Johannes Schwerk

Translating the Untranslated Region

Gene expression programs undergo constant regulation to quickly adjust to environmental stimuli that alter the physiological status of the cell, like cellular stress or infection. Gene expression is tightly regulated by multilayered regulatory elements acting in both cis and trans. Posttranscriptional regulation of the 3′ untranslated region (UTR) is a powerful regulatory process that determines the rate of protein translation from mRNA. Regulatory elements targeting the 3′ UTR include microRNAs, RNA-binding proteins, and long noncoding RNAs, which dramatically alter the immune response. We provide an overview of our current understanding of posttranscriptional regulation of immune gene expression. The focus of this review is on regulatory elements that target the 3′ UTR. We delineate how the synergistic or antagonistic interactions of posttranscriptional regulators determine gene expression levels and how dysregulation of 3′ UTR–mediated posttranscriptional control associates with human diseases.

Interferon lambda 4 expression is suppressed by the host during viral infection

Hong et al. show that IFNλ4 exhibits similar antiviral activity to IFNλ3. Humans deploy several mechanisms to limit expression of functional IFNλ4 through noncoding splice variants and nonfunctional protein isoforms.

Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling

Hepatitis C virus (HCV) infects 200 million people globally, and 60–80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2–10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.

Generation of Mouse Small Intestinal Epithelial Cell Lines That Allow the Analysis of Specific Innate Immune Functions

Cell lines derived from the small intestine that reflect authentic properties of the originating intestinal epithelium are of high value for studies on mucosal immunology and host microbial homeostasis. A novel immortalization procedure was applied to generate continuously proliferating cell lines from murine E19 embryonic small intestinal tissue. The obtained cell lines form a tight and polarized epithelial cell layer, display characteristic tight junction, microvilli and surface protein expression and generate increasing transepithelial electrical resistance during in vitro culture. Significant up-regulation of Cxcl2 and Cxcl5 chemokine expression upon exposure to defined microbial innate immune stimuli and endogenous cytokines is observed. Cell lines were also generated from a transgenic interferon reporter (Mx2-Luciferase) mouse, allowing reporter technology-based quantification of the cellular response to type I and III interferon. Thus, the newly created cell lines mimic properties of the natural epithelium and can be used for diverse studies including testing of the absorption of drug candidates. The reproducibility of the method to create such cell lines from wild type and transgenic mice provides a new tool to study molecular and cellular processes of the epithelial barrier.

Landscape of post-transcriptional gene regulation during hepatitis C virus infection

Post-transcriptional regulation of gene expression plays a pivotal role in various gene regulatory networks including, but not limited to metabolism, embryogenesis and immune responses. Different mechanisms of post-transcriptional regulation, which can act individually, synergistically, or even in an antagonistic manner have been described. Hepatitis C virus (HCV) is notorious for subverting host immune responses and indeed exploits several components of the hosts post-transcriptional regulatory machinery for its own benefit. At the same time, HCV replication is post-transcriptionally targeted by host cell components to blunt viral propagation. This review discusses the interplay of post-transcriptional mechanisms that affect host immune responses in the setting of HCV infection and highlights the sophisticated mechanisms both host and virus have evolved in the race for superiority.

IFN-λ 'guts' neutrophil-mediated inflammation

Interferon-λ (IFN-λ) curbs neutrophil-mediated intestinal inflammation by diminishing the production of reactive oxygen species and subsequent oxidative stress. This regulatory process is unique to IFN-λ and is independent of interferon-induced transcription and translation programs.