The Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon at the Level of the MAVS Adaptor Protein

Varga, Zsuzsanna T.; Ramos, Irene; Hai, Rong; Schmolke, Mirco; Garcı́a-Sastre, Adolfo; Fernández-Sesma, Ana; Palese, Peter

doi:10.1371/journal.ppat.1002067

Cited by 220 publications

(262 citation statements)

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“…46,74,75 Inhibiting apoptosis of cells that produce viral progeny and promoting apoptosis of cells of the innate immune system that attack infected cells would be beneficial for the virus. 152 In conclusion, influenza viruses evaluated under a variety of experimental protocols do appear to express a range of virulence or pathogenic capabilities. Identification of specific virulence determinants has proven to be difficult because of polygenic contributions to pathogenicity.…”

Section: Ns1mentioning

confidence: 98%

Influenza A Virus Infections in Swine

Janke

2013

Vet Pathol

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Influenza has been recognized as a respiratory disease in swine since its first appearance concurrent with the 1918 ''Spanish flu'' human pandemic. All influenza viruses of significance in swine are type A, subtype H1N1, H1N2, or H3N2 viruses. Influenza viruses infect epithelial cells lining the surface of the respiratory tract, inducing prominent necrotizing bronchitis and bronchiolitis and variable interstitial pneumonia. Cell death is due to direct virus infection and to insult directed by leukocytes and cytokines of the innate immune system. The most virulent viruses consistently express the following characteristics of infection: (1) higher or more prolonged virus replication, (2) excessive cytokine induction, and (3) replication in the lower respiratory tract. Nearly all the viral proteins contribute to virulence. Pigs are susceptible to infection with both human and avian viruses, which often results in gene reassortment between these viruses and endemic swine viruses. The receptors on the epithelial cells lining the respiratory tract are major determinants of infection by influenza viruses from other hosts. The polymerases, especially PB2, also influence cross-species infection. Methods of diagnosis and characterization of influenza viruses that infect swine have improved over the years, driven both by the availability of new technologies and by the necessity of keeping up with changes in the virus. Testing of oral fluids from pigs for virus and antibody is a recent development that allows efficient sampling of large numbers of animals.Keywords influenza virus, swine, pathogenesis, cytokines, apoptosis, virulence, cross-species infection, hemagglutinin, receptors, polymerases, diagnosisThe evolution and epidemiology of influenza A virus (IAV) infections in swine have been integrally tied to the segmented nature of the genome of the virus, which facilitates gene reassortment, and to the adaptability of these genes through mutation, which sometimes facilitates replication in a new host. 8,19,77,85,89 Influenza was first recognized as a respiratory disease entity in swine during the 1918 human Spanish flu pandemic. 67 The virus was not isolated until 1931, when nasal discharge from pigs was inoculated into ferrets and subsequently into embryonated chicken eggs. 129 In 1933, a similar virus was recovered from humans with this technique. 131 The viruses were essentially identical and served as the prototype for type A subtype H1N1 influenza viruses.All influenza viruses of significance that infect swine are type A viruses, defined by the highly conserved internal nucleoproteins and matrix proteins. Influenza A virus subtypes are based on the external hemagglutinin (HA) and neuraminidase (NA) proteins. The predominant viruses in swine populations in different parts of the world may have genes of different origin, even though the subtypes may be similar. 10,73,171 The original classic H1N1 swine influenza virus, which remained the predominant influenza virus in North American swine populations for nearl...

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Section: Ns1mentioning

confidence: 98%

Influenza A Virus Infections in Swine

Janke

2013

Vet Pathol

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“…The 1918 and USSR PB1-F2 proteins shared 86% amino acid identity. However, the shorter USSR PB1-F2 lacks the C-terminal domain, which contains a mitochondrial targeting sequence, mediates PB1 binding, promotes inflammation, and interferes with type I IFN signaling (2,17,20,30). In addition to a full-length C-terminal domain, the 1918 PB1-F2 protein has a serine at position 66 (Fig.…”

