Zebrafish NF-κB/p65 Is Required for Antiviral Responses.

Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known for its chemosensory function in neurons, causing pain and neurogenic inflammation. TRPA1 is activated by many noxious compounds including some inflammatory mediators. We and others have shown that TRPA1 is also expressed in epithelial cells, but its function in the epithelial barrier remains unclear. Here, we discovered in RNA-seq studies that inhibition of TRPA1 reduced the expression of a large number of antiviral and inflammatory genes under the influence of the key antiviral cytokine interferon beta in human A549 lung epithelial cells. In the gene ontology analysis, the terms most strongly affected by TRPA1 antagonists included many associated with antiviral defense such as "defense response to virus" and "antiviral innate immune response." To validate the RNA-seq results, selected antiviral genes such as myxovirus resistance protein 1 were further studied and found to be upregulated by TRPA1 by using reverse transcription quantitative polymerase chain reaction and western blotting, pharmacological TRPA1 inhibitors, TRPA1-targeting small interfering RNA, and ex vivo lung tissue cultures from TRPA1-deficient mice. Mechanistically, TRPA1 inhibitors partially reduced interferon beta-induced Ca2+ influx, phosphorylation of the transcription factor signal transducer and activator 1, and the interferon-sensitive response element-dependent transcription. These data suggest that TRPA1 mediates cellular signaling and biologically relevant changes in gene expression induced by type I interferons. The results offer TRPA1 as a novel treatment target for inflammatory conditions characterized by enhanced type I interferon activity such as hyperinflammatory states associated with viral infections and some autoimmune diseases, but TRPA1 inhibition may also influence interferon-induced antiviral immunity. SIGNIFICANCE STATEMENT: We found that the transient receptor potential ankyrin 1 channel can promote gene expression changes induced by type I interferons in human lung epithelial cells. Inhibiting transient receptor potential ankyrin 1 could decrease interferon-induced inflammation but could also influence the antiviral state.

Phase Ib Trial of Oncolytic Herpes Virus G207 Shows Safety of Multiple Injections and Documents Viral Replication

Anti-viral gene induction is absent upon secondary challenge with double-stranded RNA in the Pacific oyster, Crassostrea gigas

Melanoma differentiation-associated gene-5 (MDA5) acts as a cytoplasmic RNA sensor to detect viral dsRNA and mediates antiviral innate immune responses to infection by RNA viruses. Upon recognition of viral dsRNA, MDA5 is activated with K63-linked polyubiquitination and then triggers the recruitment of MAVS and activation of TBK1 and IKKα/β, subsequently leading to IRF3 and NF-κB phosphorylation. However, the specific E3 ubiquitin ligase for MDA5 K63-polyubiquitination has not been well characterized. Great numbers of symptomatic and severe infections of SARS-CoV-2 are spreading worldwide, and the poor efficacy of treatment with type I interferon and antiviral immune agents indicates that SARS-CoV-2 escapes from antiviral immune responses via several unknown mechanisms. Here, we report that SARS-CoV-2 nonstructural protein 8 (nsp8) acts as a suppressor of antiviral innate immune and inflammatory responses to promote infection of SARS-CoV-2. It downregulates the expression of type I interferon, IFN-stimulated genes and proinflammatory cytokines by binding to MDA5 and TRIM4 and impairing TRIM4-mediated MDA5 K63-linked polyubiquitination. Our findings reveal that nsp8 mediates innate immune evasion during SARS-CoV-2 infection and may serve as a potential target for future therapeutics for SARS-CoV-2 infectious diseases.

