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，每年造成约10亿人死亡