Section: Characterization Of Recombinant Viruses With Altered Pb1-f2mentioning

confidence: 99%

“…PB1-F2 also interacts with PB1 and regulates viral polymerase activity in a cell-type-and strain-specific manner (13,17,20), and a role of PB1-F2 in the interaction with the cellular antiviral response has been reported. However, while one study observed a PB1-F2-mediated exacerbation of beta interferon (IFN-␤) expression in human lung epithelial cells, a different study demonstrated an inhibition of type I IFN signaling that was associated with interaction of PB1-F2 with the mitochondrial antiviral signaling protein (MAVS) (15,30). Finally, intranasal administration of synthetic full-length or carboxy-terminal portions of A/Brevig Mission/ 1/1918 (1918) and A/Puerto Rico/8/34 (PR8) PB1-F2 peptides led to recruitment of white blood cells into the lungs and exacerbated secondary bacterial infection in mice (18,20).…”

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confidence: 99%

PB1-F2 Modulates Early Host Responses but Does Not Affect the Pathogenesis of H1N1 Seasonal Influenza Virus

Meunier

Messling

2012

J Virol

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In the context of infections with highly pathogenic influenza A viruses, the PB1-F2 protein contributes to virulence and enhances lung inflammation. In contrast, its role in the pathogenesis of seasonal influenza viral strains is less clear, especially in the H1N1 subtype, where strains can have a full-length 87-to 90-amino-acid protein, a truncated 57-amino-acid version, or lack the protein altogether. Toward this, we introduced the full-length 1918 PB1-F2, or prevented PB1-F2 expression, in H1N1 A/USSR/ 90/77, a seasonal strain that naturally expresses a truncated PB1-F2. All viruses replicated with similar efficiency in ferret or macaque ex vivo lung cultures and elicited similar cytokine mRNA profiles. In contrast, the virus expressing the 1918 PB1-F2 protein caused a delay of proinflammatory responses in ferret blood-derived macrophages, while the PB1-F2 knockout virus resulted in a more rapid response. A similar but less pronounced delay in innate immune activation was also observed in the nasal wash cells of ferrets infected with the 1918 PB1-F2-expressing virus. However, the three viruses did not differ in their virulence or clinical course in ferrets, supporting speculations that PB1-F2 is of limited importance for the pathogenesis of primary viral infection with human seasonal H1N1 viruses.

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“…PB1-F2 has been shown to modulate the induction of type I IFN (21)(22)(23); however, its main function is to induce apoptosis in host immune cells by targeting mitochondria via the basic amphipathic helix in its Significance Apoptosis refers to the ability of a cell to undergo programmed cell death under normal physiological conditions or in response to stress signals. During infection, influenza A viruses have the capacity to induce early apoptosis of immune cells, thereby preventing them from performing their antiviral function.…”

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confidence: 99%

NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein

Jaworska

François

Downey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

114

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To subvert host immunity, influenza A virus (IAV) induces early apoptosis in innate immune cells by disrupting mitochondria membrane potential via its polymerase basic protein 1-frame 2 (PB1-F2) accessory protein. Whether immune cells have mechanisms to counteract PB1-F2-mediated apoptosis is currently unknown. Herein, we define that the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 binds to viral protein PB1-F2, preventing IAV-induced macrophage apoptosis and promoting both macrophage survival and type I IFN signaling. We initially observed that Nlrx1-deficient mice infected with IAV exhibited increased pulmonary viral replication, as well as enhanced inflammatory-associated pulmonary dysfunction and morbidity. Analysis of the lungs of IAV-infected mice revealed markedly enhanced leukocyte recruitment but impaired production of type I IFN in Nlrx1 −/− mice. Impaired type I IFN production and enhanced viral replication was recapitulated in Nlrx1 −/− macrophages and was associated with increased mitochondrial mediated apoptosis. Through gain-and loss-of-function strategies for protein interaction, we identified that NLRX1 directly bound PB1-F2 in the mitochondria of macrophages. Using a recombinant virus lacking PB1-F2, we confirmed that deletion of PB1-F2 abrogated NLRX1-dependent macrophage type I IFN production and apoptosis. Thus, our results demonstrate that NLRX1 acts as a mitochondrial sentinel protecting macrophages from PB1-F2-induced apoptosis and preserving their antiviral function. We further propose that NLRX1 is critical for macrophage immunity against IAV infection by sensing the extent of viral replication and maintaining a protective balance between antiviral immunity and excessive inflammation within the lungs.innate immunity | Nod-like receptor

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The Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon at the Level of the MAVS Adaptor Protein

Cited by 220 publications

References 50 publications

Influenza A Virus Infections in Swine

Influenza A Virus Infections in Swine

PB1-F2 Modulates Early Host Responses but Does Not Affect the Pathogenesis of H1N1 Seasonal Influenza Virus

NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein

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