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Temporal dynamics of the host molecular responses underlying severe COVID-19 progression and disease resolution

机译：严重Covid-19进展和疾病分辨率下宿主分子反应的时间动态

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Background The coronavirus disease-19 (COVID-19) pandemic has cost lives and economic hardships globally. Various studies have found a number of different factors, such as hyperinflammation and exhausted/suppressed T cell responses to the etiological SARS coronavirus-2 (SARS-CoV-2), being associated with severe COVID-19. However, sieving the causative from associative factors of respiratory dysfunction has remained rudimentary. Methods We postulated that the host responses causative of respiratory dysfunction would track most closely with disease progression and resolution and thus be differentiated from other factors that are statistically associated with but not causative of severe COVID-19. To track the temporal dynamics of the host responses involved, we examined the changes in gene expression in whole blood of 6 severe and 4 non-severe COVID-19 patients across 15 different timepoints spanning the nadir of respiratory function. Findings We found that neutrophil activation but not type I interferon signaling transcripts tracked most closely with disease progression and resolution. Moreover, transcripts encoding for protein phosphorylation, particularly the serine-threonine kinases, many of which have known T cell proliferation and activation functions, were increased after and may thus contribute to the upswing of respiratory function. Notably, these associative genes were targeted by dexamethasone, but not methylprednisolone, which is consistent with efficacy outcomes in clinical trials. Interpretation Our findings suggest neutrophil activation as a critical factor of respiratory dysfunction in COVID-19. Drugs that target this pathway could be potentially repurposed for the treatment of severe COVID-19. Funding This study was sponsored in part by a generous gift from The Hour Glass. EEO and JGL are funded by the National Medical Research Council of Singapore, through the Clinician Scientist Awards awarded by the National Research Foundation of Singapore.
机译：背景技术Coronavirus疾病-19（Covid-19）大流行在全球范围内具有成本和经济困难。各种研究发现了许多不同的因素，例如对病原体SARS冠状病毒-2（SARS-COV-2）的高炎症和排出/抑制的T细胞反应，与严重的Covid-19相关。然而，筛查呼吸功能障碍联想因子的致病仍然是基本的。方法假设呼吸功能障碍的宿主应对造成呼吸功能障碍的致响应将与疾病进展和分辨率最密切地追踪，因此与统计相关的其他因素不同，但不造成严重Covid-19。要跟踪所涉及的宿主响应的时间动态，我们检查了跨越呼吸功能NadiR的15例不同时间点的6例严重和4名非严重Covid-19患者的全血中基因表达的变化。结果发现，我们发现中性粒细胞激活但不是I型干扰素信号传递转录物最密切地跟踪疾病进展和分辨率。此外，编码蛋白质磷酸化的转录物，特别是丝氨酸 - 苏氨酸激酶，其中许多已知的T细胞增殖和活化功能，因此可以有助于呼吸功能的上升。值得注意的是，这些缔合基因由地塞米松靶向，但不是甲基己酮胺，这与临床试验中的功效结果一致。解释我们的研究结果表明中性粒细胞激活作为Covid-19中呼吸功能障碍的关键因素。靶向该途径的药物可能会重新施加治疗严重的Covid-19。这项研究的资金是由小时玻璃的慷慨礼品赞助的。 EEO和JGL由新加坡国家医学研究委员会资助，通过新加坡国家研究基金会颁发的临床医生科学家奖。

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