Calandria Jorgelina M, Bazan Haydee E P, Bhattacharjee Surjyadipta, Kautzmann Marie-Audrey I, Maness Nicholas J, Bazan Nicolas G
Neuroscience Center of Excellence, Louisiana State University Health New Orleans, New Orleans, Louisiana, USA.
Tulane National Primate Research Center, Covington, Louisiana, USA.
FASEB J. 2025 May 31;39(10):e70563. doi: 10.1096/fj.202403197R.
Current vaccines rely on the sequence of Spike (S) protein to induce immunity against the severe acute respiratory coronavirus-2 (SARS-CoV-2) virus. Because of the high mutation rate of the viral S protein, new mutant strains are developed to generate new infectivity profiles. Bioactive lipid mediators (LMs) derived from docosahexaenoic acid (DHA) are synthesized on demand to sustain homeostasis. The purpose of this study was to determine the action of selected LMs in the viral replication of SARS-CoV-2 Omicron BA.5 variant in human lung and nasal epithelial cells. Cells from healthy donors were infected with Omicron BA.5 for one hour and treated with 500 nM Elovanoid (ELV)-N32, ELV-N34, Resolvin D6 isomer (RvD6i), Neuroprotection D1 (NPD1), or vehicle before and after infection. Impedance was recorded to determine cell death by infectivity. Cells were then immunostained for nucleocapsid (N) protein, microtubule-associated protein 1B-light chain 3 (LC3B), and autophagic proteins. N and S RNA were measured to assess the synthesis of viral components. The addition of ELV-N34 or RvD6i decreased the synthesis of N RNA by 76.7% and 96.9%, respectively, in lung primary culture, while NPD1 exerted the same effect in nasal epithelial cells (61.7% reduction). In lung cells, transcription of autophagy-related gene-3 (ATG3) and Sequestosome 1 (SQSTM1/p62), components of the autophagy initiation process, decreased compared to the non-treated infected cells. The results suggest that specific LMs prevent viral autophagy machinery hijacking, leading to a decrease in BA.5 replication. This novel effect of the bioactive LMs as antivirals, regardless of the protein sequence, would potentially complement vaccination and other prevention and treatment therapeutics.
目前的疫苗依靠刺突（S）蛋白序列来诱导针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒的免疫力。由于病毒S蛋白的高突变率，新的突变株不断出现，呈现出新的感染特性。源自二十二碳六烯酸（DHA）的生物活性脂质介质（LMs）可按需合成以维持体内平衡。本研究的目的是确定所选LMs对SARS-CoV-2奥密克戎BA.5变体在人肺和鼻上皮细胞中病毒复制的作用。将来自健康供体的细胞用奥密克戎BA.5感染1小时，并在感染前后用500 nM的依洛瓦底（ELV）-N32、ELV-N34、消退素D6异构体（RvD6i）、神经保护素D1（NPD1）或溶剂处理。记录阻抗以通过感染性确定细胞死亡。然后对细胞进行核衣壳（N）蛋白、微管相关蛋白1B轻链3（LC3B）和自噬蛋白的免疫染色。测量N和S RNA以评估病毒成分的合成。在肺原代培养物中，添加ELV-N34或RvD6i分别使N RNA的合成减少76.7%和96.9%，而NPD1在鼻上皮细胞中也有同样的效果（减少61.7%）。在肺细胞中，与未处理的感染细胞相比，自噬起始过程的成分自噬相关基因-3（ATG3）和聚集体蛋白1（SQSTM1/p62）的转录减少。结果表明，特定的LMs可防止病毒自噬机制被劫持，从而导致BA.5复制减少。生物活性LMs作为抗病毒药物的这种新作用，无论蛋白质序列如何，都可能补充疫苗接种及其他预防和治疗方法。
