Effect of Forsythiaside A on the RLRs Signaling Pathway in the Lungs of Mice Infected with the Influenza A Virus FM1 Strain

Forsythiaside A, a phenylethanoid glycoside monomer extracted from Forsythia suspensa, shows anti-inflammatory, anti-infective, anti-oxidative, and antiviral pharmacological effects. The precise mechanism underlying the antiviral action of forsythiaside A is not completely clear. Therefore, in this study, we aimed to determine whether the anti-influenza action of forsythiaside A occurs via the retinoic acid-inducible gene-I–like receptors (RLRs) signaling pathway in the lung immune cells. Forsythiaside A was used to treat C57BL/6J mice and MAVS−/− mice infected with mouse-adapted influenza A virus FM1 (H1N1, A/FM1/1/47 strain), and the physical parameters (body weight and lung index) and the expression of key factors in the RLRs/NF-κB signaling pathway were evaluated. At the same time, the level of virus replication and the ratio of Th1/Th2 and Th17/Treg of T cell subsets were measured. Compared with the untreated group, the weight loss in the forsythiaside A group in the C57BL/6J mice decreased, and the histopathological sections showed less inflammatory damage after the infection with the influenza A virus FM1 strain. The gene and protein expression of retinoic acid-inducible gene-I (RIG-I), MAVS, and NF-κB were significantly decreased in the forsythiaside A group. Flow cytometry showed that Th1/Th2 and Th17/Treg differentiated into Th2 cells and Treg cells, respectively, after treatment with forsythiaside A. In conclusion, forsythiaside A reduces the inflammatory response caused by influenza A virus FM1 strain in mouse lungs by affecting the RLRs signaling pathway in the mouse lung immune cells.

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Mismatches in the Influenza A Virus RNA Panhandle Prevent Retinoic Acid-Inducible Gene I (RIG-I) Sensing by Impairing RNA/RIG-I Complex Formation

Journal of Virology ◽

10.1128/jvi.01671-15 ◽

2015 ◽

Vol 90 (1) ◽

pp. 586-590 ◽

Cited By ~ 10

Author(s):

Stéphanie Anchisi ◽

Jessica Guerra ◽

Geneviève Mottet-Osman ◽

Dominique Garcin

Keyword(s):

Influenza Virus ◽

Retinoic Acid ◽

Complex Formation ◽

Influenza A Virus ◽

Rna Structure ◽

Influenza A ◽

Double Stranded Rna ◽

Virus Rna ◽

Inducible Gene

Influenza virus RNA (vRNA) promoter panhandle structures are believed to be sensed by retinoic acid-inducible gene I (RIG-I). The occurrence of mismatches in this double-stranded RNA structure raises questions about their effect on innate sensing. Our results suggest that mismatches in vRNA promoters decrease binding to RIG-Iin vivo, affecting RNA/RIG-I complex formation and preventing RIG-I activation. These results can be inferred to apply to other viruses and suggest that mismatches may represent a general viral strategy to escape RIG-I sensing.

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Retinoic acid inducible gene-I and mda-5 are involved in influenza A virus-induced expression of antiviral cytokines

Microbes and Infection ◽

10.1016/j.micinf.2006.02.028 ◽

2006 ◽

Vol 8 (8) ◽

pp. 2013-2020 ◽

Cited By ~ 68

Author(s):

Jukka Sirén ◽

Tadaatsu Imaizumi ◽

Devanand Sarkar ◽

Taija Pietilä ◽

Diana L. Noah ◽

...

Keyword(s):

Retinoic Acid ◽

Influenza A Virus ◽

Influenza A ◽

Induced Expression ◽

Inducible Gene

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Inhibition of Retinoic Acid-Inducible Gene I-Mediated Induction of Beta Interferon by the NS1 Protein of Influenza A Virus

Journal of Virology ◽

10.1128/jvi.01265-06 ◽

2006 ◽

Vol 81 (2) ◽

pp. 514-524 ◽

Cited By ~ 411

Author(s):

Masaki Mibayashi ◽

Luis Martínez-Sobrido ◽

Yueh-Ming Loo ◽

Washington B. Cárdenas ◽

Michael Gale ◽

...

Keyword(s):

Retinoic Acid ◽

Influenza A Virus ◽

Transcriptional Activation ◽

Influenza A ◽

Rna Virus ◽

Nonstructural Protein ◽

Ns1 Protein ◽

Beta Interferon ◽

Nonstructural Protein 1 ◽

Inducible Gene

ABSTRACT The retinoic acid-inducible gene I product (RIG-I) has been identified as a cellular sensor of RNA virus infection resulting in beta interferon (IFN-β) induction. However, many viruses are known to encode viral products that inhibit IFN-β production. In the case of influenza A virus, the viral nonstructural protein 1 (NS1) prevents the induction of the IFN-β promoter by inhibiting the activation of transcription factors, including IRF-3, involved in IFN-β transcriptional activation. The inhibitory properties of NS1 appear to be due at least in part to its binding to double-stranded RNA (dsRNA), resulting in the sequestration of this viral mediator of RIG-I activation. However, the precise effects of NS1 on the RIG-I-mediated induction of IFN-β have not been characterized. We now report that the NS1 of influenza A virus interacts with RIG-I and inhibits the RIG-I-mediated induction of IFN-β. This inhibition was apparent even when a mutant RIG-I that is constitutively activated (in the absence of dsRNA) was used to trigger IFN-β production. Coexpression of RIG-I, its downstream signaling partner, IPS-1, and NS1 resulted in increased levels of RIG-I and NS1 within an IPS-1-rich, solubilization-resistant fraction after cell lysis. These results suggest that RIG-I, IPS-1, and NS1 become part of the same complex. Consistent with this idea, NS1 was also found to inhibit IFN-β promoter activation by IPS-1 overexpression. Our results indicate that, in addition to sequestering dsRNA, the NS1 of influenza A virus binds to RIG-I and inhibits downstream activation of IRF-3, preventing the transcriptional induction of IFN-β.

