ETV7 limits antiviral gene expression and control of influenza viruses.
Ontology highlight
ABSTRACT:
SUBMITTER: Froggatt HM
PROVIDER: S-EPMC8630980 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Influenza is a serious and frequently underestimated, but vaccine preventable disease. The adamantane derivates rimantadine and amantadine and the neuraminidase inhibitors zanamivir and oseltamivir are the only antiviral drugs currently approved in Europe for therapy and prophylaxis of influenza infections. Resistance to these drugs occurs due to mutations within the therapeutic target proteins M2 ion channel protein and viral neuraminidase. An unexpected occurrence of oseltamivir-resistant seasonal A(H1N1) viruses was detected in winter 2007/2008. The prevalence of these viruses increased rapidly and nearby all viruses circulating during the following seasons were resistant to oseltamivir. The A(H1N1)pdm09 viruses replaced the former seasonal A(H1N1) subtype during the 2009-2010 influenza season. Fortunately, resistance to neuraminidase inhibitors was detected in A(H1N1)pdm09, A(H3N2) and influenza B viruses only sporadically and was treatment related mostly. Comprehensive analyses of circulating viruses showed a high prevalence of A(H3N2) influenza viruses that are resistant to adamantane derivates since 2004/2005 and a progressive trend in the prevalence of resistant viruses up to 100% in following seasons. The M2 ion channel protein of A(H1N1)pdm09 viruses is associated with the Eurasian avian-like swine lineage and thus show "natural" resistance to adamantane derivates. Therefore, only neuraminidase inhibitors are recommended for influenza treatment today. This manuscript summarizes the occurrence and spread of antiviral resistant influenza viruses and highlights the importance for developing and/or approving new antiviral compounds.
| S-EPMC6301739 | biostudies-other
Project description:There are three classes of antiviral drugs approved for the treatment of influenza: the M2 ion channel inhibitors (amantadine, rimantadine), neuraminidase (NA) inhibitors (laninamivir, oseltamivir, peramivir, zanamivir), and the protease inhibitor (favipiravir); some of the agents are only available in selected countries [1, 2]. These agents are effective at treating the signs and symptoms of influenza in patients infected with susceptible viruses. Clinical failure has been demonstrated in patients infected with viruses with primary resistance, i.e., antivirals can be present in the virus initially infecting the patient, or resistance may emerge during the course of therapy [3–5]. NA inhibitors are active against all nine NA subtypes recognized in nature [6], including highly pathogenic avian influenza A/H5N1 and recent low-pathogenic avian influenza A/H7N9 viruses [7]. Since seasonal influenza is usually an acute, self-limited illness in which viral clearance usually occurs rapidly due to innate and adaptive host immune responses, the emergence of drug-resistant variants would be anticipated to have limited effect on clinical recovery in otherwise healthy patients, as has been demonstrated clinically [3, 8, 9]. Unfortunately, immunocompromised or immunologically naïve hosts, such as young children and infants or those exposed to novel strains, are more likely to have mutations that confer resistance emergence during therapy; such resistant variants may also result in clinically significant adverse outcomes [10–13].
| S-EPMC7122614 | biostudies-literature
Project description:Neuraminidase inhibitors (NAIs) are first-line agents for the treatment and prevention of influenza virus infections. As for other antivirals, the development of resistance to NAIs has become an important concern particularly in the case of A(H1N1) viruses and oseltamivir. The most frequently reported change conferring oseltamivir resistance in that viral context is the H275Y neuraminidase mutation (N1 numbering). Recent studies have shown that, in the presence of the appropriate permissive mutations, the H275Y variant can retain virulence and transmissibility in some viral backgrounds. Most oseltamivir-resistant influenza A virus infections can be managed with the use of inhaled or intravenous zanamivir, another NAI. New NAI compounds and non-neuraminidase agents as well as combination therapies are currently in clinical evaluation for the treatment for severe influenza infections.
