COVID-19 ORF3a Viroporin-Influenced Common and Unique Cellular Signaling Cascades in Lung, Heart, and the Brain Choroid Plexus Organoids with Additional Enriched MicroRNA Network Analyses for Lung and the Brain Tissues

Tissue-specific implications
of SARS-CoV-2-encoded accessory proteins
are not fully understood. SARS-CoV-2 infection can severely affect
three major organsthe heart, lungs, and brain. We analyzed
SARS-CoV-2 ORF3a interacting host proteins in these three major organs.
Furthermore, we identified common and unique interacting host proteins
and their targeting miRNAs (lung and brain) and delineated associated
biological processes by reanalyzing RNA-seq data from the brain (COVID-19-infected/uninfected
choroid plexus organoid study), lung tissue from COVID-19 patients/healthy
subjects, and cardiomyocyte cells-based transcriptomics analyses.
Our in silico studies showed ORF3a interacting proteins could vary
depending upon tissues. The number of unique ORF3a interacting proteins
in the brain, lungs, and heart were 10, 7, and 1, respectively. Though
common pathways influenced by SARS-CoV-2 infection were more, unique
21 brain and 7 heart pathways were found. One unique pathway for the
heart was negative regulation of calcium ion transport. Reported observations
of COVID-19 patients with a history of hypertension taking calcium
channel blockers (CCBs) or dihydropyridine CCBs had an elevated rate
of intubation or increased rate of intubation/death, respectively.
Also, the likelihood of hospitalization of chronic CCB users with
COVID-19 was greater in comparison to long-term angiotensin-converting
enzyme inhibitors/angiotensin receptor blockers users. Further studies
are necessary to confirm this. miRNA analysis of ORF3a interacting
proteins in the brain and lungs revealed 3 of 37 brain miRNAs and
1 of 25 lung miRNAs with high degree and betweenness indicating their
significance as hubs in the interaction network. Our study could help
in identifying potential tissue-specific COVID-19 drug/drug repurposing
targets.

严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）编码的附属蛋白的组织特异性效应尚未完全阐明。新冠病毒感染可严重累及心脏、肺脏与大脑三大脏器。本研究针对上述三大脏器中的SARS-CoV-2开放阅读框3a（ORF3a）宿主互作蛋白展开了系统分析。此外，我们还鉴定出了共有的与独特的宿主互作蛋白及其靶向微小RNA（miRNA），并针对肺与脑组织中的靶标miRNA，通过重新分析三类RNA测序（RNA-seq）数据阐明了相关生物学过程：分别为新冠感染与未感染状态下的脑脉络丛类器官研究脑组织数据、新冠患者与健康受试者的肺组织数据，以及基于心肌细胞的转录组学分析数据。本研究的计算机模拟分析（in silico）显示，ORF3a的宿主互作蛋白会因组织类型不同而存在差异。脑、肺与心脏中独特的ORF3a宿主互作蛋白数量分别为10、7与1。尽管受新冠病毒感染影响的共有通路数量更多，但我们仍鉴定出21条独特的脑源性通路与7条独特的心脏源性通路。心脏独有的一条生物学通路为钙离子转运负调控。已有临床报道显示，有高血压病史的新冠患者若服用钙离子通道阻滞剂（CCBs）或二氢吡啶类CCBs，其气管插管率或插管/死亡率分别升高。此外，与长期服用血管紧张素转换酶抑制剂/血管紧张素受体阻滞剂的患者相比，长期使用CCBs的新冠患者住院风险更高。目前仍需开展进一步研究以验证上述结论。针对脑与肺组织中ORF3a互作蛋白的miRNA分析显示，37个脑源性miRNA中有3个、25个肺源性miRNA中有1个呈现出较高的度与介数中心性，提示它们在互作网络中作为枢纽节点发挥关键作用。本研究可为鉴定组织特异性新冠治疗药物或药物重定位靶点提供重要参考。