scholarly journals Interferon Inducer IFI35 regulates RIG-I-mediated innate antiviral response through mutual antagonism with Influenza protein NS1

2021 ◽  
Author(s):  
Hui Yang ◽  
Wendy Winkler ◽  
Xiaopeng Wu
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Respiratory Infections ◽  
Type I ◽  
H7n9 Virus ◽  
Viral Immunity ◽  
Interferon Inducer ◽  
Interferon Stimulated Genes ◽  
Mutual Antagonism ◽  
Innate Antiviral Response

Interferon-stimulated genes (ISGs) create multiple lines of defense against viral infection. Here we show that interferon induced protein 35 (IFI35) inhibits swine (H3N2) influenza virus replication by directly interacting with the viral protein NS1. IFI35 binds more preferentially to the effector domain of NS1 (128-207aa) than to the viral RNA sensor RIG-I. This promotes mutual antagonism between IFI35 and NS1, and frees RIG-I from IFI35-mediated K48-linked ubiquitination and degradation. However, IFI35 does not interact with the NS1 encoded by avian (H7N9) influenza virus, resulting in IFI35 playing an opposite virus enabling role during highly pathogenic H7N9 virus infection. Notably, replacing the 128-207aa region of NS1-H7N9 with the corresponding region of NS1-H3N2 results in the chimeric NS1 acquiring the ability to bind to and mutually antagonize IFI35. IFI35 deficient mice accordingly exhibit more resistance to lethal H7N9 infection than their wild-type control exhibit. Our data uncover a novel mechanism by which IFI35 regulates RIG-I-mediated anti-viral immunity through mutual antagonism with influenza protein NS1. IMPORTANCE IAV infection poses a global health threat, and is among the most common contagious pathogens to cause severe respiratory infections in humans and animals. ISGs play a key role in host defense against IAV infection. In line with others, we show IFI35-mediated ubiquitination of RIG-I to be involved in innate immunity. Moreover, we define a novel role of IFI35 in regulating the type I IFN pathway during IAV infection. We found that IFI35 regulates RIG-I mediated antiviral signaling by interacting with IAV-NS1. H3N2 NS1, but notably not H7N9 NS1, interacts with IFI35 and efficiently suppresses IFI35-dependent ubiquitination of RIG-I. IFI35 deficiency protected mice from H7N9 virus infection. Therefore, manipulation of the IFI35-NS1 provides a new approach for the development of anti-IAV treatments.

Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice

2019 ◽  
Vol 513 (2) ◽  
pp. 405-411 ◽  
Author(s):  
Ho Namkoong ◽  
Makoto Ishii ◽  
Hideki Fujii ◽  
Takahiro Asami ◽  
Kazuma Yagi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Type I Interferon ◽  
Influenza Virus Infection ◽  
Type I ◽  
Interferon Induction

scholarly journals Pandemic (H1N1) 2009 Influenza Virus Infection in A Survivor Who Has Recovered from Severe H7N9 Virus Infection, China

2016 ◽  
Vol 7 ◽  
Author(s):  
Shan-Hui Chen ◽  
Meng-Na Wu ◽  
Yan-Hua Qian ◽  
Guang-Yuan Ma ◽  
Guo-Lin Wang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Pandemic H1n1 ◽  
H7n9 Virus ◽  
Pandemic H1n1 2009

scholarly journals Type I IFN Receptor Signals Directly Stimulate Local B Cells Early following Influenza Virus Infection

2006 ◽  
Vol 176 (7) ◽  
pp. 4343-4351 ◽  
Author(s):  
Elizabeth S. Coro ◽  
W. L. William Chang ◽  
Nicole Baumgarth
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Type I ◽  
Type I Ifn

scholarly journals Immunopathogenesis of SARS-CoV-2-induced pneumonia: lessons from influenza virus infection

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Masaaki Miyazawa
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Tissue Injury ◽  
Influenza Virus Infection ◽  
T Cell Responses ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Viral Spread ◽  
Cell Responses

Abstract Factors determining the progression of frequently mild or asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection into life-threatening pneumonia remain poorly understood. Viral and host factors involved in the development of diffuse alveolar damage have been extensively studied in influenza virus infection. Influenza is a self-limited upper respiratory tract infection that causes acute and severe systemic symptoms and its spread to the lungs is limited by CD4+ T-cell responses. A vicious cycle of CCL2- and CXCL2-mediated inflammatory monocyte and neutrophil infiltration and activation and resultant massive production of effector molecules including tumor necrosis factor (TNF)-α, nitric oxide, and TNF-related apoptosis-inducing ligand are involved in the pathogenesis of progressive tissue injury. SARS-CoV-2 directly infects alveolar epithelial cells and macrophages and induces foci of pulmonary lesions even in asymptomatic individuals. Mechanisms of tissue injury in SARS-CoV-2-induced pneumonia share some aspects with influenza virus infection, but IL-1β seems to play more important roles along with CCL2 and impaired type I interferon signaling might be associated with delayed virus clearance and disease severity. Further, data indicate that preexisting memory CD8+ T cells may play important roles in limiting viral spread in the lungs and prevent progression from mild to severe or critical pneumonia. However, it is also possible that T-cell responses are involved in alveolar interstitial inflammation and perhaps endothelial cell injury, the latter of which is characteristic of SARS-CoV-2-induced pathology.

scholarly journals Bacterial Outer Membrane Vesicles Provide Broad-Spectrum Protection against Influenza Virus Infection via Recruitment and Activation of Macrophages

