Type I IFN promotes pathogenic inflammatory monocyte maturation during H5N1 infection

Ly6Chi inflammatory monocytes show high IFN responses, and contribute to both protective and pathogenic functions following influenza virus infection. In order to understand the significance of IFN responses in this subset, we examined monocytes during infection with a lethal H5N1 virus that induces high levels of IFN and a low-pathogenicity H1N1 virus that induces low levels of IFN. We show that H5N1 infection results in early recruitment of high numbers of Ly6Chi monocytes and induction of chemokines and Ifnb1. Using unbiased transcriptomic and proteomic approaches, we also find that monocytes are significantly enriched during H5N1 infection and are associated with chemokine and IFN signatures in mice, and with severity of symptoms after influenza virus infection in humans. Recruited Ly6Chi monocytes subsequently become infected in the lung, produce IFN-β, and mature into FasL+ monocyte-derived cells (FasL+MCs) expressing dendritic cell markers. Both Ccr2-/- and Faslgld mice are protected from lethal infection, indicating that monocytes contribute to pathogenesis. Global loss of type I and type III IFN signaling in Stat2-/- mice results in loss of monocyte recruitment, likely reflecting a requirement for IFN-dependent chemokine induction. Here we show that IFN is not directly required for monocyte recruitment on an IFN-sufficient background, but is required for maturation to FasL+MCs. Loss of IFN signaling skews to a Ly6Clo phenotype associated with tissue repair, suggesting that IFN signaling in monocytes is a critical determinant of influenza virus pathogenesis.

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DNA Vaccine Encoding Hemagglutinin Provides Protective Immunity against H5N1 Influenza Virus Infection in Mice

Journal of Virology ◽

10.1128/jvi.73.3.2094-2098.1999 ◽

1999 ◽

Vol 73 (3) ◽

pp. 2094-2098 ◽

Cited By ~ 92

Author(s):

Shantha Kodihalli ◽

Hideo Goto ◽

Darwyn L. Kobasa ◽

Scott Krauss ◽

Yoshihiro Kawaoka ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Dna Vaccine ◽

Influenza Virus Infection ◽

Glycosylation Site ◽

Mammalian Host ◽

H5n1 Infection ◽

H5n1 Avian Influenza

ABSTRACT In Hong Kong in 1997, a highly lethal H5N1 avian influenza virus was apparently transmitted directly from chickens to humans with no intermediate mammalian host and caused 18 confirmed infections and six deaths. Strategies must be developed to deal with this virus if it should reappear, and prospective vaccines must be developed to anticipate a future pandemic. We have determined that unadapted H5N1 viruses are pathogenic in mice, which provides a well-defined mammalian system for immunological studies of lethal avian influenza virus infection. We report that a DNA vaccine encoding hemagglutinin from the index human influenza isolate A/HK/156/97 provides immunity against H5N1 infection of mice. This immunity was induced against both the homologous A/HK/156/97 (H5N1) virus, which has no glycosylation site at residue 154, and chicken isolate A/Ck/HK/258/97 (H5N1), which does have a glycosylation site at residue 154. The mouse model system should allow rapid evaluation of the vaccine’s protective efficacy in a mammalian host. In our previous study using an avian model, DNA encoding hemagglutinin conferred protection against challenge with antigenic variants that differed from the primary antigen by 11 to 13% in the HA1 region. However, in our current study we found that a DNA vaccine encoding the hemagglutinin from A/Ty/Ir/1/83 (H5N8), which differs from A/HK/156/97 (H5N1) by 12% in HA1, prevented death but not H5N1 infection in mice. Therefore, a DNA vaccine made with a heterologous H5 strain did not prevent infection by H5N1 avian influenza viruses in mice but was useful in preventing death.

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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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Muramyl Dipeptide Induces NOD2-Dependent Ly6Chigh Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection

PLoS ONE ◽

10.1371/journal.pone.0036734 ◽

2012 ◽

Vol 7 (5) ◽

pp. e36734 ◽

Cited By ~ 37

Author(s):

François Coulombe ◽

Stéphanie Fiola ◽

Shizuo Akira ◽

Yvon Cormier ◽

Jean Gosselin

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Virus Infection ◽

Muramyl Dipeptide ◽

Monocyte Recruitment

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

Journal of Virology ◽

10.1128/jvi.02260-16 ◽

2017 ◽

Vol 91 (12) ◽

Cited By ~ 4

Author(s):

Dongjo Shin ◽

Jihye Lee ◽

Ji Hoon Park ◽

Ji-Young Min

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Crucial Role ◽

Influenza Virus Infection ◽

Host Factors ◽

Viral Escape ◽

Type I ◽

Plant Homeodomain ◽

Novel Host ◽

The Relationship

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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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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