The multifaceted effect of PB1-F2 specific antibodies on influenza A virus infection

Košík, Ivan; Krejnusová, Ingrid; Práznovská, Margaréta; Russ, G

doi:10.1016/j.virol.2013.08.022

Cited by 6 publications

(8 citation statements)

References 32 publications

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“…Furthermore, Nter failed to induce cytotoxic effects on epithelial cells in cell medium of physiological pH. Currently many low pathogenic AIV strains do not express full-length PB1-F2 or express its C terminally truncated PB1-F2 form (PB1-F2 (1-52)) (12,38). Virus expression of truncated PB1-F2, which fails to induce cytotoxicity under physiological conditions, may be correlated to the viral fitness to prevent the deleterious cytotoxicity of the full-length PB1-F2.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity

Vidić

Richard

Péchoux

et al. 2016

Journal of Biological Chemistry

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PB1-F2 is a small accessory protein encoded by an alternative open reading frame in PB1 segments of most influenza A virus. PB1-F2 is involved in virulence by inducing mitochondria-mediated immune cells apoptosis, increasing inflammation, and enhancing predisposition to secondary bacterial infections. Using biophysical approaches we characterized membrane disruptive activity of the full-length PB1-F2 (90 amino acids), its N-terminal domain (52 amino acids), expressed by currently circulating H1N1 viruses, and its C-terminal domain (38 amino acids). Both full-length and N-terminal domain of PB1-F2 are soluble at pH values <6, whereas the C-terminal fragment was found soluble only at pH < 3. All three peptides are intrinsically disordered. At pH > 7, the C-terminal part of PB1-F2 spontaneously switches to amyloid oligomers, whereas full-length and the N-terminal domain of PB1-F2 aggregate to amorphous structures. When incubated with anionic liposomes at pH 5, full-length and the C-terminal part of PB1-F2 assemble into amyloid structures and disrupt membrane at nanomolar concentrations. PB1-F2 and its C-terminal exhibit no significant antimicrobial activity. When added in the culture medium of mammalian cells, PB1-F2 amorphous aggregates show no cytotoxicity, whereas PB1-F2 pre-assembled into amyloid oligomers or fragmented nanoscaled fibrils was highly cytotoxic. Furthermore, the formation of PB1-F2 amyloid oligomers in infected cells was directly reflected by membrane disruption and cell death as observed in U937 and A549 cells. Altogether our results demonstrate that membrane-lytic activity of PB1-F2 is closely linked to supramolecular organization of the protein.

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Section: Discussionmentioning

confidence: 99%

Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity

Vidić

Richard

Péchoux

et al. 2016

Journal of Biological Chemistry

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“…However, both CN01 and CN02 had an S31N mutation in the M2 protein, which confers resistance to adamantine. No truncated PB1-F2, associated with increased virulence [26,27], was observed in CN01 and CN02. Aspartic acid at PB2 residue 701 (present in CN01 and CN02) is associated with reduced transmissibility [28].…”

Section: Environmental Samplesmentioning

confidence: 92%

Limited human-to-human transmission of avian influenza A(H7N9) virus, Shanghai, China, March to April 2013

Zhu

Zhao

et al. 2014

Eurosurveillance

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In April 2013, two members of one family were successively confirmed as cases of avian influenza A(H7N9) virus infection in Shanghai, China. Respiratory specimens from the two cases and their close contacts were tested using real-time reverse-transcription (RT)-PCR. Paired serum specimens from contacts were tested by haemagglutination inhibition assay and microneutralisation test. The index patient developed severe pneumonia. Her husband presented with pneumonia shortly thereafter. Both cases had highly similar clinical features and infection with A(H7N9) virus was confirmed in both cases by genetic analysis. Phylogenetic analysis revealed a high level of similarity between the sequences from the two patients and environmental samples collected from wet markets in Minhang and Changning districts. Six samples from the Changning wet market were confirmed as A(H7N9) positive. Of 27 close contacts, one developed mild respiratory symptoms and another tested positive for A(H7N9) antibodies, but both were negative by real-time RT-PCR. The other 25 close contacts of both cases were A(H7N9) negative. Limited human-to-human transmission of the virus most likely occurred in the family cluster. However, other close contacts did not test positive for the virus, suggesting limited potential for extensive human-to-human transmission of the virus.

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“…A large amount of studies have also demonstrated that another accessory protein, PB1-F2, acts as a virulence regulatory factor in the pathogenesis of influenza virus. Multifunctional roles have been attributed to this protein, including inducing cell death, increasing pathogenesis and cytokine dysfunction, enhancing secondary bacterial pneumonia and so on [Reviewed in [85][86][87][88][89]. However, apparently the PA-X protein behaves in an opposite way by decreasing cell death, diminishing cytokine and inflammatory response and decreasing the pathogenicity of H5N1 and H1N1 influenza viruses [6,11,12,15] (see also Fig.…”

Section: Discussionmentioning

confidence: 99%

PA-X-associated early alleviation of the acute lung injury contributes to the attenuation of a highly pathogenic H5N1 avian influenza virus in mice

Zhao

et al. 2016

Med Microbiol Immunol

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PA-X is a novel discovered accessory protein encoded by the PA mRNA. Our previous study demonstrated that PA-X decreases the virulence of a highly pathogenic H5N1 strain A/Chicken/Jiangsu/k0402/2010 in mice. However, the underlying mechanism of virulence attenuation associated with PA-X is still unknown. In this study, we compared two PA-X-deficient mutant viruses and the parental virus in terms of induction of pathology and manipulation of host response in the mouse lung, stimulation of cell death and PA nuclear accumulation. We first found that down-regulated PA-X expression markedly aggravated the acute lung injury of the infected mice early on day 1 post-infection (p.i.). We then determined that loss of PA-X expression induced higher levels of cytokines, chemokines and complement-derived peptides (C3a and C5a) in the lung, especially at early time point's p.i. In addition, in vitro assays showed that the PA-X-deficient viruses enhanced cell death and increased expression of reactive oxygen species (ROS) in mammalian cells. Moreover, we also found that PA nuclear accumulation of the PA-X-null viruses accelerated in MDCK cells. These results demonstrate that PA-X decreases the level of complement components, ROS, cell death and inflammatory response, which may together contribute to the alleviated lung injury and the attenuation of the virulence of H5N1 virus in mice.

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The multifaceted effect of PB1-F2 specific antibodies on influenza A virus infection

Cited by 6 publications

References 32 publications

Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity

Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity

Limited human-to-human transmission of avian influenza A(H7N9) virus, Shanghai, China, March to April 2013

PA-X-associated early alleviation of the acute lung injury contributes to the attenuation of a highly pathogenic H5N1 avian influenza virus in mice

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