The 1918 Influenza Virus PB2 Protein Enhances Virulence through the Disruption of Inflammatory and Wnt-Mediated Signaling in Mice

Forero, Adriana; Tisoncik-Go, Jennifer; Watanabe, Tokiko; Zhong, Gongxun; Hatta, Masato; Tchitchek, Nicolas; Selinger, Christian; Chang, Jean; Barker, Kristi; Morrison, Juliet; Berndt, Jason D.; Moon, Randall T.; Josset, Laurence; Kawaoka, Yoshihiro; Katze, Michael G.

doi:10.1128/jvi.02974-15

Cited by 34 publications

(29 citation statements)

References 71 publications

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“…All infected samples were confirmed to express viral M2 mRNA by quantitative RT-PCR (Forero et al, 2015; McCown and Pekosz, 2005). Individual cRNA samples were then hybridized to oligonucleotide microarrays for gene expression profiling using SurePrint G3 Human Gene Expression v2 Microarray Kit (G4851A; Agilent Technologies).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the innate immune responses to influenza and live-attenuated influenza vaccine infection in primary differentiated human nasal epithelial cells

Forero

Fenstermacher

Wohlgemuth

et al. 2017

Vaccine

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The host innate immune response to influenza virus is a key determinant of pathogenic outcomes and long-term protective immune responses against subsequent exposures. Here, we present a direct contrast of the host responses in primary differentiated human nasal epithelial cell (hNEC) cultures following infection with either a seasonal H3N2 influenza virus (WT) or the antigenically-matched live-attenuated vaccine (LAIV) strain. Comparison of the transcriptional profiles obtained 24 and 36 hours post-infection showed that the magnitude of gene expression was greater in LAIV infected relative to that observed in WT infected hNEC cultures. Functional enrichment analysis revealed that the antiviral and inflammatory responses were largely driven by type III IFN induction in both WT and LAIV infected cells. However, the enrichment of biological pathways involved in the recruitment of mononuclear leukocytes, antigen-presenting cells, and T lymphocytes was uniquely observed in LAIV infected cells. These observations were reflective of the host innate immune responses observed in individuals acutely infected with influenza viruses. These findings indicate that cell-intrinsic type III IFN-mediated innate immune responses in the nasal epithelium are not only crucial for viral clearance and attenuation, but may also play an important role in the induction of protective immune responses with live-attenuated vaccines.

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Section: Methodsmentioning

confidence: 99%

Evaluation of the innate immune responses to influenza and live-attenuated influenza vaccine infection in primary differentiated human nasal epithelial cells

Forero

Fenstermacher

Wohlgemuth

et al. 2017

Vaccine

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“…In a very recent study, the 1918 influenza virus PB2 protein was shown to be a virulence factor interfering with inflammatory and Wnt-mediated signaling in mice. Both, beta-catenin-dependent and -independent Wnt signaling pathways were repressed and associated with impaired lung regeneration and repair (139). Taken together, this illustrates that depending on the infection mechanism and the infected host cell, pathogens may exploit the Wnt signaling machinery in a very specific manner.…”

Section: Pathogens Exploiting Wnt Signalingmentioning

confidence: 99%

The Wnt Blows: On the Functional Role of Wnt Signaling in Mycobacterium tuberculosis Infection and Beyond

Brandenburg

Reiling

2016

Front. Immunol.

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In recent years, it has become apparent that the Wnt signaling pathway, known for its essential functions in embryonic development and tissue homeostasis, exerts immunomodulatory functions during inflammation and infection. Most functional studies indicate that Wnt5a exerts pro-inflammatory functions on its cellular targets, which include various types of immune and non-immune cells. Wnt5a expression has also been linked to the pathogenesis of chronic inflammatory diseases. Activation of beta-catenin-dependent Wnt signaling, e.g., by Wnt3a, has however been shown to limit inflammation by interfering with the nuclear factor kappa-light chain-enhancer of activated B-cells (NF-kappaB) pathway. This review focuses on the regulation of Wnt5a, Wnt3a, and the recently identified Wnt6 and their functional role in bacterial infections with a primary focus on pulmonary tuberculosis, a leading infectious cause of morbidity and mortality worldwide.

