A groundbreaking study conducted in China has revealed a significant discovery regarding the interaction between the SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 NP), trimethylamine N-oxide (TMAO), and inflammation in vascular smooth muscle cells (VSMCs). The study aims to understand the combined effects of these factors on inflammation by exploring the modulatory effect of SARS-CoV-2 NP on TMAO-induced lipogenesis and NLRP3 inflammasome activation.
Previous research has identified several proteins associated with inflammation in coronavirus infections, such as the SARS-CoV envelope protein and 3a protein. However, this study focuses specifically on the role of SARS-CoV-2 NP in promoting the secretion of inflammatory cytokines by enhancing NLRP3 inflammasome assembly and activation. TMAO, a byproduct of gut microbiota, is known to recruit the NLRP3 inflammasome and trigger inflammation.
The study demonstrates that SARS-CoV-2 NP activates the sterol regulatory element-binding protein (SREBP) by causing the dissociation of SCAP from the endoplasmic reticulum. This activation leads to the upregulation of lipogenic genes and the activation of the NLRP3 inflammasome. TMAO, on the other hand, facilitates the translocation of the SCAP-SREBP complex, creating an environment that allows SARS-CoV-2 NP to directly bind to the NLRP3 protein and promote NLRP3 inflammasome assembly.
The researchers discovered that inhibiting the SCAP-SREBP2 pathway effectively reduces lipogenic gene expression and alleviates NLRP3 inflammasome-mediated systemic inflammation in VSMCs stimulated with TMAO and SARS-CoV-2 NP. These findings underscore the critical role of the SCAP-SREBP signaling pathway in amplifying TMAO-induced lipogenesis and NLRP3 inflammasome activation by SARS-CoV-2 NP.
Given the severe cardiovascular complications observed in COVID-19 patients and their association with higher mortality rates, understanding the impact of SARS-CoV-2 on vascular dysfunction is of utmost importance. The interaction between the virus and the SCAP-SREBP signaling pathway raises concerns about its implications for cardiovascular health. This study not only unravels the molecular intricacies of the interplay between SARS-CoV-2 NP, TMAO, and inflammation but also identifies the SCAP-SREBP signaling pathway as a potential target for intervention in COVID-19-related cardiovascular diseases.
As the world grapples with the ongoing pandemic, gaining a comprehensive understanding of the virus-host interaction at the molecular level is crucial for the development of targeted therapeutic strategies and the mitigation of the severe consequences of COVID-19. The findings of this study have been published in the esteemed peer-reviewed journal Tissue and Cell, shedding new light on the intricate mechanisms underlying COVID-19-related inflammation and cardiovascular dysfunction.