PLNC8 αβ Potently Inhibits the Flavivirus Kunjin and Modulates Inflammatory and Intracellular Signaling Responses of Alveolar Epithelial Cells.

IF 3.8 3区 医学 Q2 VIROLOGY Viruses-Basel Pub Date : 2024-11-13 DOI:10.3390/v16111770
Abubakr A M Omer, Sanjiv Kumar, Bo Söderquist, Wessam Melik, Torbjörn Bengtsson, Hazem Khalaf
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Abstract

PLNC8 αβ is a cationic antimicrobial peptide that previously has been reported to express both antibacterial and antiviral properties. This study aimed to further elucidate the antiviral effects of PLNC8 αβ and its impact on virus-induced cytotoxicity and inflammatory signaling in human alveolar epithelial cells (A549) infected with the flavivirus Kunjin. Complementary in silico analyses using molecular dynamics (MD) simulation were conducted to investigate the mechanism of action of PLNC8 αβ by studying the interaction of PLNC8 α and β with models of a flavivirus membrane and a eukaryotic plasma membrane, respectively. Our findings demonstrated that PLNC8 αβ significantly reduces both extracellular and intracellular viral loads, as confirmed by plaque reduction assays and RT-PCR. The peptide also mitigated virus-induced cytotoxicity and inflammation. Notably, PLNC8 αβ modulated the virus-induced dysregulation of key signaling and inflammatory genes, such as TLR9, TLR3, NOD2, FOS, JUN, IL6, and CXCL8. MD simulation revealed that PLNC8 αβ exhibits higher binding affinity for a flavivirus membrane model compared to a model of the plasma membrane, likely due to stronger electrostatic interactions with anionic phospholipids. This selective interaction possibly accounts for a potent antiviral activity of PLNC8 αβ combined with a minimal cytotoxicity toward human cells. Overall, PLNC8 αβ shows significant promise as an antiviral agent against flavivirus infections and warrants further exploration for peptide-based antiviral therapies.

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PLNC8 αβ 能有效抑制黄病毒昆金并调节肺泡上皮细胞的炎症反应和细胞内信号反应
PLNC8 αβ是一种阳离子抗菌肽,据报道它具有抗菌和抗病毒两种特性。本研究旨在进一步阐明 PLNC8 αβ 的抗病毒作用及其对感染黄病毒昆金的人肺泡上皮细胞(A549)中病毒诱导的细胞毒性和炎症信号转导的影响。通过研究PLNC8 α和β分别与黄病毒膜和真核细胞质膜模型的相互作用,我们利用分子动力学(MD)模拟进行了互补的硅学分析,以研究PLNC8 α和β的作用机制。我们的研究结果表明,PLNC8 αβ能显著降低细胞外和细胞内的病毒载量,斑块还原试验和RT-PCR也证实了这一点。该肽还能减轻病毒引起的细胞毒性和炎症。值得注意的是,PLNC8 αβ调节了病毒诱导的关键信号转导和炎症基因的失调,如TLR9、TLR3、NOD2、FOS、JUN、IL6和CXCL8。MD 模拟显示,与质膜模型相比,PLNC8 αβ 与黄病毒膜模型的结合亲和力更高,这可能是由于与阴离子磷脂的静电相互作用更强。这种选择性相互作用可能是 PLNC8 αβ 具有强效抗病毒活性且对人类细胞的细胞毒性极低的原因。总之,PLNC8 α β 作为一种抗黄病毒感染的抗病毒药物前景广阔,值得进一步探索基于多肽的抗病毒疗法。
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来源期刊
Viruses-Basel
Viruses-Basel VIROLOGY-
CiteScore
7.30
自引率
12.80%
发文量
2445
审稿时长
1 months
期刊介绍: Viruses (ISSN 1999-4915) is an open access journal which provides an advanced forum for studies of viruses. It publishes reviews, regular research papers, communications, conference reports and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. We also encourage the publication of timely reviews and commentaries on topics of interest to the virology community and feature highlights from the virology literature in the ''News and Views'' section. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.
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