Lessons from Lipids in the Fight against Influenza

Influenza is a leading cause of morbidity and mortality worldwide, with vaccines and antiviral drugs having limited efficacy thus far. Two recent studies in Cell apply lipidomics approaches to identify bioactive lipid mediators influencing host inflammation, viral replication, and disease progression

Antiviral Response in Pandemic Influenza Viruses

The regulatory activities of the nonstructural protein 1 appear to affect the ability of influenza viruses to infect multiple animal species

Predicting the pathogenesis of influenza from genomic response: a step toward early diagnosis

Infection with influenza virus does not always lead to symptomatic illness, but it is not currently possible to predict who will be severely affected and who will have mild or no symptoms. Gene expression profiling of biofluids might unlock the complex dynamics of response to acute respiratory virus infections such as influenza. A recent article by Alfred Hero and colleagues used transcriptional microarray analyses to follow the response to symptomatic and asymptomatic influenza infection over time, and revealed a role for type I IFN (IFNβ and IFNα) signaling and the NLRP3 inflammasome in determining the outcome in human infections

Recent strategies to identify broadly neutralizing antibodies against influenza A virus

Recent technologies have made it possible to efficiently identify several broadly cross-neutralizing antibodies against the hemagglutinin of influenza A virus. With these advances comes a potential new age in influenza virus vaccine development and the possibility of effective, therapeutic immunotherapy

Nonconserved Nucleotides at the 3′ and 5′ Ends of an Influenza A Virus RNA Play an Important Role in Viral RNA Replication

AbstractThe genome of influenza A viruses is composed of eight negative-strand RNA segments which contain short noncoding regions at their 3′ and 5′ ends. The signals required for replication, transcription, and packaging of the viral RNAs are thought to be located in these regions. The highly conserved noncoding nucleotides, which form “panhandle” or “fork” structures by partial complementarity, are important for the transcriptional activity of the viral RNA polymerase. In contrast, the nonconserved noncoding nucleotides located close to the open reading frame of the viral RNAs had not been implicated in RNA transcription. Using a reverse-genetics system, we have now rescued influenza A/WSN/33 viruses whose NA-specific RNA segments have deletions in these nonconserved noncoding regions. Deletion either of the nucleotide residues between the poly(U) stretch and the stop codon at the 5′ end or of the nucleotides between position 15 and the start codon at the 3′ end did not affect the amount of NA-RNA species found in virions or infected cells. However, a combination of deletions at both the 3′ and the 5′ ends decreased by 60 times the levels of NA-specific viral RNA found in infected cells at late periods of infection and in virions. This double deletion was also responsible for a fourfold reduction of the steady-state levels of the NA-specific mRNA in infected cells. Viruses whose NA-specific open reading frames were flanked by the noncoding regions of the PB1- or the NS-RNA segments of influenza A/WSN/33 virus also showed a reduction in the NA-specific viral RNA in virions and in infected cells. The present results demonstrate that the nonconserved nucleotides at the 3′ and 5′ ends of the NA-RNA segment of influenza A virus play an important role in the replication of this segment

eIF5A is activated by virus infection or dsRNA and facilitates virus replication through modulation of interferon production

Active hypusine-modified initiation elongation factor 5A is critical for cell proliferation and differentiation, embryonic development, and innate immune response of macrophages to bacterial infection. Here, we demonstrate that both virus infection and double-stranded RNA viral mimic stimulation induce the hypusination of eIF5A. Furthermore, we show that activation of eIF5A is essential for the replication of several RNA viruses including influenza A virus, vesicular stomatitis virus, chikungunya virus, mayaro virus, una virus, zika virus, and punta toro virus. Finally, our data reveal that inhibition of eIF5A hypusination using the spermidine analog GC7 or siRNA-mediated downmodulation of eIF5A1 induce upregulation of endoplasmic reticulum stress marker proteins and trigger the transcriptional induction of interferon and interferon-stimulated genes, mechanisms that may explain the broad-spectrum antiviral activity of eIF5A inhibition

ISG15 is counteracted by vaccinia virus E3 protein and controls the proinflammatory response against viral infection

Conjugation of ISG15 inhibits replication of several viruses. Here, using an expression system for assaying human and mouse ISG15 conjugations (ISGylations), we have demonstrated that vaccinia virus E3 protein binds and antagonizes human and mouse ISG15 modification. To study ISGylation importance in poxvirus infection, we used a mouse model that expresses deconjugating proteases. Our results indicate that ISGylation restricts in vitro replication of the vaccinia virus VV E3L mutant but unconjugated ISG15 is crucial to counteract the inflammatory response produced after VV E3L infectionThis work was supported by grants from the Spanish Ministry of Health, FIS2011-00127, and UAM-Banco de Santander to S.G. and was also partly supported by NIAID grant U19AI083025 to A.G.-

Human interactome of the influenza B virus NS1 protein

This work was partially supported by NIAID grant U19AI106754, and by CRIP (Center for Research in Influenza Pathogenesis), an NIAID funded Center of Excellence for Influenza Research and Surveillance (CEIRS, contract #HHSN272201400008C) to A. G-S. Work at the University of Zurich was supported by the Swiss National Science Foundation (grant 31003A_159993 to BGH).NS1 proteins of influenza A and B viruses share limited sequence homology, yet both are potent manipulators of host cell processes, particularly interferon (IFN) induction. Although many cellular partners are reported for A/NS1, only a few (e.g. PKR and ISG15) have been identified for B/NS1. Here, affinity-purification and mass spectrometry were used to expand the known host interactome of B/NS1. We identified 22 human proteins as new putative targets for B/NS1, validating several, including DHX9, ILF3, YBX1 and HNRNPC. Consistent with two RNA-binding domains in B/NS1, many of the identified factors bind RNA and some interact with B/NS1 in an RNA-dependent manner. Functional characterization of several B/NS1 interactors identified SNRNP200 as a potential positive regulator of host IFN responses, while ILF3 exhibited dual roles in both IFN induction and influenza B virus replication. These data provide a resource for future investigations into the mechanisms underpinning host cell modulation by influenza B virus NS1.Publisher PDFPeer reviewe