Using dsRNA: nanoparticles to determine a link between type I interferons, ACE2 and susceptibility to coronaviruses similar to COVID-19

病毒是专性细胞内病原体，需要宿主细胞才能复制。2019年底在中国武汉出现的新型冠状病毒SARS-CoV-2是一种主要感染气道上皮的病毒。然而，越来越明显的是，气道上皮细胞并不是唯一易受SARS-CoV-2感染的细胞类型。胃肠道细胞，特别是胃、十二指肠和直肠腺上皮细胞以及肾小管上皮细胞也能够支持SARS-CoV-2复制。细胞保护自己免受病毒感染的主要方法之一是产生I型干扰素（IFN）。最近的一篇论文表明，SARS-CoV-2的表面受体血管紧张素转换酶2（ACE 2）是由IFN诱导的。这表明宿主的先天免疫反应可能使个体更容易感染病毒。目前的提案旨在使用Glysantis，Inc生产的IFN的有效诱导剂pIC：PhG来研究IFN，ACE 2和冠状病毒易感性之间的联系。PIC：PhG由两种成分组成;先天性免疫刺激剂聚肌苷酸：聚胞苷酸（pIC）与植物糖原纳米颗粒（PhG）结合，并且能够诱导比单独的pIC显著更多的IFN。本研究的三个目的是：（1）测试pIC：PhG在原代人气道（HAE）、肾小管（RPTEC）和十二指肠上皮细胞（HDuEpC）中的作用，以确认其在这些细胞类型中诱导IFN的能力，（2）测试pIC：PhG诱导的IFN是否在这些细胞类型中诱导ACE 2，以及（3）将ACE 2表达增加与对人冠状病毒感染和复制的易感性增加相关联。这项工作将为Glysantis提供对其纳米颗粒及其诱导IFN的能力的基本了解，并将为科学界提供更好地了解先天免疫反应对冠状病毒易感性的影响。

Viruses are obligate intracellular pathogens that require a host cell in order to replicate. The novel coronavirus, SARS-CoV-2, that emerged late 2019 in Wuhan China is a virus that primarily infects the airway epithelium. It is becoming more evident; however, that airway epithelial cells are not the only cell type susceptible to SARS-CoV-2 infection. Cells of the gastrointestinal tract, specifically gastric, duodenal and rectum glandular epithelial cells, as well as kidney tubule epithelial cells are also capable of supporting SARS-CoV-2 replication. One of the principle ways cells protect themselves from virus infections is by producing type I interferons (IFNs). A recent paper has suggested that the surface receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is induced by IFNs. This suggests that the host's innate immune response may be making an individual more susceptible to the virus. The current proposal aims to use a potent inducer of IFNs, pIC:PhG, produced by Glysantis, Inc, to study the linkages between IFN, ACE2 and coronavirus susceptibility. PIC:PhG consists of two components; the innate immune stimulant, poly inosinic: poly cytidylic acid (pIC) bound to a phytoglycogen nanoparticle (PhG) and is capable of inducing significantly more IFNs than pIC alone. The three objectives of this study will be: (1) to test the effect of pIC:PhG in primary human airway (HAE), renal tubule (RPTEC) and duodenum epithelial cells (HDuEpC) to confirm its ability to induce IFNs in these cell types, (2) to test whether pIC:PhG-induced IFNs induce ACE2 in these cell types and (3) to correlate increased ACE2 expression with increased susceptibility to human coronavirus infection and replication. This work will provide Glysantis with fundamental understanding of their nanoparticle and its ability to induce IFNs, and will provide the scientific community with a better understanding of the influence of the innate immune response on coronavirus susceptibility.