| S-EPMC6499333 | biostudies-literature
Project description:BackgroundDue to the lack of timely access to resources for critical care, strategic use of antiviral drugs is crucial for mitigating the impact of novel influenza viruses with pandemic potential in remote and isolated communities. We sought to evaluate the effect of antiviral treatment and prophylaxis of close contacts in a Canadian remote northern community.MethodsWe used an agent-based, discrete-time simulation model for disease spread in a remote community, which was developed as an in-silico population using population census data. Relative and cumulative age-specific attack rates, and the total number of infections in simulated model scenarios were obtained.ResultsWe found that early initiation of antiviral treatment is more critical for lowering attack rates in a remote setting with a low population-average age compared to an urban population. Our results show that a significant reduction in the relative, age-specific attack rates due to increasing treatment coverage does not necessarily translate to a significant reduction in the overall arrack rate. When treatment coverage varies from low to moderate, targeted prophylaxis has a very limited impact in reducing attack rates and should be offered at a low level (below 10%) to avoid excessive waste of drugs.ConclusionsIn contrast to previous work, for conservative treatment coverages, our results do not provide any convincing evidence for the implementation of targeted prophylaxis. The findings suggest that public health strategies in remote communities should focus on the wider availability (higher coverage) and timely distribution of antiviral drugs for treatment of clinically ill individuals.
| S-EPMC3931825 | biostudies-literature
Project description:According to the 'ceRNA hypothesis', microRNAs (miRNAs) may act as mediators of an effective positive interaction between long coding or non-coding RNA molecules, carrying significant potential implications for a variety of biological processes. Here, inspired by recent work providing a quantitative description of small regulatory elements as information-conveying channels, we characterize the effectiveness of miRNA-mediated regulation in terms of the optimal information flow achievable between modulator (transcription factors) and target nodes (long RNAs). Our findings show that, while a sufficiently large degree of target derepression is needed to activate miRNA-mediated transmission, (a) in case of differential mechanisms of complex processing and/or transcriptional capabilities, regulation by a post-transcriptional miRNA-channel can outperform that achieved through direct transcriptional control; moreover, (b) in the presence of large populations of weakly interacting miRNA molecules the extra noise coming from titration disappears, allowing the miRNA-channel to process information as effectively as the direct channel. These observations establish the limits of miRNA-mediated post-transcriptional cross-talk and suggest that, besides providing a degree of noise buffering, this type of control may be effectively employed in cells both as a failsafe mechanism and as a preferential fine tuner of gene expression, pointing to the specific situations in which each of these functionalities is maximized.
| S-EPMC4727922 | biostudies-literature
Project description:Type I interferons (IFNs) play an essential role in the host response to viral infection through the induction of numerous IFN-stimulated genes (ISGs), including important antiviral molecules such as PKR, RNase L, Mx, and iNOS. Yet, additional antiviral ISGs likely exist. IFN-stimulated gene 15 (ISG15) is a ubiquitin homolog that is rapidly up-regulated after viral infection, and it conjugates to a wide array of host proteins. Although it has been hypothesized that ISG15 functions as an antiviral molecule, the initial evaluation of ISG15-deficient mice revealed no defects in their responses to vesicular stomatitis virus or lymphocytic choriomeningitis virus, leaving open the important question of whether ISG15 is an antiviral molecule in vivo. Here we demonstrate that ISG15 is critical for the host response to viral infection. ISG15-/- mice are more susceptible to influenza A/WSN/33 and influenza B/Lee/40 virus infections. ISG15-/- mice also exhibited increased susceptibility to both herpes simplex virus type 1 and murine gammaherpesvirus 68 infection and to Sindbis virus infection. The increased susceptibility of ISG15-/- mice to Sindbis virus infection was rescued by expressing wild-type ISG15, but not a mutant form of ISG15 that cannot form conjugates, from the Sindbis virus genome. The demonstration of ISG15 as a novel antiviral molecule with activity against both RNA and DNA viruses provides a target for the development of therapies against important human pathogens.
