Hypercapnia and Suppression of Antiviral Host Defense

高碳酸血症和抗病毒宿主防御的抑制

• 批准号: 10486540
• 负责人: PETER H SPORN
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486540
• 关键词: Acute; Alveolar; Alveolar Macrophages; Attenuated; Bacterial Infections; Blood; Breeding; Carbon Dioxide; Cells; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Cystic Fibrosis; DNA Methylation; Drosophila genus; Exhibits; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; Homeobox; Host Defense; Human; Hypercapnia; Hypermethylation; Immune; Immune system; Immunosuppression; Infection; Inflammation; Inflammatory; Influenza A virus; Injury; Interferon Type I; Intubation; Investigation; Laboratories; Lung; Lung diseases; Lung infections; Macrophage; Mediator; Methylation; Mus; Myelogenous; Nucleic Acid Regulatory Sequences; Orthologous Gene; Outcome; Pathway interactions; Patients; Reporting; Research; Risk Factors; Testing; Tissues; Viral; Viral Genes; Viral Pneumonia; Virus Diseases; Virus Replication; ZFHX3 gene; Zinc Fingers; adverse outcome; community acquired pneumonia; improved outcome; influenza infection; influenzavirus; lung injury; monocyte; mortality; mortality risk; mouse model; novel; preservation; prevent; recruit; response; transcription factor

Hypercapnia, elevated PCO2 in blood and tissue, commonly develops in patients with severe acute and chronic pulmonary disease. Hypercapnia is a risk factor for mortality in COPD, community-acquired pneumonia, cystic fibrosis and adenoviral lung infection. We have shown that hypercapnia inhibits transcription of NF-κB- regulated innate immune and host defense genes, independent of pH, in human, mouse and Drosophila cells, and that it increases the mortality of bacterial infections in mice and Drosophila. We have also reported that hypercapnia inhibits type I interferon (IFN) pathway antiviral gene expression in alveolar macrophages (AM) and increases viral replication, lung injury and mortality in mice infected with influenza A virus (IAV). Based on previous studies in which we identified the zinc finger homeobox transcription factor zfh2 as a mediator of CO2-induced immune suppression in Drosophila, we bred a mouse lacking Zfhx3, a mammalian ortholog of zfh2, in the myeloid lineage. Our recent studies show that myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of antiviral genes and increased IAV growth in macrophages, and that it reduces the hypercapnia-induced increase in mortality of IAV infection in mice. We also show that hypercapnia increases and Zfhx3 deficiency decreases methylation of multiple genes in AM, including host genes that are essential for IAV replication. Recent studies from our laboratories have established that monocyte-derived AM (MoAM) recruited to the alveolar space in response to diverse insults, including IAV infection, are pro-inflammatory and drive lung injury. This is in contrast to tissue resident AM (TRAM), which are protective against IAV-induced injury. Thus, we hypothesize that hypercapnia worsens outcomes of IAV infection by suppressing antiviral genes and increasing expression of inflammation/injury-associated genes in TRAM and MoAM, and that this results from hypercapnia-induced alterations in methylation of regulatory regions of these genes. We further hypothesize that genetic deficiency of Zfhx3 in macrophages mitigates hypercapnia-induced changes in DNA methylation, and that this preserves antiviral gene expression and reduces lung injury caused by IAV in the setting of hypercapnia. To test these hypotheses, we will determine whether hypercapnia worsens outcomes of IAV infection by decreasing expression of antiviral genes and increasing expression of inflammation/injury-associated genes in TRAM and MoAM in mice; whether hypercapnia-induced changes in DNA methylation cause these changes in antiviral and inflammation/injury-associated gene expression; and whether hypercapnia is associated with similar changes in DNA methylation and gene expression in AM from humans with severe viral pneumonia. This investigation will define novel mechanisms by which elevated levels of CO2 suppress antiviral host defense, a previously-unrecognized adverse consequence of hypercapnia, and will lay the basis for future studies aimed at preventing hypercapnia-induced immunosuppression in patients with advanced lung disease.

高碳酸血症，即血液和组织中PCO 2升高，通常发生在严重急性和慢性阻塞性肺疾病患者中。 慢性肺病高碳酸血症是COPD、社区获得性肺炎 囊性纤维化和腺病毒肺部感染。我们已经证明高碳酸血症抑制NF-κB B的转录。 在人、小鼠和果蝇细胞中，调节先天免疫和宿主防御基因，不依赖于pH， 并且它增加了小鼠和果蝇的细菌感染的死亡率。我们还报告说， 高碳酸血症抑制肺泡巨噬细胞（AM）中I型干扰素（IFN）途径抗病毒基因表达， 增加感染甲型流感病毒（IAV）的小鼠的病毒复制、肺损伤和死亡率。 基于先前的研究，我们鉴定了锌指同源盒转录因子zfh 2作为一种转录因子。 在果蝇中，Zfhx 3是CO2诱导的免疫抑制的介质，我们培育了一只缺乏Zfhx 3的小鼠， ZFH 2的直系同源物，在髓系中。我们最近的研究表明，髓样Zfhx 3缺陷可以保护 高碳酸血症诱导的抗病毒基因抑制和巨噬细胞中IAV生长增加， 降低高碳酸血症诱导的小鼠IAV感染死亡率的增加。我们还发现高碳酸血症 增加和Zfhx 3缺陷减少AM中多个基因的甲基化，包括宿主基因， 对IAV复制至关重要。 我们实验室最近的研究已经确定，单核细胞来源的AM（MoAM）招募到 肺泡空间对包括IAV感染在内各种损伤的反应是促炎性的并驱动肺 损伤这与组织驻留AM（TRAM）形成对比，其对IAV诱导的损伤具有保护作用。因此，在本发明中， 我们假设高碳酸血症通过抑制抗病毒基因而减轻IAV感染的后果， 增加TRAM和MoAM中炎症/损伤相关基因的表达，这是由于 高碳酸血症诱导的这些基因调控区甲基化的改变。我们进一步假设， 巨噬细胞中Zfhx 3的遗传缺陷减轻了高碳酸血症诱导的DNA甲基化变化，并且 这保留了抗病毒基因的表达，并减少了高碳酸血症环境中由IAV引起的肺损伤。 为了验证这些假设，我们将通过以下方法确定高碳酸血症是否会影响IAV感染的结果： 降低抗病毒基因的表达和增加炎症/损伤相关基因的表达， 小鼠中的TRAM和MoAM;高碳酸血症诱导的DNA甲基化变化是否导致这些变化， 抗病毒和炎症/损伤相关的基因表达;以及高碳酸血症是否与类似的 严重病毒性肺炎患者AM中DNA甲基化和基因表达的变化 这项研究将确定CO2水平升高抑制抗病毒宿主的新机制 防御，以前未被认识到的高碳酸血症的不良后果，并将奠定基础，为未来 旨在预防晚期肺病患者中高碳酸血症诱导的免疫抑制的研究。