LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

Abstract

As the global prototypical zoonotic hantavirus, Hantaan virus (HTNV) is prevalent in Asia and is the leading causative agent of severe hemorrhagic fever with renal syndrome (HFRS), which has profound morbidity and mortality. Macrophages are crucial components of the host innate immune system and serve as the first line of defense against HTNV infection. Previous studies indicated that the viral replication efficiency in macrophages determines hantavirus pathogenicity, but it remains unknown which factor manipulates the macrophage activation pattern and the virus-host interaction process. Here, we performed the transcriptomic analysis of HTNV-infected mouse bone marrow-derived macrophages and identified the long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1), especially the isoform NEAT1-2, as one of the lncRNAs that is differentially expressed at the early phase. Based on coculture experiments, we revealed that silencing NEAT1-2 hinders inflammatory macrophage activation and facilitates HTNV propagation, while enhancing NEAT1-2 transcription effectively restrains viral replication. Furthermore, sterol response element binding factor-2 (SREBP2), which controls the cholesterol metabolism process, was found to stimulate macrophages by promoting the production of multiple inflammatory cytokines upon HTNV infection. NEAT1-2 could potentiate SREBP2 activity by upregulating Srebf1 expression and interacting with SREBP2, thus stimulating inflammatory macrophages and limiting HTNV propagation. More importantly, we demonstrated that the NEAT1-2 expression level in patient monocytes was negatively correlated with viral load and HFRS disease progression. Our results identified a function and mechanism of action for the lncRNA NEAT1 in heightening SREBP2-mediated macrophage activation to restrain hantaviral propagation and revealed the association of NEAT1 with HFRS severity.

IL-15 induced bystander activation of CD8+ T cells may mediate endothelium injury through NKG2D in Hantaan virus infection

“…Annually, 150,000–200,000 clinical cases of hantavirus infection are reported worldwide with mortality rates of HFRS and HCPS up to 15% and 50%, respectively ( Mir, 2021 ). According to the report of the Chinese Center for Disease Control and Prevention, a total of 106,939 HFRS cases were reported during 2012–2021 in China (Statistics, 2021; Yang et al., 2022 ), contributing to more than 80% of the global cases. Therefore, studies on the immune response in HTNV infection could help us to better understand the pathogenesis of HFRS and develop better treatment for HFRS patients.…”

DecipheringStaphylococcus aureus-host dynamics using dual activity-based protein profiling of ATP-interacting proteins

“…PNN located in epithelial cell desmosomes, regulates cell integrity and adhesion (133). Host factors such as NEAT-1, associated with PNN, triggers macrophage inflammation (134, 135). Silencing NEAT-1 by ALYREF repression reduces ATP and mitochondrial energy production (136).…”

Deciphering Staphylococcus aureus– host dynamics using dual activity-based protein profiling of ATP-interacting proteins

“…PNN located in epithelial cell desmosomes regulates cell integrity and adhesion ( 138 ). Host factors such as NEAT-1, associated with PNN, trigger macrophage inflammation ( 139 , 140 ). Silencing NEAT-1 by ALYREF repression reduces ATP and mitochondrial energy production ( 141 ).…”