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Interactions between the Influenza A Virus RNA Polymerase Components and Retinoic Acid-Inducible Gene I

Journal of Virology ◽

10.1128/jvi.01383-14 ◽

2014 ◽

Vol 88 (18) ◽

pp. 10432-10447 ◽

Cited By ~ 27

Author(s):

W. Li ◽

H. Chen ◽

T. Sutton ◽

A. Obadan ◽

D. R. Perez

Keyword(s):

Retinoic Acid ◽

Rna Polymerase ◽

Influenza A Virus ◽

Influenza A ◽

Virus Rna ◽

Inducible Gene

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Tbx21 and Foxp3 Are Epigenetically Stabilized in T-Bet+ Tregs That Transiently Accumulate in Influenza A Virus-Infected Lungs

International Journal of Molecular Sciences ◽

10.3390/ijms22147522 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7522

Author(s):

Yassin Elfaki ◽

Juhao Yang ◽

Julia Boehme ◽

Kristin Schultz ◽

Dunja Bruder ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Influenza A Virus ◽

Influenza A ◽

T Cell Subsets ◽

T Helper 1 ◽

T Box ◽

Cell Responses ◽

Accumulation Kinetics ◽

Kinetics Of

During influenza A virus (IAV) infections, CD4+ T cell responses within infected lungs mainly involve T helper 1 (Th1) and regulatory T cells (Tregs). Th1-mediated responses favor the co-expression of T-box transcription factor 21 (T-bet) in Foxp3+ Tregs, enabling the efficient Treg control of Th1 responses in infected tissues. So far, the exact accumulation kinetics of T cell subsets in the lungs and lung-draining lymph nodes (dLN) of IAV-infected mice is incompletely understood, and the epigenetic signature of Tregs accumulating in infected lungs has not been investigated. Here, we report that the total T cell and the two-step Treg accumulation in IAV-infected lungs is transient, whereas the change in the ratio of CD4+ to CD8+ T cells is more durable. Within lungs, the frequency of Tregs co-expressing T-bet is steadily, yet transiently, increasing with a peak at Day 7 post-infection. Interestingly, T-bet+ Tregs accumulating in IAV-infected lungs displayed a strongly demethylated Tbx21 locus, similarly as in T-bet+ conventional T cells, and a fully demethylated Treg-specific demethylated region (TSDR) within the Foxp3 locus. In summary, our data suggest that T-bet+ but not T-bet− Tregs are epigenetically stabilized during IAV-induced infection in the lung.

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Host Non-Coding RNA Regulates Influenza A Virus Replication

Viruses ◽

10.3390/v14010051 ◽

2021 ◽

Vol 14 (1) ◽

pp. 51

Author(s):

Yuejiao Liao ◽

Shouqing Guo ◽

Geng Liu ◽

Zhenyu Qiu ◽

Jiamin Wang ◽

...

Keyword(s):

Signaling Pathway ◽

Influenza A Virus ◽

Influenza A ◽

Janus Kinase ◽

Research Progress ◽

Receptor Signaling ◽

Non Coding Rna ◽

Receptor Signaling Pathway ◽

Non Coding Rnas ◽

Virus Interactions

Outbreaks of influenza, caused by the influenza A virus (IAV), occur almost every year in various regions worldwide, seriously endangering human health. Studies have shown that host non-coding RNA is an important regulator of host–virus interactions in the process of IAV infection. In this paper, we comprehensively analyzed the research progress on host non-coding RNAs with regard to the regulation of IAV replication. According to the regulation mode of host non-coding RNAs, the signal pathways involved, and the specific target genes, we found that a large number of host non-coding RNAs directly targeted the PB1 and PB2 proteins of IAV. Nonstructural protein 1 and other key genes regulate the replication of IAV and indirectly participate in the regulation of the retinoic acid-induced gene I-like receptor signaling pathway, toll-like receptor signaling pathway, Janus kinase signal transducer and activator of transcription signaling pathway, and other major intracellular viral response signaling pathways to regulate the replication of IAV. Based on the above findings, we mapped the regulatory network of host non-coding RNAs in the innate immune response to the influenza virus. These findings will provide a more comprehensive understanding of the function and mechanism of host non-coding RNAs in the cellular anti-virus response as well as clues to the mechanism of cell–virus interactions and the discovery of antiviral drug targets.

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Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Journal of Virology ◽

10.1128/jvi.02749-15 ◽

2015 ◽

Vol 90 (5) ◽

pp. 2403-2417 ◽

Cited By ~ 41

Author(s):

Chuan Xia ◽

Madhuvanthi Vijayan ◽

Curtis J. Pritzl ◽

Serge Y. Fuchs ◽

Adrian B. McDermott ◽

...

Keyword(s):

Signaling Pathway ◽

Influenza A Virus ◽

Influenza A ◽

Type I Interferon ◽

Innate Immune ◽

Host Cells ◽

Type I ◽

Type I Ifn ◽

Type I Ifns ◽

Ha Protein

ABSTRACTInfluenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.IMPORTANCEInfluenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.

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