Mx Is Dispensable for Interferon-Mediated Resistance of Chicken Cells against Influenza A Virus

Schusser, Benjamin; Reuter, Antje; Malsburg, Alexander von der; Penski, Nicola; Weigend, Steffen; Kaspers, Bernd; Staeheli, Peter; Härtle, Sonja

doi:10.1128/jvi.00535-11

Cited by 49 publications

(50 citation statements)

References 45 publications

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“…One speculative possibility is that homologs of MxA in other hosts have selected for some level of generalized MxA resistance in all NPs. Determining whether this is the case will require characterizing whether MxA homologs of the relevant species do in fact exert selection on influenza virus: there is evidence that swine MxA restricts influenza [48, 49], but the anti-influenza activity of avian MxA remains incompletely characterized across most bird species that are hosts for influenza [50–52]. Even if other MxA homologs exert selection, we would not expect non-human viruses to be optimally resistant to human MxA since MxA homologs have different specificities [53].…”

Section: Discussionmentioning

confidence: 99%

Deep mutational scanning identifies sites in influenza nucleoprotein that affect viral inhibition by MxA

et al. 2017

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The innate-immune restriction factor MxA inhibits influenza replication by targeting the viral nucleoprotein (NP). Human influenza virus is more resistant than avian influenza virus to inhibition by human MxA, and prior work has compared human and avian viral strains to identify amino-acid differences in NP that affect sensitivity to MxA. However, this strategy is limited to identifying sites in NP where mutations that affect MxA sensitivity have fixed during the small number of documented zoonotic transmissions of influenza to humans. Here we use an unbiased deep mutational scanning approach to quantify how all single amino-acid mutations to NP affect MxA sensitivity in the context of replication-competent virus. We both identify new sites in NP where mutations affect MxA resistance and re-identify mutations known to have increased MxA resistance during historical adaptations of influenza to humans. Most of the sites where mutations have the greatest effect are almost completely conserved across all influenza A viruses, and the amino acids at these sites confer relatively high resistance to MxA. These sites cluster in regions of NP that appear to be important for its recognition by MxA. Overall, our work systematically identifies the sites in influenza nucleoprotein where mutations affect sensitivity to MxA. We also demonstrate a powerful new strategy for identifying regions of viral proteins that affect inhibition by host factors.

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Section: Discussionmentioning

confidence: 99%

Deep mutational scanning identifies sites in influenza nucleoprotein that affect viral inhibition by MxA

et al. 2017

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“…RT was performed using Revertaid (Fermentas) with oligo(dT) (for measuring chMx and chIL28RA mRNA) or random hexamers (for measuring viral RNA) with 1 g of DNase-treated RNA in a final volume of 20 l. One microliter of RT product was used for qPCR analysis using the Sensifast SybrHi-Rox kit (Bioline, Luckenwalde, Germany) according to the manufacturer's instructions. Primers for influenza A virus detection were derived from Fouchier et al (24), and primers for chMx mRNA amplification were derived from Schusser et al (25). Primers qPCRmbRA-F (5=-GAAGCCG GATCTGAAGACAA-3=) and qPCRmbRA-R (5=-TGATATCTTAAC ACATCCTTCCTCAG-3=) were used for detecting chIL28RA mRNA.…”

Section: Methodsmentioning

confidence: 99%

Antiviral Activity of Lambda Interferon in Chickens

Reuter

Soubies

Härtle

et al. 2014

J Virol

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“…In analogy to the mammalian system the avian Mx orthologue was considered to have potent antiviral properties [25, 26]. Surprisingly, in vitro and in vivo studies clearly demonstrated that chicken Mx does not limit influenza virus replication despite strong induction of the protein by IFN [27, 28]. Thus, it remains to be elucidated which IRGs confer antiviral resistance in different viral disease.…”

Section: Introductionmentioning

confidence: 99%

Tissue and time specific expression pattern of interferon regulated genes in the chicken

Röll

Härtle²,

Lütteke

et al. 2017

BMC Genomics

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BackgroundType I interferons are major players against viral infections and mediate their function by the induction of Interferon regulated genes (IRGs). Recently, it became obvious that these cytokines have a multitude of additional functions. Due to the unique features of the chickens’ immune system, available data from mouse models are not easily transferable; hence we performed an extensive analysis of chicken IRGs.ResultsA broad database search for homologues to described mammalian IRGs (common IRGs, cIRGs) was combined with a transcriptome analysis of spleen and lung at different time points after application of IFNα. To apply physiological amounts of IFN, half-life of IFN in the chicken was determined. Interestingly, the calculated 36 min are considerably shorter than the ones obtained for human and mouse. Microarray analysis revealed many additional IRGs (newly identified IRGs; nIRGs) and network analysis for selected IRGs showed a broad interaction of nIRGs among each other and with cIRGs. We found that IRGs exhibit a highly tissue and time specific expression pattern as expression quality and quantity differed strongly between spleen and lung and over time. While in the spleen for many affected genes changes in RNA abundance peaked already after 3 h, an increasing or plateau-like regulation after 3, 6 and 9 h was observed in the lung.ConclusionsThe induction or suppression of IRGs in chickens is both tissue and time specific and beside known antiviral mechanisms type I IFN induces many additional cellular functions. We confirmed many known IRGs and established a multitude of so far undescribed ones, thus providing a large database for future research on antiviral mechanisms and additional IFN functions in non-mammalian species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3641-6) contains supplementary material, which is available to authorized users.

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Mx Is Dispensable for Interferon-Mediated Resistance of Chicken Cells against Influenza A Virus

Abstract: Finally, we found that both isoforms of chicken Mx protein appear to lack GTPase activity, which might explain the observed lack of antiviral activity.

Cited by 49 publications

References 45 publications

Deep mutational scanning identifies sites in influenza nucleoprotein that affect viral inhibition by MxA

Deep mutational scanning identifies sites in influenza nucleoprotein that affect viral inhibition by MxA

Antiviral Activity of Lambda Interferon in Chickens

Tissue and time specific expression pattern of interferon regulated genes in the chicken

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