Viruses infecting vertebrate hosts must overcome the interferon (IFN)-mediated antiviral response to replicate and propagate to new hosts. The complex regulation of the IFN response allows viruses to ...antagonize IFN at multiple levels. However, no single strategy appears to be the golden ticket, and viruses have adopted multiple means to dampen this host defense. This Review does not exhaustively cover all mechanisms of viral IFN antagonism. Rather it examines the ten most common strategies that viruses use to subvert the IFN response with examples from publications appearing in the last 10 years of Cell Host & Microbe. The virus-host interactions involved in induction and evasion of IFN represent a fertile area of research due to the significant large number of host and viral products that regulate this response, resulting in an intricate dance between hosts and their pathogens to achieve an optimal balance between virus replication, host disease, and survival.
Viruses are formidable pathogens that take advantage of the infected cell machinery while disarming the antiviral host defenses. García-Sastre reviews the most common mechanisms used by viruses to antagonize the antiviral interferon response, illustrating the complexity of pathways that sense viral infection and regulate antiviral innate immune responses.
Influenza A and B viruses are a major cause of respiratory disease in humans. In addition, influenza A viruses continuously re-emerge from animal reservoirs into humans causing human pandemics every ...10–50 years of unpredictable severity. Among the first lines of defense against influenza virus infection, the type I interferon (IFN) response plays a major role. In the last 10 years, there have been major advances in understanding how cells recognize being infected by influenza viruses, leading to secretion of type I IFN, and on the effector mechanisms by how IFN exerts its antiviral activity. In addition, we also now know that influenza virus uses multiple mechanisms to attenuate the type I IFN response, allowing for successful infection of their hosts. This review highlights some of these findings and illustrates future research avenues that might lead to new vaccines and antivirals based on the further understanding of the mechanisms of induction and evasion of type I IFN responses by influenza viruses.
The current COVID‐19 pandemic has a tremendous impact on daily life world‐wide. Despite the ability to dampen the spread of SARS‐CoV‐2, the causative agent of the diseases, through restrictive ...interventions, it is believed that only effective vaccines will provide sufficient control over the disease and revert societal live back to normal. At present, a double‐digit number of efforts are devoted to the development of a vaccine against COVID‐19. Here, we provide an overview of these (pre)clinical efforts and provide background information on the technologies behind these vaccines. In addition, we discuss potential hurdles that need to be addressed prior to mass scale clinical translation of successful vaccine candidates.
A mass vaccination campaign against the SARS‐CoV‐2 virus is likely to be the most effective measure to fight the current COVID‐19 pandemic. Here the current COVID‐19 vaccine development efforts in (pre‐)clinical stage are reviewed.
Tripartite motif (TRIM) proteins have been implicated in multiple cellular functions, including antiviral activity. Research efforts so far indicate that the antiviral activity of TRIMs relies, for ...the most part, on their function as E3-ubiquitin ligases. A substantial number of the TRIM family members have been demonstrated to mediate innate immune cell signal transduction and subsequent cytokine induction. In addition, a subset of TRIMs has been shown to restrict viral replication by directly targeting viral proteins. Although the body of work on the cellular roles of TRIM E3-ubiquitin ligases has rapidly grown over the last years, many aspects of their molecular workings and multi-functionality remain unclear. The antiviral function of many TRIMs seems to be conferred by specific isoforms, by sub-cellular localization and in cell-type-specific contexts. Here we review recent findings on TRIM antiviral functions, current limitations and an outlook for future research.
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•The TRIM family of proteins inhibits replication of various viruses.•TRIMs act as E3-ubiquitin ligases for activation of innate immune signaling.•TRIMs evolved as a component of the immune response.
There is a realistic expectation that the global effort in vaccination will bring the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) under control. Nonetheless, ...uncertainties remain about the type of long-term association that the virus will establish with the human population and, in particular, whether coronavirus disease 2019 (COVID-19) will become an endemic disease. Although the trajectory is difficult to predict, the conditions, concepts and variables that influence this transition can be anticipated. Persistence of SARS-CoV-2 as an endemic virus, perhaps with seasonal epidemic peaks, may be fuelled by pockets of susceptible individuals and waning immunity after infection or vaccination, changes in the virus through antigenic drift that diminish protection and re-entries from zoonotic reservoirs. Here we review relevant observations from previous epidemics and discuss the potential evolution of SARS-CoV-2 as it adapts during persistent transmission in the presence of a level of population immunity. Lack of effective surveillance or adequate response could enable the emergence of new epidemic or pandemic patterns from an endemic infection of SARS-CoV-2. There are key pieces of data that are urgently needed in order to make good decisions; we outline these and propose a way forward.
Intracellular detection of virus infections is a critical component of innate immunity carried out by molecules known as pathogen recognition receptors (PRRs). Activation of PRRs by their respective ...pathogen-associated molecular patterns (PAMPs) leads to production of proinflamatory cytokines, including type I IFN, and the establishment of an antiviral state in the host. Out of all PRRs found to date, retinoic acid inducible gene (RIG-I) has been shown to play a key role in recognition of RNA viruses. On the basis of in vitro and transfection studies, 5′ppp RNA produced during virus replication is thought to bind and activate this important sensor. However, the nature of RNA molecules that interact with endogenous RIG-I during the course of viral infection has not been determined. In this work we use next-generation RNA sequencing to show that RIG-I preferentially associates with shorter, 5′ppp containing viral RNA molecules in infected cells. We found that during Sendai infection RIG-I specifically bound the genome of the defective interfering (DI) particle and did not bind the full-length virus genome or any other viral RNAs. In influenza-infected cells RIG-I preferentially associated with shorter genomic segments as well as subgenomic DI particles. Our analysis for the first time identifies RIG-I PAMPs under natural infection conditions and implies that full-length genomes of single segmented RNA virus families are not bound by RIG-I during infection.
How transcription affects genome 3D organization is not well understood. We found that during influenza A (IAV) infection, rampant transcription rapidly reorganizes host cell chromatin interactions. ...These changes occur at the ends of highly transcribed genes, where global inhibition of transcription termination by IAV NS1 protein causes readthrough transcription for hundreds of kilobases. In these readthrough regions, elongating RNA polymerase II disrupts chromatin interactions by inducing cohesin displacement from CTCF sites, leading to locus decompaction. Readthrough transcription into heterochromatin regions switches them from the inert (B) to the permissive (A) chromatin compartment and enables transcription factor binding.
Data from non-viral transcription stimuli show that transcription similarly affects cohesin-mediated chromatin contacts within gene bodies. Conversely, inhibition of transcription elongation allows cohesin to accumulate at previously transcribed intragenic CTCF sites and to mediate chromatin looping and compaction. Our data indicate that transcription elongation by RNA polymerase II remodels genome 3D architecture.
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•Influenza A virus NS1 protein causes global readthrough transcription past gene ends•Readthrough transcription remodels genome 3D organization downstream of genes•Transcription elongation disrupts cohesin-mediated CTCF-anchored chromatin loops•Transcription into heterochromatin can cause B-to-A compartment transition
Transcription can displace cohesin to remodel genome architecture.
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