在IAV感染后上调IL-10 R、PD-1和PD-L1。此外，IAV感染的IL-10-KO/Rag-WT小鼠， 其NK和T细胞不上调IL-10 R、PD-1、PD-L1或PD-L2，以及IAV感染的WT小鼠，其中 PD-L1被阻断，在IAV清除后发生延长的免疫浸润和免疫病理学。我们的研究结果 都是新奇而令人惊讶的。PD/PD-L通路的诱导通常与淋巴细胞 在癌症或慢性感染中耗尽（通过T细胞表达的PD-1），而不是调节淋巴细胞 对急性病毒性疾病的反应。我们假设流感病毒诱导的MC-IL-10平衡 通过NK细胞中的PDL 1信号传导和PD-1和/或 T细胞中的PD-L1信号传导。我们提出了IAV/MC/IL-10/PD-L1介导的NK细胞的作用机制 和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感染的贡献 清除率与肺组织损伤。我们的建议对人类健康具有重要意义，因为它具有巨大的潜力， 鉴定用于减轻IAV免疫病理学相关死亡率和发病率的治疗靶点。