| S-EPMC1783119 | biostudies-literature
Project description:Influenza A viruses (IAVs) encode their genome across eight, negative sense RNA segments. During viral assembly, the failure to package all eight segments, or packaging a mutated segment, renders the resulting virion incompletely infectious. It is known that the accumulation of these defective particles can limit viral disease by interfering with the spread of fully infectious particles. In order to harness this phenomenon therapeutically, we defined which viral packaging signals were amenable to duplication and developed a viral genetic platform which produced replication competent IAVs that require up to two additional artificial genome segments for full infectivity. The modified and artificial genome segments propagated by this approach are capable of acting as "decoy" segments that, when packaged by coinfecting wild-type viruses, lead to the production of non-infectious viral particles. Although IAVs which require 10 genomic segments for full infectivity are able to replicate themselves and spread in vivo, their genomic modifications render them avirulent in mice. Administration of these viruses, both prophylactically and therapeutically, was able to rescue animals from a lethal influenza virus challenge. Together, our results show that replicating IAVs designed to propagate and spread defective genomic segments represent a potent anti-influenza biological therapy that can target the conserved process of particle assembly to limit viral disease.
| S-EPMC6881065 | biostudies-literature
Project description:Previous studies have described the role of p53 isoforms, including p53? and ?133p53?, in the modulation of the activity of full-length p53, which regulates cell fate. In the context of influenza virus infection, an interplay between influenza viruses and p53 has been described, with p53 being involved in the antiviral response. However, the role of physiological p53 isoforms has never been explored in this context. Here, we demonstrate that p53 isoforms play a role in influenza A virus infection by using silencing and transient expression strategies in human lung epithelial cells. In addition, with the help of a panel of different influenza viruses from different subtypes, we also show that infection differentially regulates the expressions of p53? and ?133p53?. Altogether, our results highlight the role of p53 isoforms in the viral cycle of influenza A viruses, with p53? and ?133p53? acting as regulators of viral production in a p53-dependent manner.
| S-EPMC3421759 | biostudies-literature
Project description:Influenza is still a serious threat to human health with significant morbidity and mortality. The emergence of drug-resistant influenza viruses poses a great challenge to existing antiviral drugs. Traditional Chinese medicines (TCMs) may be an alternative to overcome the challenge. Here, 10 oral proprietary Chinese medicines were selected to evaluate their anti-influenza activities. These drugs exhibit potent inhibitory effects against influenza A H1N1, influenza A H3N2, and influenza B virus. Importantly, they demonstrate potent antiviral activities against drug-resistant strains. In the study of mechanisms, we found that Xiaoqinglong mixture could increase antiviral interferon production by activating p38 MAPK, JNK/SAPK pathway, and relative nuclear transcription factors. Lastly, our studies also indicate that some of these medicines show inhibitory activities against EV71 and CVB strains. In conclusion, the 10 traditional Chinese medicines, as kind of compound combination medicines, show broad-spectrum antiviral activities, possibly also including inhibitory activities against strains resistant to available antiviral drugs.
| S-EPMC4618326 | biostudies-literature
Project description:ObjectivesDrugs that target host cell processes can be employed to complement drugs that specifically target viruses, and iminosugar compounds that inhibit host ?-glucosidases have been reported to show antiviral activity against multiple viruses. Here the effect and mechanism of two iminosugar ?-glucosidase inhibitors, N-butyl-deoxynojirimycin (NB-DNJ) and N-nonyl-deoxynojirimycin (NN-DNJ), on human influenza A viruses was examined.MethodsThe viruses examined were a recently circulating seasonal influenza A(H3N2) virus strain A/Brisbane/10/2007, an older H3N2 strain A/Udorn/307/72, and A/Lviv/N6/2009, a strain representative of the currently circulating pandemic influenza A(H1N1)pdm09 virus.ResultsThe inhibitors had the strongest effect on Brisbane/10 and NN-DNJ was more potent than NB-DNJ. Both compounds showed antiviral activity in cell culture against three human influenza A viruses in a strain-specific manner. Consistent with its action as an ?-glucosidase inhibitor, NN-DNJ treatment resulted in an altered glycan processing of influenza haemagglutinin (HA) and neuraminidase (NA), confirmed by MS. NN-DNJ treatment was found to reduce the cell surface expression of the H3 subtype HA. The level of sialidase activity of NA was reduced in infected cells, but the addition of exogenous sialidase to the cells did not complement the NN-DNJ-mediated inhibition of virus replication. Using reassortant viruses, the drug susceptibility profile was determined to correlate with the origin of the HA.ConclusionsNN-DNJ inhibits influenza A virus replication in a strain-specific manner that is dependent on the HA.
| S-EPMC4267503 | biostudies-literature