Double Plant Homeodomain Fingers 2 (DPF2) Promotes the Immune Escape of Influenza Virus by Suppressing Beta Interferon Production

ABSTRACT The high mutation rates of the influenza virus genome facilitate the generation of viral escape mutants, rendering vaccines and drugs against influenza virus-encoded targets potentially ineffective. Therefore, we identified host cell determinants dispensable for the host but crucial for virus replication, with the goal of preventing viral escape and finding effective antivirals. To identify these host factors, we screened 2,732 human genes using RNA interference and focused on one of the identified host factors, the double plant homeodomain fingers 2 (DPF2/REQ) gene, for this study. We found that knockdown of DPF2 in cells infected with influenza virus resulted in decreased expression of viral proteins and RNA. Furthermore, production of progeny virus was reduced by two logs in the multiple-cycle growth kinetics assay. We also found that DPF2 was involved in the replication of seasonal influenza A and B viruses. Because DPF2 plays a crucial role in the noncanonical NF-κB pathway, which negatively regulates type I interferon (IFN) induction, we examined the relationship between DPF2 and IFN responses during viral infection. The results showed that knockdown of DPF2 resulted in increased expression of IFN-β and induced phosphorylation of STAT1 in infected cells. In addition, high levels of several cytokines/chemokines (interleukin-8 [IL-8], IP-10, and IL-6) and antiviral proteins (MxA and ISG56) were produced by DPF2 knockdown cells. In conclusion, we identified a novel host factor, DPF2, that is required for influenza virus to evade the host immune response and that may serve as a potential antiviral target. IMPORTANCE Influenza virus is responsible for seasonal epidemics and occasional pandemics and is an ongoing threat to public health worldwide. Influenza virus relies heavily on cellular factors to complete its life cycle. Here we identified a novel host factor, DPF2, which is involved in influenza virus infection. Our results showed that DPF2 plays a crucial role in the replication and propagation of influenza virus. DPF2 functions in the noncanonical NF-κB pathway, which negatively regulates type I IFN induction. Thus, we investigated the relationship between the IFN response and DPF2 in influenza virus infection. Upon influenza virus infection, DPF2 dysregulated IFN-β induction and expression of cytokines/chemokines and antiviral proteins. This study provides evidence that influenza virus utilizes DPF2 to escape host innate immunity.

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

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.03.211 ◽

2019 ◽

Vol 513 (2) ◽

pp. 405-411 ◽

Cited By ~ 4

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

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Influenza virus infection exacerbates experimental autoimmune encephalomyelitis disease by promoting type I T cells infiltration into central nervous system

Journal of Autoimmunity ◽

10.1016/j.jaut.2016.10.006 ◽

2017 ◽

Vol 77 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Qingyun Chen ◽

Yinping Liu ◽

Aizhen Lu ◽

Ke Ni ◽

Zheng Xiang ◽

...

Keyword(s):

Central Nervous System ◽

T Cells ◽

Nervous System ◽

Influenza Virus ◽

Virus Infection ◽

Experimental Autoimmune Encephalomyelitis ◽

Influenza Virus Infection ◽

Type I ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

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

The Journal of Immunology ◽

10.4049/jimmunol.176.7.4343 ◽

2006 ◽

Vol 176 (7) ◽

pp. 4343-4351 ◽

Cited By ~ 131

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

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The relationship between in vivo antiviral activity and pharmacokinetic parameters of peramivir in influenza virus infection model in mice

Antiviral Research ◽

10.1016/j.antiviral.2014.06.016 ◽

2014 ◽

Vol 109 ◽

pp. 110-115 ◽

Cited By ~ 4

Author(s):

Makoto Kodama ◽

Ryu Yoshida ◽

Takahiro Hasegawa ◽

Masaaki Izawa ◽

Mitsutaka Kitano ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Antiviral Activity ◽

Influenza Virus Infection ◽

Pharmacokinetic Parameters ◽

Infection Model ◽

The Relationship ◽

Virus Infection Model

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

Inflammation and Regeneration ◽

10.1186/s41232-020-00148-1 ◽

2020 ◽

Vol 40 (1) ◽

Cited By ~ 3

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.

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

Journal of Innate Immunity ◽

10.1159/000494098 ◽

2019 ◽

Vol 11 (4) ◽

pp. 316-329 ◽

Cited By ~ 5

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.

