scholarly journals The Role of Interferon in Influenza Virus Tissue Tropism

1998 ◽  
Vol 72 (11) ◽  
pp. 8550-8558 ◽  
Author(s):  
Adolfo García-Sastre ◽  
Russell K. Durbin ◽  
Hongyong Zheng ◽  
Peter Palese ◽  
Rachel Gertner ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Cell Lines ◽  
Virus Replication ◽  
Influenza A ◽  
Type I Interferon ◽  
Influenza Virus Infection ◽  
Fibroblast Cell ◽  
Type I ◽  
Fibroblast Cell Lines

ABSTRACT We have studied the pathogenesis of influenza virus infection in mice that are unable to respond to type I or II interferons due to a targeted disruption of the STAT1 gene. STAT1−/− animals are 100-fold more sensitive to lethal infection with influenza A/WSN/33 virus than are their wild-type (WT) counterparts. Virus replicated only in the lungs of WT animals following intranasal (i.n.) virus inoculation, while STAT1−/− mice developed a fulminant systemic influenza virus infection following either i.n. or intraperitoneal inoculation. We investigated the mechanism underlying this altered virus tropism by comparing levels of virus replication in fibroblast cell lines and murine embryonic fibroblasts derived from WT mice, STAT−/− mice, and mice lacking gamma interferon (IFNγ−/− mice) or the IFN-α receptor (IFNαR−/− mice). Influenza A/WSN/33 virus replicates to high titers in STAT1−/− or IFNαR−/− fibroblasts, while cells derived from WT or IFNγ−/− animals are resistant to influenza virus infection. Immunofluorescence studies using WT fibroblast cell lines demonstrated that only a small subpopulation of WT cells can be infected and that in the few infected WT cells, virus replication is aborted at an early, nuclear phase. In all organs examined except the lung, influenza A WSN/33 virus infection is apparently prevented by an intact type I interferon response. Our results demonstrate that type I interferon plays an important role in determining the pathogenicity and tissue restriction of influenza A/WSN/33 virus in vivo and in vitro.

scholarly journals Novel Mode of ISG15-Mediated Protection against Influenza A Virus and Sendai Virus in Mice

2014 ◽  
Vol 89 (1) ◽  
pp. 337-349 ◽  
Author(s):  
David J. Morales ◽  
Kristen Monte ◽  
Lulu Sun ◽  
Jessica J. Struckhoff ◽  
Eugene Agapov ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Type I ◽  
Induced Genes

ABSTRACTISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15−/−mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replicationin vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15−/−mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15in vivo.IMPORTANCEIt has previously been demonstrated that ISG15−/−mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protectionin vivo. In these studies we have found that while ISG15−/−mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15in vivo.

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 Influenza Virus Evades Innate and Adaptive Immunity via the NS1 Protein

2006 ◽  
Vol 80 (13) ◽  
pp. 6295-6304 ◽  
Author(s):  
Ana Fernandez-Sesma ◽  
Svetlana Marukian ◽  
Barbara J. Ebersole ◽  
Dorothy Kaminski ◽  
Man-Seong Park ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Influenza Virus ◽  
Virus Infection ◽  
Adaptive Immunity ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Type I ◽  
Ns1 Protein ◽  
Dc Maturation

ABSTRACT Both antibodies and T cells contribute to immunity against influenza virus infection. However, the generation of strong Th1 immunity is crucial for viral clearance. Interestingly, we found that human dendritic cells (DCs) infected with influenza A virus have lower allospecific Th1-cell stimulatory abilities than DCs activated by other stimuli, such as lipopolysaccharide and Newcastle disease virus infection. This weak stimulatory activity correlates with a suboptimal maturation of the DCs following infection with influenza A virus. We next investigated whether the influenza A virus NS1 protein could be responsible for the low levels of DC maturation after influenza virus infection. The NS1 protein is an important virulence factor associated with the suppression of innate immunity via the inhibition of type I interferon (IFN) production in infected cells. Using recombinant influenza and Newcastle disease viruses, with or without the NS1 gene from influenza virus, we found that the induction of a genetic program underlying DC maturation, migration, and T-cell stimulatory activity is specifically suppressed by the expression of the NS1 protein. Among the genes affected by NS1 are those coding for macrophage inflammatory protein 1β, interleukin-12 p35 (IL-12 p35), IL-23 p19, RANTES, IL-8, IFN-α/β, and CCR7. These results indicate that the influenza A virus NS1 protein is a bifunctional viral immunosuppressor which inhibits innate immunity by preventing type I IFN release and inhibits adaptive immunity by attenuating human DC maturation and the capacity of DCs to induce T-cell responses. Our observations also support the potential use of NS1 mutant influenza viruses as live attenuated influenza virus vaccines.

scholarly journals Differential Type I Interferon Induction by Respiratory Syncytial Virus and Influenza A Virus In Vivo

2007 ◽  
Vol 81 (18) ◽  
pp. 9790-9800 ◽  
Author(s):  
Nancy A. Jewell ◽  
Negin Vaghefi ◽  
Sara E. Mertz ◽  
Parvis Akter ◽  
R. Stokes Peebles ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Syncytial Virus ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Syncytial Virus

