Role of Intestinal Barrier Integrity in Modulating the Host Glycome During COVID-19

COVID-19 期间肠道屏障完整性在调节宿主糖类中的作用

• 批准号: 10168868
• 负责人: Mohamed Abdel Mohsen
• 金额: $ 45.68万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10168868
• 关键词: 2019-nCoV; Age; Anti-Inflammatory Agents; Antibodies; Bacteria; Bacterial Translocation; Binding; Binding Proteins; Biopsy; Blood; COVID-19; Carbohydrates; Cells; Cessation of life; Clinical; Complement Activation; Data; Development; Disease; Disease Outcome; Enzymes; Epithelial; Epithelium; Ethnic Origin; FCGR2B gene; Foundations; Functional disorder; Future; Galactose; Galactosidase; Gender; Glycoproteins; HIV; HIV Infections; Immunoglobulin A; Immunoglobulin G; Immunologic Markers; Impairment; Individual; Infection; Inflammation; Inflammatory; Knowledge; Lead; Link; Measures; Mediating; Mucous Membrane; Neuraminidase; Outcome; Pathogenesis; Patients; Peripheral; Permeability; Plasma; Polysaccharides; Risk stratification; Role; Sialic Acids; Signal Transduction; Source; Structure; Surface; T-Cell Activation; TLR4 gene; Testing; Therapeutic; Validation; Virus Diseases; base; cytokine release syndrome; dectin 1; disorder risk; dysbiosis; glycosylation; gut bacteria; gut microbes; gut microbiome; immune activation; innovation; intestinal barrier; macrophage; member; microbial; monocyte; novel marker; novel therapeutic intervention; prevent; sialic acid binding Ig-like lectin; sialylation; treatment response

PROJECT SUMMARY. Hyper-inflammation and complement activation have been implicated in Coronavirus disease 2019 (COVID-19) pathogenesis and outcomes; however, the pathophysiological mechanisms underlying these phenomena remain unknown. SARS-CoV2 infects gut cells, and viral infections in the gut causes changes in gut structure and breakdown of the epithelial barrier, which can increase permeability to gut microbes and microbial products. This microbial translocation has a direct impact on systemic inflammation, but it may also indirectly impact it by modulating circulating glycomes. Recently, it has been shown that viral- infections-mediated alterations to glycans, in particular loss of sialic acid and loss of galactose, on circulating glycoproteins and antibodies (IgG and IgA) mediate and drive inflammation and complement activation. Gut microbial translocation is a potential source of glycomic alterations during viral infections. Translocation of glycan-degrading enzymes (such as sialidase and galactosidases) released by several members of the gut microbiome can efficiently alter circulating glycomes, leading to the exacerbation of inflammation. In our preliminary data, we found that levels of several gut bacteria genera correlate with plasma IgG glycosylation during viral infection. We also found that these pro-inflammatory glycans on IgG correlate with both markers of microbial translocation, as well as with markers of systemic inflammation. These data suggest a link between microbial dysbiosis, microbial translocation, circulating glycomes, and systemic inflammation during viral infections. However, the role of circulating glycomes in regulating inflammation during COVID-19 has never been investigated. To fill this knowledge gap, we propose to test the hypothesis that SARS-CoV2 impairs intestinal barrier integrity leading to translocation of microbial products that alter circulating glycomes, which impact COVID-19 pathogenesis and outcomes. In Aim 1, we will test the hypothesis that severe COVID-19 is associated with disrupted intestinal barrier integrity and dysregulated circulating glycomes. 1.a) We will compare plasma markers of mucosal structural integrity, bacterial translocation, and microbial metabolites of 120 COVID- 19 patients (with varying disease outcomes); and 120 controls (matched for age, gender, and ethnicity). 1.b) We will compare the glycomic profiles of total plasma, plasma IgG, and plasma IgA of the 120 COVID-19 patients and controls. 1.c) We will test if levels of plasma markers of mucosal structural integrity and bacterial translocation associate with the glycosylation of plasma, plasma IgG, and plasma IgA. In Aim 2, we will test the hypothesis that circulating hyposialylated and agalactosylated glycomic signatures are linked to higher inflammation, higher immune activation, and worse clinical outcomes during COVID-19. This supplement can advance our knowledge of the microbial and glycomic underpinnings of COVID-19, which can serve as 1) novel biomarkers for disease risk stratification, disease course, and therapeutic response (to be used immediately upon validation); and 2) a foundation to develop innovative therapeutics in the future.

项目摘要。过度炎症和补体激活与冠状病毒有关 2019 年疾病 (COVID-19) 发病机制和结果；然而，病理生理机制 这些现象背后的原因仍然未知。 SARS-CoV2 感染肠道细胞和肠道内的病毒感染 引起肠道结构的变化和上皮屏障的破坏，从而增加肠道的通透性 微生物和微生物产品。这种微生物易位对全身炎症有直接影响，但是 它还可能通过调节循环糖组来间接影响它。最近，有研究表明，病毒 感染介导的聚糖改变，特别是唾液酸的损失和半乳糖的损失，对循环 糖蛋白和抗体（IgG 和 IgA）介导和驱动炎症和补体激活。肠道 微生物易位是病毒感染期间糖组改变的潜在来源。易位 由肠道的几个成员释放的聚糖降解酶（例如唾液酸酶和半乳糖苷酶） 微生物组可以有效地改变循环糖组，导致炎症加剧。在我们的 初步数据，我们发现几种肠道细菌属的水平与血浆 IgG 糖基化相关 病毒感染期间。我们还发现 IgG 上的这些促炎聚糖与两种标记物相关 微生物易位，以及全身炎症标志物。这些数据表明两者之间存在联系 病毒感染期间的微生物失调、微生物易位、循环糖组和全身炎症 感染。然而，循环糖组在 COVID-19 期间调节炎症中的作用从未被研究过。 调查了。为了填补这一知识空白，我们建议检验 SARS-CoV2 损害肠道的假设 屏障完整性导致微生物产物易位，从而改变循环糖组，从而 影响 COVID-19 的发病机制和结果。在目标 1 中，我们将检验以下假设：严重的 COVID-19 是 与肠道屏障完整性破坏和循环糖组失调有关。 1.a) 我们将比较 120 种新冠病毒的粘膜结构完整性、细菌易位和微生物代谢物的血浆标记物 19 名患者（具有不同的疾病结果）；和 120 个对照（年龄、性别和种族匹配）。 1.b) 我们 将比较 120 名 COVID-19 患者的总血浆、血浆 IgG 和血浆 IgA 的血糖曲线 和控制。 1.c) 我们将测试粘膜结构完整性和细菌的血浆标志物水平是否 易位与血浆、血浆 IgG 和血浆 IgA 的糖基化有关。在目标 2 中，我们将测试 假设循环低唾液酸化和半乳糖基化糖组特征与更高的 COVID-19 期间的炎症、更高的免疫激活和更差的临床结果。这个补充可以 增进我们对 COVID-19 的微生物和糖组学基础的了解，这可以作为 1) 新颖 用于疾病风险分层、病程和治疗反应的生物标志物（立即使用 经验证）； 2）为未来开发创新疗法奠定基础。