Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2.

Type I and III interferons (IFN-I/λ) are important antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDC) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely via a local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to develop this response could be important to understand severe cases of COVID-19.

The DEAD box RNA helicase DDX42 is an intrinsic inhibitor of positive-strand RNA viruses.

Genome-wide screens are powerful approaches to unravel regulators of viral infections. Here, a CRISPR screen identifies the RNA helicase DDX42 as an intrinsic antiviral inhibitor of HIV-1. Depletion of endogenous DDX42 increases HIV-1 DNA accumulation and infection in cell lines and primary cells. DDX42 overexpression inhibits HIV-1 infection, whereas expression of a dominant-negative mutant increases infection. Importantly, DDX42 also restricts LINE-1 retrotransposition and infection with other retroviruses and positive-strand RNA viruses, including CHIKV and SARS-CoV-2. However, DDX42 does not impact the replication of several negative-strand RNA viruses, arguing against an unspecific effect on target cells, which is confirmed by RNA-seq analysis. Proximity ligation assays show DDX42 in the vicinity of viral elements, and cross-linking RNA immunoprecipitation confirms a specific interaction of DDX42 with RNAs from sensitive viruses. Moreover, recombinant DDX42 inhibits HIV-1 reverse transcription in vitro. Together, our data strongly suggest a direct mode of action of DDX42 on viral ribonucleoprotein complexes. Our results identify DDX42 as an intrinsic viral inhibitor, opening new perspectives to target the life cycle of numerous RNA viruses.

Shaping the Innate Immune Response Through Post-Transcriptional Regulation of Gene Expression Mediated by RNA-Binding Proteins

Innate immunity is the frontline of defense against infections and tissue damage. It is a fast and semi-specific response involving a myriad of processes essential for protecting the organism. These reactions promote the clearance of danger by activating, among others, an inflammatory response, the complement cascade and by recruiting the adaptive immunity. Any disequilibrium in this functional balance can lead to either inflammation-mediated tissue damage or defense inefficiency. A dynamic and coordinated gene expression program lies at the heart of the innate immune response. This expression program varies depending on the cell-type and the specific danger signal encountered by the cell and involves multiple layers of regulation. While these are achieved mainly via transcriptional control of gene expression, numerous post-transcriptional regulatory pathways involving RNA-binding proteins (RBPs) and other effectors play a critical role in its fine-tuning. Alternative splicing, translational control and mRNA stability have been shown to be tightly regulated during the innate immune response and participate in modulating gene expression in a global or gene specific manner. More recently, microRNAs assisting RBPs and post-transcriptional modification of RNA bases are also emerging as essential players of the innate immune process. In this review, we highlight the numerous roles played by specific RNA-binding effectors in mediating post-transcriptional control of gene expression to shape innate immunity.