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CD151, a novel host factor of nuclear export signaling in influenza virus infection

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2017.11.032 ◽

2018 ◽

Vol 141 (5) ◽

pp. 1799-1817 ◽

Cited By ~ 12

Author(s):

Yongkang Qiao ◽

Yan Yan ◽

Kai Sen Tan ◽

Sheryl S.L. Tan ◽

Ju Ee Seet ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Nuclear Export ◽

Influenza Virus Infection ◽

Host Factor ◽

Novel Host

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Host factors involved in influenza virus infection

Emerging Topics in Life Sciences ◽

10.1042/etls20200232 ◽

2020 ◽

Vol 4 (4) ◽

pp. 401-410

Author(s):

Matloob Husain

Keyword(s):

Influenza Virus ◽

Plasma Membrane ◽

Life Cycle ◽

Virus Infection ◽

Mammalian Cells ◽

Influenza Virus Infection ◽

Host Factors ◽

Tremendous Amount ◽

Human Viruses ◽

Insight Into

Influenza virus causes an acute febrile respiratory disease in humans that is commonly known as ‘flu’. Influenza virus has been around for centuries and is one of the most successful, and consequently most studied human viruses. This has generated tremendous amount of data and information, thus it is pertinent to summarise these for, particularly interdisciplinary readers. Viruses are acellular organisms and exist at the interface of living and non-living. Due to this unique characteristic, viruses require another organism, i.e. host to survive. Viruses multiply inside the host cell and are obligate intracellular pathogens, because their relationship with the host is almost always harmful to host. In mammalian cells, the life cycle of a virus, including influenza is divided into five main steps: attachment, entry, synthesis, assembly and release. To complete these steps, some viruses, e.g. influenza utilise all three parts — plasma membrane, cytoplasm and nucleus, of the cell; whereas others, e.g. SARS-CoV-2 utilise only plasma membrane and cytoplasm. Hence, viruses interact with numerous host factors to complete their life cycle, and these interactions are either exploitative or antagonistic in nature. The host factors involved in the life cycle of a virus could be divided in two broad categories — proviral and antiviral. This perspective has endeavoured to assimilate the information about the host factors which promote and suppress influenza virus infection. Furthermore, an insight into host factors that play a dual role during infection or contribute to influenza virus-host adaptation and disease severity has also been provided.

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Influenza A Virus Infection Triggers Pyroptosis and Apoptosis of Respiratory Epithelial Cells through the Type I Interferon Signaling Pathway in a Mutually Exclusive Manner

Journal of Virology ◽

10.1128/jvi.00396-18 ◽

2018 ◽

Vol 92 (14) ◽

Cited By ~ 22

Author(s):

SangJoon Lee ◽

Mikako Hirohama ◽

Masayuki Noguchi ◽

Kyosuke Nagata ◽

Atsushi Kawaguchi

Keyword(s):

Cell Death ◽

Influenza Virus ◽

Epithelial Cells ◽

Virus Infection ◽

Signaling Pathway ◽

Influenza Virus Infection ◽

Type I ◽

Respiratory Epithelial Cells ◽

Respiratory Epithelial ◽

Early Phases

ABSTRACT Respiratory epithelial cell death by influenza virus infection is responsible for the induction of inflammatory responses, but the exact cell death mechanism is not understood. Here we showed that influenza virus infection induces apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced only in malignant tumor cells infected with influenza virus. In human precancerous respiratory epithelial cells (PL16T), the number of apoptotic cells increased at early phases of infection, but pyroptotic cells were observed at late phases of infection. These findings suggest that apoptosis is induced at early phases of infection but the cell death pathway is shifted to pyroptosis at late phases of infection. We also found that the type I interferon (IFN)-mediated JAK-STAT signaling pathway promotes the switch from apoptosis to pyroptosis by inhibiting apoptosis possibly through the induced expression of the Bcl-xL anti-apoptotic gene. Further, the inhibition of JAK-STAT signaling repressed pyroptosis but enhanced apoptosis in infected PL16T cells. Collectively, we propose that type I IFN signaling pathway triggers pyroptosis but not apoptosis in the respiratory epithelial cells in a mutually exclusive manner to initiate proinflammatory responses against influenza virus infection. IMPORTANCE Respiratory epithelium functions as a sensor of infectious agents to initiate inflammatory responses along with cell death. However, the exact cell death mechanism responsible for inflammatory responses by influenza virus infection is still unclear. We showed that influenza virus infection induced apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced at early phases of infection, but the cell death pathway was shifted to pyroptosis at late phases of infection under the regulation of type I IFN signaling to promote proinflammatory cytokine production. Taken together, our results indicate that the type I IFN signaling pathway plays an important role to induce pyroptosis but represses apoptosis in the respiratory epithelial cells to initiate proinflammatory responses against influenza virus infection.

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