2019 ◽  
Vol 11 (4) ◽  
pp. 316-329 ◽  
Author(s):  
Eun-Hye Bae ◽  
Sang Hwan Seo ◽  
Chang-Ung Kim ◽  
Min Seong Jang ◽  
Min-Suk Song ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Protective Effect ◽  
Outer Membrane ◽  
Lethal Dose ◽  
Influenza Virus Infection ◽  
Outer Membrane Vesicles ◽  
Type I ◽  
Wide Range ◽  
Bacterial Outer Membrane

Influenza A virus (IAV) poses a constant worldwide threat to human health. Although conventional vaccines are available, their protective efficacy is type or strain specific, and their production is time-consuming. For the control of an influenza pandemic in particular, agents that are immediately effective against a wide range of virus variants should be developed. Although pretreatment of various Toll-like receptor (TLR) ligands have already been reported to be effective in the defense against subsequent IAV infection, the efficacy was limited to specific subtypes, and safety concerns were also raised. In this study, we investigated the protective effect of an attenuated bacterial outer membrane vesicle ­harboring modified lipid A moiety of lipopolysaccharide (fmOMV) against IAV infection and the underlying mechanisms. Administration of fmOMV conferred significant protection against a lethal dose of pandemic H1N1, PR8, H5N2, and highly pathogenic H5N1 viruses; this broad antiviral activity was dependent on macrophages but independent of neutrophils. fmOMV induced recruitment and activation of macrophages and elicited type I IFNs. Intriguingly, fmOMV showed a more significant protective effect than other TLR ligands tested in previous reports, without exhibiting any adverse effect. These results show the potential of fmOMV as a prophylactic agent for the defense against influenza virus infection.

scholarly journals Histone Deacetylase 6 Knockout Mice Exhibit Higher Susceptibility to Influenza A Virus Infection

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 728 ◽  
Author(s):  
Mark Zanin ◽  
Jennifer DeBeauchamp ◽  
Gowthami Vangala ◽  
Richard J. Webby ◽  
Matloob Husain
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Histone Deacetylase ◽  
Influenza A Virus ◽  
Influenza A ◽  
Antiviral Response ◽  
Histone Deacetylase 6 ◽  
Influenza A Virus Infection ◽  
Innate Antiviral Response ◽  
Mouse Lungs

The host innate defence against influenza virus infection is an intricate system with a plethora of antiviral factors involved. We have identified host histone deacetylase 6 (HDAC6) as an anti-influenza virus factor in cultured cells. Consistent with this, we report herein that HDAC6 knockout (KO) mice are more susceptible to influenza virus A/PR/8/1934 (H1N1) infection than their wild type (WT) counterparts. The KO mice lost weight faster than the WT mice and, unlike WT mice, could not recover their original body weight. Consequently, more KO mice succumbed to infection, which corresponded with higher lung viral loads. Conversely, the expression of the critical innate antiviral response genes interferon alpha/beta, CD80, CXCL10 and IL15 was significantly downregulated in KO mouse lungs compared to WT mouse lungs. These data are consistent with the known function of HDAC6 of de-acetylating the retinoic acid inducible gene-I (RIG-I) and activating the host innate antiviral response cascade. Loss of HDAC6 thus leads to a blunted innate response and increased susceptibility of mice to influenza A virus infection.

Gut microbiota modulates type I interferon and antibody-mediated immune responses in chickens infected with influenza virus subtype H9N2

2018 ◽  
Vol 9 (3) ◽  
pp. 417-427 ◽  
Author(s):  
A. Yitbarek ◽  
T. Alkie ◽  
K. Taha-Abdelaziz ◽  
J. Astill ◽  
J.C. Rodriguez-Lecompte ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Virus Infection ◽  
Gut Microbiota ◽  
Type I Interferon ◽  
Influenza Viruses ◽  
H9n2 Virus ◽  
Type I ◽  
Virus Shedding ◽  
Virus Subtype

Commensal gut microbes play a critical role in shaping host defences against pathogens, including influenza viruses. The current study was conducted to assess the role and mechanisms of action of commensal gut microbiota on the innate and antibody-mediated responses of layer chickens against influenza virus subtype H9N2. A total of 104 one-day-old specific pathogen free chickens were assigned to either of the four treatments, which included two levels of antibiotics treatment (ABX- and ABX+) and two levels of H9N2 virus infection (H9N2- and H9N2+). At day 17 of age, chickens in the H9N2+ group were infected via the oral-nasal route with 400 μl of 107 TCID50/ml (200 μl/each route). Oropharyngeal and cloacal swabs at days 1, 3, 5, 7 and 9 post-infection (p.i.) for virus shedding, tissue samples at 12 h, 24 h and 36 h p.i. for mRNA measurement, and serum samples at days 7 and 14 p.i. for hemagglutination inhibition (HI) assay and IgG antibodies were collected. Virus shedding analysis showed that antibiotic treated (depleted)-H9N2 virus infected chickens showed a significantly higher oropharyngeal virus shedding at all time points, and cloacal shedding at days 3 and 5 p.i. compared to control treated (undepleted)-H9N2 infected chickens. Analysis of mRNA expression showed that infection of depleted chickens with H9N2 virus resulted in significantly down-regulated type I interferon responses both in the respiratory and gastrointestinal tracts compared to undepleted-H9N2 infected chickens. However, antibody-mediated immune response analysis showed a significantly higher HI antibody titre and IgG levels in the serum of chickens depleted with antibiotics and infected with H9N2 virus compared to undepleted-H9N2 infected chickens. In conclusion, findings from the current study suggest that the gut microbiota of chickens plays an important role in the initiation of innate responses against influenza virus infection, while the antibody-mediated immune response remains unaffected.

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