College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, China.
J Virol. 2024 Jul 23;98(7):e0045824. doi: 10.1128/jvi.00458-24. Epub 2024 May 30.
Tryptophan metabolism plays a crucial role in facilitating various cellular processes essential for maintaining normal cellular function. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan (Trp) into kynurenine (Kyn), thereby initiating the degradation of Trp. The resulting Kyn metabolites have been implicated in the modulation of immune responses. Currently, the role of IDO1-mediated tryptophan metabolism in the process of viral infection remains relatively unknown. In this study, we discovered that classical swine fever virus (CSFV) infection of PK-15 cells can induce the expression of IDO1, thereby promoting tryptophan metabolism. IDO1 can negatively regulate the NF-κB signaling by mediating tryptophan metabolism, thereby facilitating CSFV replication. We found that silencing the IDO1 gene enhances the expression of IFN-α, IFN-β, and IL-6 by activating the NF-κB signaling pathway. Furthermore, our observations indicate that both silencing the IDO1 gene and administering exogenous tryptophan can inhibit CSFV replication by counteracting the cellular autophagy induced by Rapamycin. This study reveals a novel mechanism of IDO1-mediated tryptophan metabolism in CSFV infection, providing new insights and a theoretical basis for the treatment and control of CSFV.IMPORTANCEIt is well known that due to the widespread use of vaccines, the prevalence of classical swine fever (CSF) is shifting towards atypical and invisible infections. CSF can disrupt host metabolism, leading to persistent immune suppression in the host and causing significant harm when co-infected with other diseases. Changes in the host's metabolic profiles, such as increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, can also influence virus replication. Mammals utilize various pathways to modulate immune responses through amino acid utilization, including increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, thereby limiting viral replication. Therefore, this study proposes that targeting the modulation of tryptophan metabolism may represent an effective approach to control the progression of CSF.
色氨酸代谢在促进各种细胞过程中起着至关重要的作用，这些过程对于维持正常细胞功能至关重要。吲哚胺 2,3-双加氧酶 1（IDO1）催化色氨酸（Trp）转化为犬尿氨酸（Kyn），从而启动 Trp 的降解。由此产生的 Kyn 代谢物被认为参与了免疫反应的调节。目前，IDO1 介导的色氨酸代谢在病毒感染过程中的作用尚不清楚。在这项研究中，我们发现猪瘟病毒（CSFV）感染 PK-15 细胞可以诱导 IDO1 的表达，从而促进色氨酸代谢。IDO1 可以通过介导色氨酸代谢来负调控 NF-κB 信号通路，从而促进 CSFV 的复制。我们发现，沉默 IDO1 基因可以通过激活 NF-κB 信号通路来增强 IFN-α、IFN-β 和 IL-6 的表达。此外，我们的观察结果表明，沉默 IDO1 基因和给予外源性色氨酸都可以通过拮抗 Rapamycin 诱导的细胞自噬来抑制 CSFV 的复制。这项研究揭示了 IDO1 介导的色氨酸代谢在 CSFV 感染中的新机制，为 CSFV 的治疗和控制提供了新的见解和理论依据。
重要性：
众所周知，由于疫苗的广泛使用，猪瘟（CSF）的流行趋势正在向非典型和隐形感染转变。CSF 可破坏宿主代谢，导致宿主持续免疫抑制，并在与其他疾病合并感染时造成重大危害。宿主代谢谱的变化，如氨基酸分解代谢增加和免疫调节代谢物及其衍生物的产生，也会影响病毒复制。哺乳动物通过氨基酸利用来调节免疫反应，包括增加氨基酸的分解代谢和产生免疫调节代谢物及其衍生物，从而限制病毒复制。因此，本研究提出靶向色氨酸代谢的调节可能是控制 CSF 进展的有效方法。
