Posts Tagged ‘Influenza’

Reasons to be cheeful: Influenza treatment

Friday, April 11th, 2014

Lung immunity against influenza virus As we find out that Tamiflu is no more effective than paracetamol or ibuprofen in treating influenza infection (NHS Choices: Effectiveness of Tamiflu and Relenza questioned) – giving Ben Goldacre the right to say I told you so – maybe there is some reason to be more optimistic about treating influenza.

A new paper in Immunity [subscription] shows that prostaglandin E2 (PGE2) is upregulated during influenza A virus infection, and this inhibits macrophage recruitment to the lungs as well as interferon production and apoptosis in influenza virus-infected macrophages. This results in impaired macrophage antigen presentation and reduced adaptive immunity against influenza virus. The good news is that suppression of PGE2 with prostaglandin inhibitors protects against influenza infection. And we’ve got lots of prostaglandin inhibitors, including ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) that work by inhibiting a molecule called cyclooxygenase (COX). The lung innate immune system has a critical role in limiting respiratory viral infections, particularly in the case of the nastier strains of flu such as the 1918 Spanish Influenza virus (and those still to come). So this is potentially very good news.

The catch? Well this paper refers to studies in mice and clinical trials will need to be done in humans to show the same effects. Clinical trials will be easy to do as many COX- and PGE-inhibitors are already approved for human use. All we need to do is avoid Roche doing the trial, or we may never find out the results.

Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages. Immunity, 10 April 2014 doi: http://dx.doi.org/10.1016/j.immuni.2014.02.013
Summary: Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.

[Editorial comment: I can just imaging the authors and journal editors doing the happy dance that this paper came out on sthe same day as the Tamiflu news.]

Silent mode on H7N9

Friday, July 19th, 2013

Bad news There’s some pretty worrying news coming out about influenza H7N9.

The problem is that the media has (justifiably) concentrated so much on influenza threat over the past five years that the public … doesn’t want to hear any more. So MicrobiologyBytes is going into silent mode over H7N9 until it (or whatever comes next in the never-ending sequence of influenza nasties) starts to get really bad. Then it will be time to start reporting on this story again.

 

Will we ever have a universal flu vaccine?

Wednesday, June 26th, 2013

Will we ever have a universal flu vaccine

“It takes just two shots of the MMR vaccine to protect a child against measles, mumps and rubella for life. The same is true for polio and hepatitis B, a few injections grant life-long immunity against these viral diseases. By showing samples of the viruses to our immune system, we teach it to store a permanent memory of these enemies and guard against them in perpetuity.

Influenza is a different matter. There is a vaccine, but we have to take it every year. That’s because flu viruses evolve at tremendous speed. They copy themselves with surprising sloppiness, producing thousands of slightly different daughter viruses. If different strains infect the same cell, they can carry out the viral version of sex by mingling their genetic material to make hybrid daughters. And occasionally, entirely new strains that we’ve never encountered before can spill over into humans from animals.”

Read more:

Will we ever have a universal flu vaccine? – Ed Yong

Gene Therapy … Against Influenza?

Thursday, May 30th, 2013




Gene Therapy … Against Influenza?

Interesting proof of concept experiment. Just one squirt of antibody-expressing modified AAV up the nose and animals are protected against a wide range of influenza strains – and potentially many other diseases. But there’s a long way to go before this becomes a reality in human medicine.

Intranasal Antibody Gene Transfer in Mice and Ferrets Elicits Broad Protection Against Pandemic Influenza.  Sci Transl Med Vol. 5, Issue 187, p. 187ra72 DOI: 10.1126/scitranslmed.3006299

The emergence of a new influenza pandemic remains a threat that could result in a substantial loss of life and economic disruption worldwide. Advances in human antibody isolation have led to the discovery of monoclonal antibodies (mAbs) that have broad neutralizing activity against various influenza strains, although their direct use for prophylaxis is impractical. To overcome this limitation, our approach is to deliver antibody via adeno-associated virus (AAV) vectors to the site of initial infection, which, for respiratory viruses such as influenza, is the nasopharyngeal mucosa. AAV vectors based on serotype 9 were engineered to express a modified version of the previously isolated broadly neutralizing mAb to influenza A, FI6. We demonstrate that intranasal delivery of AAV9.FI6 into mice afforded complete protection and log reductions in viral load to 100 LD50 (median lethal dose) of three clinical isolates of H5N1 and two clinical isolates of H1N1, all of which have been associated with historic human pandemics (including H1N1 1918). Similarly, complete protection was achieved in ferrets challenged with lethal doses of H5N1 and H1N1. This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available.

How important is influenza as a human pathogen?

Monday, April 15th, 2013

MxA

Pretty damn important.

How do we know? Because humans have a gene encoding a protein which seems to be dedicated to preventing influenza virus infection. Interferon-inducible dynamin-like myxovirus resistance protein (MxA) is found in membranes of the smooth endoplasmic reticulum–Golgi intermediate compartment. On influenza virus infection of the cell, it redistributes to sites of virus replication and promotes missorting of the myxovirus nucleocapsid (N) protein into membrane-associated, large perinuclear complexes. By preventing the N protein entering the nucleus, influenza virus replication is disrupted.

Influenza A viruses of avian or swine origin sporadically enter the human population but do not readily transmit between individuals. In rare cases, however, they establish a new virus lineage in humans. The mechanisms by which invading viruses overcome the species barrier are not well understood, but multiple adaptations to the new host are required. Surprisingly little is known about adaptive mutations that overcome restriction factors of the intrinsic and innate host defense system.

