Autophagy in Virus Infection: A Race between Host Immune Response and Viral Antagonism.

Virus-infected cells trigger a robust innate immune response and facilitate virus replication. Here, we review the role of autophagy in virus infection, focusing on both pro-viral and anti-viral host responses using a select group of viruses. Autophagy is a cellular degradation pathway operated at the basal level to maintain homeostasis and is induced by external stimuli for specific functions. The degradative function of autophagy is considered a cellular anti-viral immune response. However, autophagy is a double-edged sword in viral infection; viruses often benefit from it, and the infected cells can also use it to inhibit viral replication. In addition to viral regulation, autophagy pathway proteins also function in autophagy-independent manners to regulate immune responses. Since viruses have co-evolved with hosts, they have developed ways to evade the anti-viral autophagic responses of the cells. Some of these mechanisms are also covered in our review. Lastly, we conclude with the thought that autophagy can be targeted for therapeutic interventions against viral diseases.

Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities.

The ubiquitously expressed transcription factor interferon (IFN) regulatory factor 3 (IRF3) is critical for the induction of antiviral genes, e.g., type-I IFN. In addition to its transcriptional function, IRF3 also activates a nontranscriptional, proapoptotic signaling pathway. While the proapoptotic function of IRF3 protects against viral infections, it is also involved in harmful immune responses that trigger hepatocyte cell death and promote liver disease. Thus, we hypothesized that a small-molecule inhibitor of the proapoptotic activity of IRF3 could alleviate fatty-acid-induced hepatocyte cell death. We conducted a high-throughput screen, which identified auranofin as a small-molecule inhibitor of the proapoptotic activity of IRF3. In addition to the nontranscriptional apoptotic pathway, auranofin also inhibited the transcriptional activity of IRF3. Using biochemical and genetic tools in human and mouse cells, we uncovered a novel mechanism of action for auranofin, in which it induces cellular autophagy to degrade IRF3 protein, thereby suppressing IRF3 functions. Autophagy-deficient cells were unable to degrade IRF3 upon auranofin treatment, suggesting that the autophagic degradation of IRF3 is a novel approach to regulate IRF3 activities. Using a physiologically relevant in vitro model, we demonstrated that auranofin inhibited fatty-acid-induced apoptotic cell death of hepatocytes. In summary, auranofin is a novel inhibitor of IRF3 functions and may represent a potential therapeutic option in diseases where IRF3 is deleterious.

Sex moderates the relationship between resting heart rate variability and self-reported difficulties in emotion regulation.

Lower resting vagally mediated heart rate variability (HRV) is thought to reflect poorer function of the neurophysiological pathways underlying emotion regulation (ER) and thus, poorer ER abilities. Sex differences in resting HRV exists such that women typically exhibit higher resting HRV than men. It is proposed that greater HRV in women reflects compensation for greater negative affect such as anxiety and depression. However, research has not yet investigated how the association between resting HRV and every day perceived difficulties in ER may be moderated by sex. The current study sought to test this in a sample of 362 young participants (207 females, mean age of 19). Resting HRV was assessed during a 5-min baseline period using an electrocardiogram. Participants then completed the 36-item Difficulties in Emotion Regulation Scale (DERS) designed to evaluate participant's daily difficulties in ER. Controlling for several covariates, sex significantly moderated the relationship between resting HRV and ER difficulties, such that women showed a much stronger relationship compared with men. Specifically, women with lower HRV reported greater difficulties in ER compared with men with lower HRV, whereas women with higher HRV reported slightly lesser difficulties in ER compared with all men. Overall, this study supports a deeper understanding of how neurophysiological differences in ER between men and women-as indexed by resting HRV-may contribute to how effectively individuals regulate their emotions on a day-to-day basis, with implications for well-being. (PsycINFO Database Record (c) 2019 APA, all rights reserved).