BACKGROUND TMPRSS2, ACE2 and TMPRSS11D are genes coding for proteins necessary for SARS-CoV-2 activation, infection and transmission. Once SARS-CoV-2 enters the host cell, it leads to an exaggerated inflammatory state of the lungs mediated by overexpressed TNF-, IL-6, and IL-1β. We assessed azithromycin's effect on the aforementioned genes and their associated pathways to evaluate its potential use as a possible treatment. OBJECTIVE Confirm the role azithromycin may play in the regulation of pathways and genes involved in inflammation and SARS-CoV-2 activation and cell-to-cell transmission. METHODS Primary airway nasal epithelial cells collected from nasal biopsies of three patients with chronic rhinosinusitis (CRS) were primary cultured and treated or not with 10µg of azithromycin. RNA was extracted from these samples and analyzed using a microarray chip. Differential gene expression profiles and gene set enrichment analysis (GSEA) were obtained between both groups. RESULTS Cell cultures treated with 10µg of azithromycin significantly downregulated receptor-mediated endocytosis canonical pathways involving TMPRSS2 and TMPRSS11D genes. Downregulated inflammation-associated genes included IL-1β and NDST1. Interestingly, numerous genes in the cholesterol biosynthesis pathway were significantly upregulated as part of a potential process named drug-induced phospholipidosis (DLP). CONCLUSIONS This proof of concept demonstrates azithromycin downregulates pathways involving serine proteases TMPRSS2 and TMPRSS11D required for SARS-CoV-2 activation and its cell-to-cell transmission while downregulating pro-inflammatory cytokine IL-1β, NDST-1 and their associated pathways. This may help reduce the characteristic excessive respiratory epithelial inflammation, key feature of SARS-CoV-2 infection. Finally, azithromycin may also decrease available cholesterol in lipid rafts which may hinder SARS-CoV-2 infection.

中文翻译：

---

阿奇霉素下调SARS-CoV-2所需的IL-1β基因表达以及涉及TMPRSS2和TMPRSS11D的途径。

背景技术TMPRSS2，ACE2和TMPRSS11D是编码SARS-CoV-2激活，感染和传播所必需的蛋白质的基因。一旦SARS-CoV-2进入宿主细胞，它就会导致由过表达的TNF-，IL-6和IL-1β介导的肺部过度炎症。我们评估了阿奇霉素对上述基因及其相关途径的作用，以评估其潜在用途。目的确认阿奇霉素可能在调节与炎症，SARS-CoV-2活化和细胞间传递有关的途径和基因中发挥作用。方法对3例慢性鼻鼻窦炎（CRS）患者鼻腔活检中收集的原发气道鼻上皮细胞进行原代培养，并用10μg阿奇霉素进行或不采用阿奇霉素进行处理。从这些样品中提取RNA，并使用微阵列芯片进行分析。两组之间均获得了差异基因表达谱和基因集富集分析（GSEA）。结果用10μg阿奇霉素处理的细胞培养物显着下调了涉及TMPRSS2和TMPRSS11D基因的受体介导的内吞经典途径。下调的炎症相关基因包括IL-1β和NDST1。有趣的是，胆固醇生物合成途径中的许多基因被显着上调，这是称为药物诱导的磷脂病（DLP）的潜在过程的一部分。结论该概念证明了阿奇霉素下调了SARS-CoV-2激活及其细胞间传递所需的丝氨酸蛋白酶TMPRSS2和TMPRSS11D的途径，同时下调了促炎性细胞因子IL-1β，NDST-1及其相关途径。这可能有助于减少特征性过度呼吸道上皮炎症，这是SARS-CoV-2感染的关键特征。最后，阿奇霉素还可以降低脂筏中的有效胆固醇，这可能会阻止SARS-CoV-2感染。