A recent paper in PLOS Pathogens identifies adaptive mutations in pandemic strains of influenza that confer resistance to the interferon-induced antiviral factor MxA. The resistance-enhancing mutations changed several amino acids in the viral nucleoprotein which is the main nucleocapsid component. These mutations were sufficient to increase the pathogenicity of an avian influenza virus strain in a Mx-positive mouse model. Interestingly, the resistance-associated amino acids are counter-selected in circulating avian influenza strains, because they compromise general viral replication fitness. Innate immunity factor MxA provides a barrier against zoonotic introduction of influenza A viruses and adaptive mutations in the influenza N protein should be carefully monitored.

Why should you care about this? -> H7N9

 

Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein. (2013) PLoS Pathog 9(3): e1003279. doi:10.1371/journal.ppat.1003279
The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.

 

Making a Flu Vaccine Without the Virus 

Monday, November 26th, 2012

A new vaccine strategy could make flu shots cheaper, safer, and easier to produce. Using synthetic messenger RNA (mRNA) instead of proteins purified from viruses, German scientists have shown they can protect mice, ferrets, and pigs against influenza. Science Now: http://goo.gl/0E6n5
Nature Biotechnology: http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.2436.html

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One influenza virus particle packages eight unique viral RNAs

Wednesday, July 4th, 2012

Influenza RNAs The segmented nature of the influenza virus genome complicates the process of genome packaging because at least one complete set of eight viral RNA segments has to be packaged into a virus particle to produce infectious progeny. The mechanism by which influenza virus ensures correct packaging of its genome has been unclear. Two models have been proposed for the incorporation of influenza viral RNAs: (i) the random incorporation model; and (ii) the selective incorporation model.

This paper describes detection and quantification of the viral RNAs within influenza virions at single-virus resolution using single-molecule (sm)FISH technique. Most if not all influenza virus particles package heterogeneous viral RNAs and each viral RNA segment was packaged only once. These data provide direct evidence that the packaging mechanism in the influenza virus is very robust and the majority of virus particles package the unique eight viral RNAs.

 

One influenza virus particle packages eight unique viral RNAs as shown by FISH analysis. PNAS USA 30 April 2012 doi: 10.1073/pnas.1206069109
Influenza A virus possesses a segmented genome of eight negative-sense, single-stranded RNAs. The eight segments have been shown to be represented in approximately equal molar ratios in a virus population; however, the exact copy number of each viral RNA segment per individual virus particles has not been determined. We have established an experimental approach based on multicolor single-molecule fluorescent in situ hybridization (FISH) to study the composition of viral RNAs at single-virus particle resolution. Colocalization analysis showed that a high percentage of virus particles package all eight different segments of viral RNAs. To determine the copy number of each RNA segment within individual virus particles, we measured the photobleaching steps of individual virus particles hybridized with fluorescent probes targeting a specific viral RNA. By comparing the photobleaching profiles of probes against the HA RNA segment for the wild-type influenza A/Puerto Rico/8/34 (PR8) and a recombinant PR8 virus carrying two copies of the HA segment, we concluded that only one copy of HA segment is packaged into a wild type virus particle. Our results showed similar photobleaching behaviors for other RNA segments, suggesting that for the majority of the virus particles, only one copy of each RNA segment is packaged into one virus particle. Together, our results support that the packaging of influenza viral genome is a selective process.

Negative strand RNA viruses – the state of the art

Wednesday, January 18th, 2012

Virus Research It was my priveledge to work with Brian Mahy many years ago. Brian has just retired as long-serving Editor of Virus Research, and his swansong is an excellent special issue on negative strand RNA viruses – an important read for all virologists and an even more impirtant one for all aspiring virologists.

Virus Research: Negative Strand RNA Viruses Special Issue

  • Insights on influenza pathogenesis from the grave
  • Taming influenza viruses
  • Induction and evasion of type I interferon responses by influenza viruses
  • Immune responses to influenza virus infection
  • Novel vaccines against influenza viruses
  • Prospects for controlling future pandemics of influenza
  • New concepts in measles virus replication: Getting in and out in vivo and modulating the host cell environment
  • Recombinant vaccines against the mononegaviruses—What we have learned from animal disease controls
  • Biological feasibility of measles eradication
  • Progress in understanding and controlling respiratory syncytial virus: Still crazy after all these years
  • An unconventional pathway of mRNA cap formation by vesiculoviruses
  • Rhabdovirus accessory genes
  • Structural insights into the rhabdovirus transcription/replication complex
  • Hantavirus pulmonary syndrome
  • Progress in recombinant DNA-derived vaccines for Lassa virus and filoviruses
  • Borna disease virus – Fact and fantasy
  • A review of Nipah and Hendra viruses with an historical aside
  • Negative-strand RNA viruses: The plant-infecting counterparts
  • Quasispecies as a matter of fact: Viruses and beyond

 

The changing nature of avian influenza A virus (H5N1)

Friday, December 16th, 2011

Influenza virus Although it has not been in the news much recently, the highly pathogenic avian influenza A virus subtype H5N1 has been endemic in some bird species since its emergence in 1996 and its ecology, genetics and antigenic properties continue to evolve. This has allowed diverse virus strains to emerge in endemic areas with altered receptor specificity, including a new H5 sublineage with enhanced binding affinity to the human-type receptor. The pandemic potential of H5N1 viruses is alarming and may be increasing. This article reviews the complex and changing nature of the H5N1 virus that may contribute to the emergence of pandemic strains – with really serious consequences.

 

The changing nature of avian influenza A virus (H5N1). Tresnd in Microbiology, 5 December 2011