Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn’t. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.
Global coronavirus disease 2019 (COVID‐19) pandemics highlight the need of developing vaccines with universal and durable protection against emerging SARS‐CoV‐2 variants. Here we developed an extended‐release vaccine delivery system (GP‐diABZI‐RBD), consisting the original SARS‐CoV‐2 WA1 strain receptor‐binding domain (RBD) as the antigen and diABZI stimulator of interferon genes (STING) agonist in conjunction with yeast β‐glucan particles (GP‐diABZI) as the platform. GP‐diABZI‐RBD could activate STING pathway and inhibit SARS‐CoV‐2 replication. Compared to diABZI‐RBD, intraperitoneal injection of GP‐diABZI‐RBD elicited robust cellular and humoral immune responses in mice. Using SARS‐CoV‐2 GFP/ΔN transcription and replication‐competent virus‐like particle system (trVLP), we demonstrated that GP‐diABZI‐RBD‐prototype vaccine exhibited the strongest and durable humoral immune responses and antiviral protection; whereas GP‐diABZI‐RBD‐Omicron displayed minimum neutralization responses against trVLP. By using pseudotype virus (PsVs) neutralization assay, we found that GP‐diABZI‐RBD‐Prototype, GP‐diABZI‐RBD‐Delta, and GP‐diABZI‐RBD‐Gamma immunized mice sera could efficiently neutralize Delta and Gamma PsVs, but had weak protection against Omicron PsVs. In contrast, GP‐diABZI‐RBD‐Omicron immunized mice sera displayed the strongest neutralization response to Omicron PsVs. Taken together, the results suggest that GP‐diABZI can serve as a promising vaccine delivery system for enhancing durable humoral and cellular immunity against broad SARS‐CoV‐2 variants. Our study provides important scientific basis for developing SARS‐CoV‐2 VOC‐specific vaccines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.