Airway Epithelial-Myeloid cell crosstalk as a key mechanism in the pathogenesis of COVID-19

气道上皮-骨髓细胞串扰是 COVID-19 发病机制的关键机制

• 批准号: BB/V01854X/1
• 负责人: Ian Sayers
• 金额: $ 31.58万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV01854X%2F1
• 关键词: Airway; Epithelial; Myeloid; cell; crosstalk

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of COVID-19, causes mild to severe respiratory illness exacerbated by aging and comorbidities. Patients can develop acute respiratory distress syndrome (ARDS) or multi-organ injuries associated with elevated levels of pro-inflammatory cytokines, including IL-6 and TNF-alpha, alongside minimal amounts of type I IFNs. Reduced Type I IFN production is likely caused by viral antagonism of innate immune responses hampering induction of a robust anti-viral state in the airway epithelium and surrounding tissues facilitating increased viral titres. We hypothesise that crosstalk between infected lung epithelial cells, targeted by SARS-CoV-2 but poor cytokine producers, and myeloid cells, not susceptible to SARS-CoV-2 infection but major producers of cytokines, will contribute to the cytokine imbalance and storm characteristic of COVID-19. The main objective of this study is to establish the role of monocytes/macrophages as amplifiers of inflammatory responses during SARS-CoV-2 infection including evaluating the effect of existing or new drugs. Towards this aim we will (1) Characterise SARS-CoV-2 infection in differentiated primary human airway epithelial cells, both nasal and bronchial cells including; viral growth, cytotoxicity and cytokine production. (2) Determine if crosstalk between airway epithelial cells and monocytes/macrophages influences SARS-CoV-2 infection and can be targeted by existing and new drugs. We will use individual and co-cultures of airway epithelial cells and monocytes/macrophage to (i) investigate changes in cytokine production, (ii) determine if SARS-CoV-2 infection of epithelial cells can be augmented by the presence of myeloid cells, (iii) if monocytes/macrophages can become targets for SARS-CoV-2 and (iv) the effect of drugs on each aspect.

严重急性呼吸综合征冠状病毒(SARS-CoV)-2是COVID-19的病因，可引起轻度至重度呼吸系统疾病，因衰老和合并症而加重。患者可发生急性呼吸窘迫综合征（ARDS）或多器官损伤，这些损伤与促炎细胞因子水平升高有关，包括IL-6和tnf - α，以及少量的I型ifn。I型IFN产生的减少可能是由于先天免疫反应的病毒拮抗作用，阻碍了气道上皮和周围组织中强大的抗病毒状态的诱导，从而促进了病毒滴度的增加。我们假设，被SARS-CoV-2靶向但细胞因子产生能力较差的被感染肺上皮细胞与对SARS-CoV-2感染不敏感但细胞因子产生能力较强的髓系细胞之间的串扰将导致细胞因子失衡和COVID-19的风暴特征。本研究的主要目的是确定单核/巨噬细胞在SARS-CoV-2感染期间作为炎症反应放大器的作用，包括评估现有药物或新药的效果。为此，我们将(1)表征SARS-CoV-2感染分化的原代人气道上皮细胞，包括鼻和支气管细胞，包括；病毒生长，细胞毒性和细胞因子的产生。(2)确定气道上皮细胞与单核/巨噬细胞之间的串扰是否影响SARS-CoV-2感染，是否可被现有药物和新药靶向。我们将使用气道上皮细胞和单核/巨噬细胞的单独和共培养来(i)研究细胞因子产生的变化，（ii）确定骨髓细胞的存在是否会增强上皮细胞对SARS-CoV-2的感染，（iii）单核/巨噬细胞是否可以成为SARS-CoV-2的靶点，以及（iv）药物对各方面的影响。