A dual-role of SARS-CoV-2 nucleocapsid protein in regulating innate immune response

The recently emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is the causative agent of ongoing global pan demic of COVID-19,may trigger imm uno suppression in the early stage and overactive immune resp onse in the late stage of infection;However,the un derlying mecha nisms are not well understood.Here we dem on strated that the SARS-CoV-2 nucleocapsid(N)protein dually regulated innate immune responses,i.e.,the low-dose N protein suppressed type I interferon(IFN-I)signaling and inflammatory cytokines,whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines.Mechanistically,the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3,STAT1,and STAT2.Additi on ally,low-dose N protein combined with TRIM25 could suppress the ubiquitination and activatio n of retinoic acidinducible gene I(RIG-I).Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein,which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses,and development of more effective strategies for controlling COVID-19.

IL-33 drives the antitumor effects of dendritic cells via the induction of Tc9 cells

Dendritic cell(DC)tumor vaccines exert their antitumor effects through the induction of effector T cells.We recently identified Tc9 cells as a new potent antitumor effector T cell subset.However,approaches to direct DCs to preferably prime antitumor Tc9 cells should be further exploited.Here,we demonstrate that the addition of interleukin(IL)-33 potently promotes the induction of Tc9 cells by DCs in vitro and in vivo.IL-33 treatment also drives the cytotoxic activities of DC-induced Tc9 cells.Notably,IL-33 treatment enhances cell survival and proliferation of DC-primed CD8+T cells.More importantly,the addition of IL-33 during in vitro priming of tumor-specific Tc9 cells by DCs increases the antitumor capability of Tc9 cells.Mechanistic studies demonstrated that IL-33 treatment inhibits exhaustive CD8+T cell differentiation by inhibiting PD-1 and 2B4 expression and increasing IL-2 and CD127(IL-7 receptor-α,IL-7Rα)expression in CD8+T cells.Finally,the addition of IL-33 further promotes the therapeutic efficacy of DC-based tumor vaccines in the OT-I mouse model.Our study demonstrates the important role of IL-33 in DC-induced Tc9 cell differentiation and antitumor immunity and may have important clinical implications.

Host cell cycle checkpoint as antiviral target for SARS-CoV-2 revealed by integrative transcriptome and proteome analyses

Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of the COVID-19 pandemic,has posed severe threats to global public health,highlighting an urgent need to understand its pathogenesis and to develop antiviral therapies.Both DNA and RNA viruses can modulate cell cycle progression to maximize their replication.1 However,the effects of SARS-CoV-2 on cell cycle progression remains largely unknown.