Institute of Preventive Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China.
Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Hangzhou, China.
mBio. 2022 Jun 28;13(3):e0066422. doi: 10.1128/mbio.00664-22. Epub 2022 Apr 25.
To fulfill virus replication and persistent infection in hosts, viruses have to find ways to compromise innate immunity, including timely impedance on antiviral RNases and inflammatory responses. Porcine reproductive and respiratory syndrome virus (PRRSV) is a major swine pathogen causing immune suppression. MALT1 is a central immune regulator in both innate and adaptive immunity. In this study, MALT1 was confirmed to be induced rapidly upon PRRSV infection and mediate the degradation of two anti-PRRSV RNases, MCPIP1 and N4BP1, relying on its proteolytic activity, consequently facilitating PRRSV replication. Multiple PRRSV nsps, including nsp11, nsp7β, and nsp4, contributed to MALT1 elicitation. Interestingly, the elevated expression of MALT1 began to decrease once intracellular viral expression reached a high enough level. Higher infection dose brought earlier MALT1 inflection. Further, PRRSV nsp6 mediated significant MALT1 degradation via ubiquitination-proteasome pathway. Downregulation of MALT1 suppressed NF-κB signals, leading to the decrease in proinflammatory cytokine expression. In conclusion, MALT1 expression was manipulated by PRRSV in an elaborate manner to antagonize precisely the antiviral effects of host RNases without excessive and continuous activation of inflammatory responses. These findings throw light on the machinery of PRRSV to build homeostasis in infected immune system for viral settlement. PRRSV is a major swine pathogen, suppresses innate immunity, and causes persistent infection and coinfection with other pathogens. As a central immune mediator, MALT1 plays essential roles in regulating immunity and inflammation. Here, PRRSV was confirmed to manipulate MALT1 expression in an accurate way to moderate the antiviral immunity. Briefly, multiple PRRSV nsps induced MALT1 protease to antagonize anti-PRRSV RNases N4BP1 and MCPIP1 upon infection, thereby facilitating viral replication. In contrast, PRRSV nsp6 downregulated MALT1 expression via ubiquitination-proteasome pathway to suppress the inflammatory responses upon infection aggravation, contributing to immune defense alleviation and virus survival. These findings revealed the precise expression control on MALT1 by PRRSV for antagonizing antiviral RNases, along with recovering immune homeostasis. For the first time, this study enlightens a new mechanism of PRRSV adapting antiviral innate immunity by modulating MALT1 expression.
为了在宿主中实现病毒复制和持续感染，病毒必须找到方法来损害先天免疫，包括及时抑制抗病毒核糖核酸酶和炎症反应。猪繁殖与呼吸综合征病毒（PRRSV）是一种主要的猪病原体，可导致免疫抑制。MALT1 是先天免疫和适应性免疫中的中央免疫调节剂。在这项研究中，PRRSV 感染后迅速诱导 MALT1 的表达，并依赖其蛋白水解活性介导两种抗 PRRSV RNase（MCPIP1 和 N4BP1）的降解，从而促进 PRRSV 的复制。多个 PRRSV nsps，包括 nsp11、nsp7β 和 nsp4，有助于 MALT1 的诱导。有趣的是，一旦细胞内病毒表达达到足够高的水平，MALT1 的表达就开始下降。更高的感染剂量会导致 MALT1 更早地发生转折。此外，PRRSV nsp6 通过泛素-蛋白酶体途径介导显著的 MALT1 降解。下调 MALT1 抑制 NF-κB 信号，导致促炎细胞因子表达减少。总之，PRRSV 以精细的方式操纵 MALT1 的表达，以拮抗宿主 RNase 的抗病毒作用，而不会过度和持续激活炎症反应。这些发现揭示了 PRRSV 建立感染免疫系统中病毒定居的动态平衡的机制。PRRSV 是一种主要的猪病原体，抑制先天免疫，并导致持续感染和与其他病原体的合并感染。作为中央免疫介质，MALT1 在调节免疫和炎症方面发挥着重要作用。在这里，PRRSV 被证实以精确的方式操纵 MALT1 的表达，以调节抗病毒免疫。简而言之，多种 PRRSV nsps 在感染时诱导 MALT1 蛋白酶拮抗抗 PRRSV RNase N4BP1 和 MCPIP1，从而促进病毒复制。相比之下，PRRSV nsp6 通过泛素-蛋白酶体途径下调 MALT1 表达，以抑制感染加重时的炎症反应，有助于减轻免疫防御和病毒存活。这些发现揭示了 PRRSV 对抗抗病毒先天免疫的 MALT1 的精确表达控制，以及恢复免疫稳态。这是首次揭示 PRRSV 通过调节 MALT1 表达来适应抗病毒先天免疫的新机制。