Expression profiles of antiviral response genes in chicken bursal cells stimulated with Toll-like receptor ligands

Background Early, accurate detection of respiratory viral infections is critical for clinical and public health interventions. We previously developed a whole blood mRNA detection assay (HR-B/V) measuring host gene expression biomarkers in circulating leukocytes that accurately discriminates between viral and bacterial acute respiratory infections. Herein, we evaluated performance of these immune biomarkers for detection of viral infection at early timepoints following influenza exposure using controlled human infection models (CHIMs). Methods Serial samples from 30 symptomatic, infected subjects across five influenza (H1N1 and H3N2) CHIM studies were analyzed using the Franklin Integrated Sample Prep (ISP), a sample-to-answer real-time (RT) PCR platform with ∼1 hour run-time. Blood samples (from pre-inoculation through resolution of disease) were loaded into ISP cartridges for RNA extraction and multiplex RT-PCR. Cycle threshold values were normalized, and gene expression levels were compared to clinical and virologic outcomes. Results Timing of symptom onset after inoculation was variable, but occurred approximately 50 hours after viral exposure, with peak symptoms occurring on average at ∼90 hours. Expression of genes depicting canonical antiviral immune responses was seen as early as 21 hours after inoculation. Most subjects (29/30) exhibited upregulation of ≥ 1 antiviral response gene at or before 36 hours post inoculation, and 73% (22/30) had ≥ 1 antiviral response genes exhibit increased expression prior to symptom onset. A viral model built from these genes correctly diagnosed infection in 29/30 subjects at ≥ 1 acute timepoint. Conclusion A host response-based mRNA assay targeting genes involved in canonical antiviral innate immune responses and measured on a rapid, field-deployable platform, shows promise for detection of early, even pre-symptomatic influenza infection. Disclosures Clare Camilleri, n/a, Biomeme, Inc.: Employed by Biomeme|Biomeme, Inc.: Stocks/Bonds (Private Company) Sepideh Naderi, n/a, Biomeme Inc: Employee Rachel Myers, PhD, Biomeme: Royalties on patents for gene expression classifiers of fungal infection Julie M. Steinbrink, MD, MHS, Biomeme: patents for gene expression classifiers of fungal infection|McGraw Hill Publishing: royalties Thomas W. Burke, PhD, Biomeme: Advisor/Consultant|Biomeme: Ownership Interest Christopher W. Woods, MD, MPH, Biomeme: Patents on differentiating bacterial from viral infections|Biomeme: Ownership Interest|Biomeme: Stocks/Bonds (Private Company) Micah T. McClain, MD, PhD, Biomeme: patents for gene expression classifiers of fungal infection|Darwin Biosciences: Board Member|UpToDate: Advisor/Consultant

Grouper SPL promotes STING- and IRF3-mediated antiviral immune response against iridovirus infection.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer

Rotavirus is a major cause of diarrhea worldwide and exhibits a pronounced small intestinal epithelial cell (IEC) tropism. Both human infants and neonatal mice are highly susceptible, whereas adult individuals remain asymptomatic and shed only low numbers of viral particles. Here we investigated age-dependent mechanisms of the intestinal epithelial innate immune response to rotavirus infection in an oral mouse infection model. Expression of the innate immune receptor for viral dsRNA, Toll-like receptor (Tlr) 3 was low in the epithelium of suckling mice but strongly increased during the postnatal period inversely correlating with rotavirus susceptibility, viral shedding and histological damage. Adult mice deficient in Tlr3 (Tlr3−/−) or the adaptor molecule Trif (TrifLps2/Lps2) exerted significantly higher viral shedding and decreased epithelial expression of proinflammatory and antiviral genes as compared to wild-type animals. In contrast, neonatal mice deficient in Tlr3 or Trif did not display impaired cell stimulation or enhanced rotavirus susceptibility. Using chimeric mice, a major contribution of the non-hematopoietic cell compartment in the Trif-mediated antiviral host response was detected in adult animals. Finally, a significant age-dependent increase of TLR3 expression was also detected in human small intestinal biopsies. Thus, upregulation of epithelial TLR3 expression during infancy might contribute to the age-dependent susceptibility to rotavirus infection.