ABSTRACTType I interferon (IFN) induction is an immediate response to virus infection, and very high levels of these cytokines are produced when the Toll-like receptors (TLRs) expressed at high levels by plasmacytoid dendritic cells (pDCs) are triggered by viral nucleic acids. Unlike many RNA viruses, respiratory syncytial virus (RSV) does not appear to activate pDCs through their TLRs and it is not clear how this difference affects IFN-α/β induction in vivo. In this study, we investigated type I IFN production triggered by RSV or influenza A virus infection of BALB/c mice and found that while both viruses induced IFN-α/β production by pDCs in vitro, only influenza virus infection could stimulate type I IFN synthesis by pDCs in vivo. In situ hybridization studies demonstrated that the infected respiratory epithelium was a major source of IFN-α/β in response to either infection, but in pDC-depleted animals only type I IFN induction by influenza virus was impaired.

scholarly journals Bleomycin-Induced Lung Injury Increases Resistance to Influenza Virus Infection in a Type I Interferon-Dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Sang-Uk Seo ◽  
Jae-Hyeon Jeong ◽  
Bum-Seo Baek ◽  
Je-Min Choi ◽  
Youn Soo Choi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Lung Injury ◽  
Inflammatory Cytokine ◽  
Type I Interferon ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Type I ◽  
Dependent Manner ◽  
Infection Period

Acute lung injury (ALI) results in acute respiratory disease that causes fatal respiratory diseases; however, little is known about the incidence of influenza infection in ALI. Using a ALI-mouse model, we investigated the pro-inflammatory cytokine response to ALI and influenza infection. Mice treated with bleomycin (BLM), which induces ALI, were more resistant to influenza virus infection and exhibited higher levels of type I interferon (IFN-I) transcription during the early infection period than that in PBS-treated control mice. BLM-treated mice also exhibited a lower viral burden, reduced pro-inflammatory cytokine production, and neutrophil levels. In contrast, BLM-treated IFN-I receptor 1 (IFNAR1)-knockout mice failed to show this attenuated phenotype, indicating that IFN-I is key to the antiviral response in ALI-induced mice. The STING/TBK1/IRF3 pathway was found to be involved in IFN-I production and the establishment of an antiviral environment in the lung. The depletion of plasmacytoid dendritic cells (pDCs) reduced the effect of BLM treatment against influenza virus infection, suggesting that pDCs are the major source of IFN-I and are crucial for defense against viral infection in BLM-induced lung injury. Overall, this study showed that BLM-mediated ALI in mice induced the release of double-stranded DNA, which in turn potentiated IFN-I-dependent pulmonary viral resistance by activating the STING/TBK1/IRF3 pathway in association with pDCs.

scholarly journals Influenza Virus Infection Enhances Antibody-Mediated NK Cell Functions via Type I Interferon-Dependent Pathways

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Sinthujan Jegaskanda ◽  
Hillary A. Vanderven ◽  
Hyon-Xhi Tan ◽  
Sheilajen Alcantara ◽  
Kathleen M. Wragg ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Type I Interferon ◽  
A549 Cells ◽  
Influenza Virus Infection ◽  
Type I ◽  
Cell Functions ◽  
Infected Cells

ABSTRACT Natural killer (NK) cells are an important component in the control of influenza virus infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of CD16 on NK cells by antibody-coated influenza virus-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Increasing the potency of antibody-mediated NK cell activity could ultimately lead to improved control of influenza virus infection. To understand if NK cells can be functionally enhanced following exposure to influenza virus-infected cells, we cocultured human peripheral blood mononuclear cells (PBMCs) with influenza virus-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate antibody-dependent functions. Preincubation of PBMCs with influenza virus-infected cells markedly enhanced the ability of NK cells to respond to immune complexes containing hemagglutinin (HA) and anti-HA antibodies or transformed allogeneic cells in the presence or absence of a therapeutic monoclonal antibody. Cytokine multiplex, RNA sequencing, supernatant transfer, Transwell, and cytokine-blocking/cytokine supplementation experiments showed that type I interferons released from PBMCs were primarily responsible for the influenza virus-induced enhancement of antibody-mediated NK cell functions. Importantly, the influenza virus-mediated increase in antibody-dependent NK cell functionality was mimicked by the type I interferon agonist poly(I·C). We conclude that the type I interferon secretion induced by influenza virus infection enhances the capacity of NK cells to mediate ADCC and that this pathway could be manipulated to alter the potency of anti-influenza virus therapies and vaccines. IMPORTANCE Protection from severe influenza may be assisted by antibodies that engage NK cells to kill infected cells through ADCC. Studies have primarily focused on antibodies that have ADCC activity, rather than the capacity of NK cells to become activated and mediate ADCC during an influenza virus infection. We found that type I interferon released in response to influenza virus infection primes NK cells to become highly reactive to anti-influenza virus ADCC antibodies. Enhancing the capacity of NK cells to mediate ADCC could assist in controlling influenza virus infections.

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