Systematic analysis of virus nucleic acid sensor DDX58 in malignant tumor.

Introduction: In December 2019, a novel epidemic of coronavirus pneumonia (COVID-19) was reported，and population-based studies had shown that cancer was a risk factor for death from COVID-19 infection. However, the molecular mechanism between COVID-19 and cancer remains indistinct. In this paper, we analyzed the nucleic acid sensor (DDX58) of SARS-CoV-2 virus, which is a significant gene related to virus infection. For purpose of clarifying the characteristics of DDX58 expression in malignant tumors, this study began to systematically analyze the DDX58 expression profile in the entire cancer type spectrum. Methods: Using TCGA pan-cancer database and related data resources, we analyzed the expression, survival analysis, methylation expression, mutation status, microsatellite instability (MSI), immune related microenvironment, gene related network, function and drug sensitivity of DDX58. Results: The expression level of DDX58 mRNA in most cancers was higher than the expression level in normal tissues. Through TIMER algorithm mining, we found that DDX58 expression was closely related to various levels of immune infiltration in pan-cancer. The promoter methylation level of DDX58 was significantly increased in multiple cancers. In addition, abnormal expression of DDX58 was related to MSI and TMB in multiple cancers, and the most common type of genomic mutation was "mutation." In the protein-protein interaction (PPI) network, we found that type I interferon, phagocytosis, ubiquitinase, and tumor pathways were significantly enriched. Finally, according to the expression of DDX58 indicated potential sensitive drugs such as Cediranib, VE-821, Itraconazole, JNJ-42756493, IWR-1, and Linsitinib. Discussion: In conclusion, we had gained new insights into how DDX58 might contribute to tumor development, and DDX58 could be used as an immune-related biomarker and as a potential immunotherapeutic target for COVID-19 infected cancer patients.

Endothelial Cells as a Key Cell Type for Innate Immunity: A Focused Review on RIG-I Signaling Pathway.

The vascular endothelium consists of a highly heterogeneous monolayer of endothelial cells (ECs) which are the primary target for bacterial and viral infections due to EC's constant and close contact with the bloodstream. Emerging evidence has shown that ECs are a key cell type for innate immunity. Like macrophages, ECs serve as sentinels when sensing invading pathogens or microbial infection caused by viruses and bacteria. It remains elusive how ECs senses danger signals, transduce the signal and fulfil immune functions. Retinoic acid-inducible gene-I (RIG-I, gene name also known as DDX58) is an important member of RIG-I-like receptor (RLR) family that functions as an important pathogen recognition receptor (PRR) to execute immune surveillance and confer host antiviral response. Recent studies have demonstrated that virus infection, dsRNA, dsDNA, interferons, LPS, and 25-hydroxycholesterol (25-HC) can increase RIG-1 expression in ECs and propagate anti-viral response. Of translational significance, RIG-I activation can be inhibited by Panax notoginseng saponins, endogenous PPARγ ligand 15-PGJ2, tryptanthrin and 2-animopurine. Considering the pivotal role of inflammation and innate immunity in regulating endothelial dysfunction and atherosclerosis, here we provided a concise review of the role of RIG-I in endothelial cell function and highlight future direction to elucidate the potential role of RIG-I in regulating cardiovascular diseases as well as virus infectious disease, including COVID-19. Furthered understanding of RIG-I-mediated signaling pathways is important to control disorders associated with altered immunity and inflammation in ECs.

The MAVS Immune Recognition Pathway in Viral Infection and Sepsis.

Significance: It is estimated that close to 50 million cases of sepsis result in over 11 million annual fatalities worldwide. The pathognomonic feature of sepsis is a dysregulated inflammatory response arising from viral, bacterial, or fungal infections. Immune recognition of pathogen-associated molecular patterns is a hallmark of the host immune defense to combat microbes and to prevent the progression to sepsis. Mitochondrial antiviral signaling protein (MAVS) is a ubiquitous adaptor protein located at the outer mitochondrial membrane, which is activated by the cytosolic pattern recognition receptors, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation associated gene 5 (MDA5), following binding of viral RNA agonists. Recent Advances: Substantial progress has been made in deciphering the activation of the MAVS pathway with its interacting proteins, downstream signaling events (interferon [IFN] regulatory factors, nuclear factor kappa B), and context-dependent type I/III IFN response. Critical Issues: In the evolutionary race between pathogens and the host, viruses have developed immune evasion strategies for cleavage, degradation, or blockade of proteins in the MAVS pathway. For example, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M protein and ORF9b protein antagonize MAVS signaling and a protective type I IFN response. Future Directions: The role of MAVS as a sensor for nonviral pathogens, host cell injury, and metabolic perturbations awaits better characterization in the future. New technical advances in multidimensional single-cell analysis and single-molecule methods will accelerate the rate of new discoveries. The ultimate goal is to manipulate MAVS activities in the form of immune-modulatory therapies to combat infections and sepsis. Antioxid. Redox Signal. 35, 1376-1392.