Tomalka Jeffrey A, Owings Anna, Galeas-Pena Michelle, Ziegler Carly G K, Robinson Tanya O, Wichman Thomas G, Laird Hannah, Williams Haley B, Ghaliwal Neha S, Everman Steven, Zafar Yousaf, Walsh Jaclyn M L, Shalek Alex K, Horwitz Bruce H, Ordovas-Montanes Jose, Glover Sarah C, Gibert Yann
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
FASEB J. 2025 May 15;39(9):e70600. doi: 10.1096/fj.202403195R.
Many questions remain unanswered regarding the implication of genetics and lipid metabolites with severe SARS-CoV-2 infections. We performed bulk RNA-seq and a total fatty acid panel analysis on PBMCs and plasma collected from 10 infected and 10 uninfected patients. Univariate comparison of lipid metabolites using the Mann-Whitney U-test revealed that six lipid metabolites were significantly increased in COVID-19 patients, including the lipid mediators arachidonic acid (AA) and eicosapentaenoic acid (EPA), which both give rise to eicosanoids. Key lipids implicated in inflammation, including AA and EPA, along with the fatty acids DHA and DPA, were significantly and positively correlated to the WHO disease severity score. Analysis of our bulk RNA-seq dataset demonstrated distinct transcriptional profiles leading to a segregation of COVID-19 patients based on the WHO score. Ontology, KEGG, and Reactome analysis identified several key pathways and nodes that were enriched for genes related to innate immunity, interactions between lymphoid and nonlymphoid cells, interleukin signaling, and subsequent DNA damage pathways. EPA levels correlated with heightened cell cycling and DNA damage pathways observed in patients with a high WHO score. We studied gene expression in nasopharyngeal swabs from 58 healthy and COVID-19 participants and identified that genes implicated in eicosanoid synthesis, such as alox5, alox12, and alox15B, were specifically up-regulated in high WHO score patients in several cell types of the nasopharynx, especially goblet cells across different viral variants (Deta and Omicron). Using published nasal scRNA-seq datasets from COVID-19 patients, we evaluated the expression of genes implicated in eicosanoid synthesis, such as ALOX5, ALOX15, and ALOX15B, across nasal cell types and COVID-19 severity groups. Altogether, our study highlights the fact that the increase in specific lipids implicated in inflammation and the genes required for their synthesis correlated with the severity of the SARS-CoV-2 infection.
关于遗传学和脂质代谢产物与严重的SARS-CoV-2感染之间的关系，仍有许多问题未得到解答。我们对从10名感染患者和10名未感染患者收集的外周血单核细胞（PBMC）和血浆进行了批量RNA测序和全脂肪酸谱分析。使用曼-惠特尼U检验对脂质代谢产物进行单变量比较，结果显示COVID-19患者中有六种脂质代谢产物显著增加，包括脂质介质花生四烯酸（AA）和二十碳五烯酸（EPA），这两种物质都会产生类花生酸。与炎症相关的关键脂质，包括AA和EPA，以及脂肪酸DHA和DPA，与世界卫生组织（WHO）疾病严重程度评分呈显著正相关。对我们的批量RNA测序数据集的分析表明，基于WHO评分，COVID-19患者呈现出不同的转录谱。本体论、京都基因与基因组百科全书（KEGG）和Reactome分析确定了几个关键途径和节点，这些途径和节点富含与先天免疫、淋巴细胞和非淋巴细胞之间的相互作用、白细胞介素信号传导以及随后的DNA损伤途径相关的基因。EPA水平与WHO评分高的患者中观察到的细胞周期加快和DNA损伤途径相关。我们研究了58名健康参与者和COVID-19参与者鼻咽拭子中的基因表达，发现在WHO评分高的患者中，在鼻咽的几种细胞类型中，特别是在不同病毒变体（德尔塔和奥密克戎）的杯状细胞中，参与类花生酸合成的基因，如alox5、alox12和alox15B，被特异性上调。使用来自COVID-19患者的已发表的鼻腔单细胞RNA测序数据集，我们评估了参与类花生酸合成的基因，如ALOX5、ALOX15和ALOX15B，在鼻腔细胞类型和COVID-19严重程度组中的表达。总之，我们的研究突出了这样一个事实，即与炎症相关的特定脂质及其合成所需基因的增加与SARS-CoV-2感染的严重程度相关。