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“…S4a). Interestingly, the BM18 influenza PB2 subunit has been linked to the enhancement of both the kinetics and the magnitude of the host response to viral infection, leading to the induction of strong inflammatory responses with increased cellular infiltration in the lungs of infected mice 24 . To identify PB2 amino acid residues involved in the formation of mvRNAs, we aligned the BM18, WSN, NT60 and FJ02 PB2 sequences and found four amino acid positions that distinguish the BM18 and FJ02 polymerases from the WSN and NT60 polymerases: 9 (D→N), 64 (M→T), 81 (T→M), and 661 (A→T) (Fig.…”

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confidence: 99%

Mini viral RNAs act as innate immune agonists during influenza virus infection

Velthuis

Long

Bauer

et al. 2018

Preprint

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and propose an intramolecular copy-choice mechanism for mvRNA generation. 43 By deep-sequencing RNA samples from lungs of ferrets infected with influenza 44viruses we show that mvRNAs are generated during infection of animal models. 45 We propose that mvRNAs act as main agonists of RIG-I during influenza virus 46infection and the ability of influenza virus strains to generate mvRNAs should be 47 considered when assessing their virulence potential. 48The negative sense viral RNA (vRNA) genome segments of influenza A viruses, 49 as well as the complementary RNA (cRNA) replicative intermediates, contain 5ʹ 50 triphosphates and partially complementary 5ʹ and 3ʹ termini that serve as the viral 51 promoter for replication and transcription of the viral RNA genome 6 . RIG-I has been 52 shown to bind and be activated by the dsRNA structure formed by the termini of 53 influenza virus RNAs 7,8 . However, it remains unclear how RIG-I gains access to this 54 dsRNA structure. Both vRNA and cRNA are assembled into ribonucleoprotein 55 complexes (vRNP and cRNP, respectively) in which the viral RNA polymerase, a 56 heterotrimeric complex of the viral proteins PB1, PB2 and PA, associates with the 57 partially complementary termini, while the rest of the RNA is bound by oligomeric 58 nucleoprotein (NP) 6 (Fig. 1a). The tight binding of the 5ʹ and 3ʹ termini of vRNA and 59for use under a CC0 license.This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/385716 doi: bioRxiv preprint first posted online Aug. 6, 2018; 3 cRNA by the RNA polymerase 9 is likely to preclude an interaction with RIG-I. 60Moreover, it has been demonstrated that IFN expression is triggered only in a fraction 61 of influenza virus infected cells 10,11 , suggesting that influenza viruses efficiently hide 62 their genome segments during infection by replicating them in the context of RNPs 11 . 63This led to the proposal that an aberrant RNA replication product might be binding to 64 RIG-I and triggering IFN expression 12 . Indeed, the influenza virus polymerase is known 65 to generate defective interfering (DI) RNAs, which are ≥178 nt long subgenomic RNAs 66 generated during high multiplicity infections 13 , and small viral RNAs (svRNAs), which 67 are 22-27 nt long and correspond to the 5ʹ end of vRNA segments. However, svRNAs 68 have been shown not to be involved in the induction of antiviral cellular defences 14 and 69 DI RNAs assemble into RNP structures (Fig. 1a) NP and a luciferase reporter to measure the activation of the IFN-b promoter (Fig. 1b). 82We found that the expression of mvRNAs induced significantly higher IFN expression 83 than full-length vRNA or DI RNA, comparable to the levels induced by transfection of 84 2 µg of poly(I:C), a known activator of IFN expression 18 . Similar results were ob...

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The 1918 Influenza Virus PB2 Protein Enhances Virulence through the Disruption of Inflammatory and Wnt-Mediated Signaling in Mice

Cited by 34 publications

References 71 publications

Evaluation of the innate immune responses to influenza and live-attenuated influenza vaccine infection in primary differentiated human nasal epithelial cells

Evaluation of the innate immune responses to influenza and live-attenuated influenza vaccine infection in primary differentiated human nasal epithelial cells

The Wnt Blows: On the Functional Role of Wnt Signaling in Mycobacterium tuberculosis Infection and Beyond

Mini viral RNAs act as innate immune agonists during influenza virus infection

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