Steigmann Jacob C, Zhou Xiaofeng, Suttenberg Lauren N, Salman Irha, Rehmathullah Zainab F, Weinberg Jason B
Department of Pediatrics, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.
Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan, USA.
J Virol. 2024 Dec 17;98(12):e0123824. doi: 10.1128/jvi.01238-24. Epub 2024 Nov 7.
The immunoproteasome (IP) is a predominantly inducible component of the ubiquitin proteasome system that plays key roles in multiple aspects of immune function, inflammation, and protein homeostasis. We used murine hepatitis virus strain 1 (MHV-1), a mouse coronavirus, to define the role of IP activity during acute coronavirus respiratory infection. Expression of the β5i subunit of the IP and cytokines that induce IP activity, including IFN-γ, TNF-α, and IFN-β, increased in lungs and livers of CH3/HeJ mice following intranasal infection with MHV-1. IP inhibition using ONX-0914 did not affect MHV-1 replication in bone marrow-derived dendritic cells . IP inhibition exacerbated virus-induced weight loss and mortality but had no effect on virus replication in lungs or livers. IP inhibition had minimal effect on virus-induced pulmonary inflammation but led to substantially increased liver pathology, including greater upregulation of pro-inflammatory cytokines and histological evidence of inflammation and necrosis. Those findings were associated with evidence of increased endoplasmic reticulum stress although not with accumulation of ubiquitinated protein. Our results indicate that the IP is a protective host factor during acute MHV-1 infection.
Inflammatory responses triggered by acute infection by respiratory viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drive morbidity and mortality. Infection of mice with murine hepatitis virus strain 1 (MHV-1), a mouse coronavirus, is a useful model to study the pathogenesis of coronavirus respiratory infections. The immunoproteasome is an inducible component of the ubiquitin proteasome system that is poised to contribute to multiple aspects of immune function, inflammation, and protein homeostasis during an infection. We used the MHV-1 model to define the role of the immunoproteasome in coronavirus pathogenesis. We found that immunoproteasome subunit expression increases in the lungs and the liver during acute MHV-1 respiratory infection. Inhibition of immunoproteasome activity did not affect MHV-1 replication but increased MHV-1-induced weight loss, mortality, and inflammation in lungs and livers. Thus, our findings indicate that the immunoproteasome is a critical protective host factor during coronavirus respiratory infection.
免疫蛋白酶体（IP）是泛素蛋白酶体系统中主要可诱导的成分，在免疫功能、炎症和蛋白质稳态的多个方面发挥关键作用。我们使用小鼠冠状病毒鼠肝炎病毒1型（MHV-1）来确定IP活性在急性冠状病毒呼吸道感染中的作用。在用MHV-1鼻内感染后，CH3/HeJ小鼠的肺和肝中IP的β5i亚基以及诱导IP活性的细胞因子（包括IFN-γ、TNF-α和IFN-β）的表达增加。使用ONX-0914抑制IP并不影响骨髓来源的树突状细胞中MHV-1的复制。抑制IP会加剧病毒诱导的体重减轻和死亡率，但对肺或肝中的病毒复制没有影响。抑制IP对病毒诱导的肺部炎症影响最小，但会导致肝脏病理显著增加，包括促炎细胞因子的上调以及炎症和坏死的组织学证据。这些发现与内质网应激增加的证据相关，尽管与泛素化蛋白的积累无关。我们的结果表明，IP是急性MHV-1感染期间的一种保护性宿主因子。
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）等呼吸道病毒急性感染引发的炎症反应会导致发病和死亡。用小鼠冠状病毒鼠肝炎病毒1型（MHV-1）感染小鼠是研究冠状病毒呼吸道感染发病机制的有用模型。免疫蛋白酶体是泛素蛋白酶体系统的一种可诱导成分，在感染期间有望在免疫功能、炎症和蛋白质稳态的多个方面发挥作用。我们使用MHV-1模型来确定免疫蛋白酶体在冠状病毒发病机制中的作用。我们发现，在急性MHV-1呼吸道感染期间，肺和肝中免疫蛋白酶体亚基的表达增加。抑制免疫蛋白酶体活性并不影响MHV-1的复制，但会增加MHV-1诱导的体重减轻、死亡率以及肺和肝中的炎症。因此，我们的发现表明，免疫蛋白酶体是冠状病毒呼吸道感染期间一种关键的保护性宿主因子。