Herpes simplex virus type 1 (HSV-1), one of the human pathogens widely epidemic and transmitted among various groups of people in the world, often causes symptoms known as oral herpes or lifelong asymptomatic infection. HSV-1 employs many sophisticated strategies to escape host antiviral immune response based on its multiple coding proteins. However, the functions involved in the immune evasion of miRNAs encoded by HSV-1 during lytic (productive) infection remain poorly studied. Dual-luciferase reporter gene assay and bioinformatics revealed that Asp-Glu-Ala-Asp (DEAD)-box helicase 41 (DDX41), a cytosolic DNA sensor of the DNA-sensing pathway, was a putative direct target gene of HSV-1-encoded miR-H2-3p. The transfection of miR-H2-3p mimics inhibited the expression of DDX41 at the level of mRNA and protein, as well as the expression of interferon beta (IFN-β) and myxoma resistance protein I (MxI) induced by HSV-1 infection in THP-1 cells, and promoted the viral replication and its gene transcription. However, the transfection of miR-H2-3p inhibitor showed opposite effects. This finding indicated that HSV-1-encoded miR-H2-3p attenuated cytosolic DNA–stimulated antiviral immune response by manipulating host DNA sensor molecular DDX41 to enhance virus replication in cultured cells.

The exciting field of human social genomics provides an evolutionarily informed, multilevel framework for understanding how positive and negative social-environmental experiences affect the genome to impact lifelong health, well-being, behavior, and longevity. In this review, we first summarize common patterns of socially influenced changes in the expression of pro-inflammatory and antiviral immune response genes (e.g., the Conserved Transcriptional Response to Adversity), and the multilevel psychological, neural, and cell signaling pathways by which social factors regulate human gene expression. Second, we examine how these effects are moderated by genetic polymorphisms and the specific types of social-environmental experiences that most strongly affect gene expression and health. Third, we identify positive psychosocial experiences and interventions that have been found to impact gene expression. Finally, we discuss promising opportunities for future research on this topic and how health care providers can use this information to improve patient health and well-being.

170 : Targeting RIG-I-like receptor signaling and innate immunity for adjuvant activity

Long noncoding RNAs (lncRNAs) function as micro regulators to impact gene expression after multiple pathogen infections, which have been largely studied in the last few years. Although lncRNA studies on lower vertebrates have received less attention than those on mammals, current studies suggest that lncRNA plays an important role in the immune response of fish to pathogen infections. Here, we studied the effect of MIR122HG as the host gene of miR-122 and indirectly negatively regulate MAVS-mediated antiviral immune responses in miiuy croaker (Miichthys miiuy). We found that poly(I:C) significantly increases the host MIR122HG expression. The increased MIR122HG expression inhibited the production of the antiviral immune-related genes IFN-1, ISG15 and Viperin upon SCRV treatment. In addition, MIR122HG can act as a pivotally negative regulator involved in the MAVS-mediated NF-κB and IRF3 signaling pathways, which can effectively avoid an excessive immune response. Additionally, we found that MIR122HG can promote the replication of SCRV. Our study provides evidence about the involvement of lncRNAs in the antiviral immune response of fish and broadens the understanding of the function of lncRNAs as a precursor miRNA in teleost fish.

The coronavirus disease 2019 (COVID-19) was a global endemic that continues to cause a large number of severe illnesses and fatalities. There is increasing evidence that non-coding RNAs (ncRNAs) are crucial regulators of viral infection and antiviral immune response and the role of non-coding RNAs in SARS-CoV-2 infection has now become the focus of scholarly inquiry. After SARS-CoV-2 infection, some ncRNAs' expression levels are regulated to indirectly control the expression of antiviral genes and viral gene replication. However, some other ncRNAs are hijacked by SARS-CoV-2 in order to help the virus evade the immune system by suppressing the expression of type I interferon (IFN-1) and controlling cytokine levels. In this review, we summarize the recent findings of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) among non-coding RNAs in SARS-CoV-2 infection and antiviral response, discuss the potential mechanisms of actions, and prospects for the detection, treatment, prevention and future directions of SARS-CoV-2 infection research.

C21-steroidal pregnane sapogenins and their derivatives as anti-inflammatory agents