State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China.
J Virol. 2022 Feb 23;96(4):e0191921. doi: 10.1128/JVI.01919-21. Epub 2021 Dec 15.
African swine fever is one of the most serious viral diseases caused by African swine fever virus (ASFV). The metabolic changes induced by ASFV infection remain unknown. Here, porcine alveolar macrophages (PAMs) infected with ASFV was analyzed by ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) in combination with multivariate statistical analysis. A total of 90 metabolites were significantly changed after ASFV infection, and most of them were amino acids and tricarboxylic acid (TCA) cycle intermediates. ASFV infection induced an increase in most of amino acids in the host during the early stages of infection, and amino acids decreased in the late stages of infection. ASFV infection did not significantly affect the glycolysis pathway, whereas it induced increases in citrate, succinate, α-ketoglutarate, and oxaloacetate levels in the TCA cycle, suggesting that ASFV infection promoted the TCA cycle. The activities of aspartate aminotransferase and glutamate production were significantly elevated in ASFV-infected cells and pigs, resulting in reversible transition between TCA cycle and amino acid synthesis. Aspartate, glutamate, and TCA cycle were essential for ASFV replication. In addition, ASFV infection induced an increase in lactate level using lactate dehydrogenase, which led to low expression of beta interferon (IFN-β) and increased ASFV replication. Our data, for the first time, indicate that ASFV infection controls IFN-β production through RIG-I-mediated signaling pathways. These data identified a novel mechanism evolved by ASFV to inhibit host innate immune responses and provide insights for development of new preventive or therapeutic strategies targeting the altered metabolic pathways. In order to promote viral replication, viruses often cause severe immunosuppression and seize organelles to synthesize a large number of metabolites required for self-replication. African swine fever virus (ASFV) has developed many strategies to evade host innate immune responses. However, the impact of ASFV infection on host cellular metabolism remains unknown. Here, for the first time, we analyzed the metabolomic profiles of ASFV-infected PAMs. ASFV infection increased host TCA cycle and amino acid metabolism. Aspartate, glutamate, and TCA cycle promoted ASFV replication. ASFV infection also induced the increase of lactate production to inhibit innate immune responses for self-replication. This study identified novel immune evasion mechanisms utilized by ASFV and provided insights into ASFV-host interactions, which is critical for guiding the design of new prevention strategies against ASFV targeting the altered metabolic pathways.
非洲猪瘟是由非洲猪瘟病毒（ASFV）引起的最严重的病毒性疾病之一。ASFV 感染引起的代谢变化尚不清楚。在这里，我们通过超高效液相色谱-四极杆飞行时间串联质谱联用（UHPLC-QTOF-MS）结合多元统计分析方法，对感染 ASFV 的猪肺泡巨噬细胞（PAMs）进行了分析。共鉴定到 90 种代谢物在 ASFV 感染后发生显著变化，其中大部分为氨基酸和三羧酸（TCA）循环中间产物。ASFV 感染诱导宿主在感染早期大多数氨基酸增加，而在感染晚期氨基酸减少。ASFV 感染对糖酵解途径没有显著影响，而在 TCA 循环中诱导柠檬酸、琥珀酸、α-酮戊二酸和草酰乙酸水平升高，表明 ASFV 感染促进了 TCA 循环。ASFV 感染的细胞和猪中天门冬氨酸氨基转移酶和谷氨酸产量的活性显著升高，导致 TCA 循环和氨基酸合成之间的可逆转换。天冬氨酸、谷氨酸和 TCA 循环是 ASFV 复制所必需的。此外，ASFV 感染通过乳酸脱氢酶诱导乳酸水平升高，导致β干扰素（IFN-β）表达降低和 ASFV 复制增加。我们的数据首次表明，ASFV 感染通过 RIG-I 介导的信号通路控制 IFN-β 的产生。这些数据确定了 ASFV 抑制宿主固有免疫反应的新机制，并为针对改变的代谢途径开发新的预防或治疗策略提供了思路。为了促进病毒复制，病毒通常会引起严重的免疫抑制并夺取细胞器来合成大量自我复制所需的代谢物。非洲猪瘟病毒（ASFV）已经开发了许多策略来逃避宿主固有免疫反应。然而，ASFV 感染对宿主细胞代谢的影响尚不清楚。在这里，我们首次分析了感染 ASFV 的 PAMs 的代谢组学图谱。ASFV 感染增加了宿主 TCA 循环和氨基酸代谢。天冬氨酸、谷氨酸和 TCA 循环促进了 ASFV 的复制。ASFV 感染还诱导了乳酸产量的增加，以抑制自我复制的固有免疫反应。本研究确定了 ASFV 利用的新免疫逃避机制，并为 ASFV-宿主相互作用提供了见解，这对于指导针对改变的代谢途径的新的 ASFV 预防策略的设计至关重要。
