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

Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Virus recognition and induction of interferon (IFN) are critical components of the innate immune system. The Toll-like receptor (TLR) and RIG-I-like receptor families have been characterized as key players in RNA virus detection. Signaling cascades initiated by these receptors are crucial for establishment of an IFN signaling mediated antiviral state in infected and neighboring cells and containment of virus replication as well as initiation of the adaptive immune response. In this review, we focus on the diverse and overlapping functions of these receptors, their physiological importance, and respective viral inducers. We highlight the roles of TRL3, TLR7/8, retinoic acid inducible gene I, melanoma differentiation-associated gene 5, and the RNA molecules responsible for activating these viral sensors

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

TIV vaccination modulates host responses to influenza virus infection that correlate with protection against bacterial superinfection

Background: Influenza virus infection predisposes to secondary bacterial pneumonia. Currently licensed influenza vaccines aim at the induction of neutralizing antibodies and are less effective if the induction of neutralizing antibodies is low and/or the influenza virus changes its antigenic surface. We investigated the effect of suboptimal vaccination on the outcome of post-influenza bacterial superinfection. Methods: We established a mouse vaccination model that allows control of disease severity after influenza virus infection despite inefficient induction of virus-neutralizing antibody titers by vaccination. We investigated the effect of vaccination on virus-induced host immune responses and on the outcome of superinfection with Staphylococcus aureus. Results: Vaccination with trivalent inactivated virus vaccine (TIV) reduced morbidity after influenza A virus infection but did not prevent virus replication completely. Despite the poor induction of influenza-specific antibodies, TIV protected from mortality after bacterial superinfection. Vaccination limited loss of alveolar macrophages and reduced levels of infiltrating pulmonary monocytes after influenza virus infection. Interestingly, TIV vaccination resulted in enhanced levels of eosinophils after influenza virus infection and recruitment of neutrophils in both lungs and mediastinal lymph nodes after bacterial superinfection. Conclusion: These observations highlight the importance of disease modulation by influenza vaccination, even when suboptimal, and suggest that influenza vaccination is still beneficial to protect during bacterial superinfection in the absence of complete virus neutralization

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

Protective Cellular Immunity Against Influenza Virus Induced by Plasmid Inoculation of Newborn Mice

Neonate organisms display an intrinsic disability to mount effective immune responses to infectious agents or conventional vaccines. Whereas low. doses of antigens trigger a suboptimal response, higher doses are frequently associated with tolerance induction. We investigated the ability of a plasmid-expressing nucleoprotein of influenza virus to prime a specific cellular immune response when administered to newborn mice. We found that persistent exposure to antigen following plasmid inoculation of neonates leads to a vigorous priming of specific CTLs rather than tolerance induction. The CTLs were cross-reactive against multiple strains of type A influenza viruses and produced IFNγ but no IL-4. The immunity triggered by plasmid inoculation of neonates was protective in terms of pulmonary virus clearance as well as survival rate following lethal challenge with influenza virus. Whereas the persistence of the plasmid at the site of injection was readily demonstrable in adult mice at 3 months after inoculation, mice immunized as newborns displayed no plasmid at 3 months and very little at 1 month after injection. Thus, DNA-based immunization of neonates may prove an effective and safe vaccination strategy for induction of cellular immunity against microbes that cause serious infectious diseases in the early period of life

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