Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

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Soluble Host Defense Lectins in Innate Immunity to Influenza Virus

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/732191 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 18

Author(s):

Wy Ching Ng ◽

Michelle D. Tate ◽

Andrew G. Brooks ◽

Patrick C. Reading

Keyword(s):

Host Defense ◽

Influenza A ◽

Viral Infections ◽

Adaptive Immune Response ◽

Host Defenses ◽

Influenza A Viruses ◽

Complex Interplay ◽

Adaptive Immune ◽

Endogenous Lectins ◽

Host Tissues

Host defenses against viral infections depend on a complex interplay of innate (nonspecific) and adaptive (specific) components. In the early stages of infection, innate mechanisms represent the main line of host defense, acting to limit the spread of virus in host tissues prior to the induction of the adaptive immune response. Serum and lung fluids contain a range of lectins capable of recognizing and destroying influenza A viruses (IAV). Herein, we review the mechanisms by which soluble endogenous lectins mediate anti-IAV activity, including their role in modulating IAV-induced inflammation and disease and their potential as prophylactic and/or therapeutic treatments during severe IAV-induced disease.

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Innate Immune sensing of Influenza A viral RNA through IFI16 promotes pyroptotic cell death

10.1101/2021.02.13.431067 ◽

2021 ◽

Author(s):

Shalabh Mishra ◽

Athira S Raj ◽

Akhilesh Kumar ◽

Ashwathi Rajeevan ◽

Puja Kumari ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Influenza A Virus ◽

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Type I ◽

Cell Death Pathways ◽

Infected Cells ◽

Immune Sensing

AbstractProgrammed cell death pathways are triggered by various stresses or stimuli, including viral infections. The mechanism underlying the regulation of these pathways upon Influenza A virus IAV infection is not well characterized. We report that a cytosolic DNA sensor IFI16 is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified that IFI16 functions as an RNA sensor for influenza A virus by binding to genomic RNA. The activation of IFI16 triggers the production of type I, III interferons, and also other pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signaling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells). Whereas, IFI16 knockdown cells showed reduced inflammatory responses and also prevented cell mortality during IAV infection. These results demonstrate the pivotal role of IFI16-mediated IAV sensing and its essential role in activating programmed cell death pathways.

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Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are features of alpacas resolving MERS-CoV infection

PLoS Pathogens ◽

10.1371/journal.ppat.1009229 ◽

2021 ◽

Vol 17 (5) ◽

pp. e1009229

Author(s):

Nigeer Te ◽

Jordi Rodon ◽

Maria Ballester ◽

Mónica Pérez ◽

Lola Pailler-García ◽

...

Keyword(s):

Immune Response ◽

Respiratory Tract ◽

Nasal Mucosa ◽

Inflammatory Responses ◽

Adaptive Immune Response ◽

Innate Immune ◽

Mononuclear Leukocytes ◽

Post Inoculation ◽

Type I ◽

Anti Inflammatory

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, while interferon stimulated genes (ISGs) were induced along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, seems central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.

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Interferon Signaling in Chickens Plays a Crucial Role in Inhibiting Influenza Replication in DF1 Cells

Microorganisms ◽

10.3390/microorganisms10010133 ◽

2022 ◽

Vol 10 (1) ◽

pp. 133

Author(s):

Daniel S. Layton ◽

Kostlend Mara ◽

Meiling Dai ◽

Luis Fernando Malaver-Ortega ◽

Tamara J. Gough ◽

...

Keyword(s):

Avian Influenza ◽

Signaling Pathway ◽

Influenza A ◽

Cellular Response ◽

Viral Infections ◽

Influenza Infection ◽

Type I ◽

Interferon Signaling ◽

Influenza A Viruses ◽

Chicken Cell

Influenza A viruses (IAV) pose a constant threat to human and poultry health. Of particular interest are the infections caused by highly pathogenic avian influenza (HPAI) viruses, such as H5N1, which cause significant production issues. In response to influenza infection, cells activate immune mechanisms that lead to increased interferon (IFN) production. To investigate how alterations in the interferon signaling pathway affect the cellular response to infection in the chicken, we used CRISPR/Cas9 to generate a chicken cell line that lacks a functional the type I interferon receptor (IFNAR1). We then assessed viral infections with the WSN strain of influenza. Cells lacking a functional IFNAR1 receptor showed reduced expression of the interferon stimulated genes (ISG) such as Protein Kinase R (PKR) and Myxovirus resistance (Mx) and were more susceptible to viral infection with WSN. We further investigated the role or IFNAR1 on low pathogenicity avian influenza (LPAI) strains (H7N9) and a HPAI strain (H5N1). Intriguingly, Ifnar−/− cells appeared more resistant than WT cells when infected with HPAI virus, potentially indicating a different interaction between H5N1 and the IFN signaling pathway. Our findings support that ChIFNAR1 is a key component of the chicken IFN signaling pathway and these data add contributions to the field of host-avian pathogen interaction and innate immunity in chickens.

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How dendritic cells sense and respond to viral infections

Clinical Science ◽

10.1042/cs20210577 ◽

2021 ◽

Vol 135 (19) ◽

pp. 2217-2242

Author(s):

Laura Marongiu ◽

Mihai Valache ◽

Fabio A. Facchini ◽

Francesca Granucci

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Viral Infections ◽

Adaptive Immune Response ◽

Type I Interferons ◽

Type I ◽

Viral Pathogens ◽

Cross Presentation ◽

Antiviral Responses ◽

Sense And Respond

Abstract The ability of dendritic cells (DCs) to sense viral pathogens and orchestrate a proper immune response makes them one of the key players in antiviral immunity. Different DC subsets have complementing functions during viral infections, some specialize in antigen presentation and cross-presentation and others in the production of cytokines with antiviral activity, such as type I interferons. In this review, we summarize the latest updates concerning the role of DCs in viral infections, with particular focus on the complex interplay between DC subsets and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Despite being initiated by a vast array of immune receptors, DC-mediated antiviral responses often converge towards the same endpoint, that is the production of proinflammatory cytokines and the activation of an adaptive immune response. Nonetheless, the inherent migratory properties of DCs make them a double-edged sword and often viral recognition by DCs results in further viral dissemination. Here we illustrate these various aspects of the antiviral functions of DCs and also provide a brief overview of novel antiviral vaccination strategies based on DCs targeting.

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Acute non-atopic late-onset asthma induced by respiratory infection

Russian Pulmonology ◽

10.18093/0869-0189-2005-0-1-53-57 ◽

2005 ◽

pp. 53-57

Author(s):

S. A. Sobchenko ◽

O. S. Schetchikova ◽

N. V. Yakovleva

Keyword(s):

Respiratory Infection ◽

Influenza A ◽

Viral Infections ◽

Late Onset ◽

Lavage Fluid ◽

Atopic Asthma ◽

Influenza A Viruses ◽

Asthma Patients ◽

Bacterial Associations ◽

Autumn And Winter

The aim of the study was to investigate features of respiratory infection inducing acute non-atopic late-onset asthma (NLA). Virologic and microbiologic examinations of brash biopsy samples of rhinopharyngeal and bronchial mucosa and bronchial lavage fluid were performed in 116 NLA patients admitted to a hospital in autumn and winter. The leading cause of acute NLA was found to be respiratory viral infections. We noted that different clinical NLA types had different sensibility to various viruses: adenoviruses mainly caused exacerbations of aspirin-induced asthma, respiratory syncytial and influenza A viruses were prevalently determined in non-atopic asthma. Patients with posttuberculotic lesions of the lungs mostly had viral and bacterial associations. Such mixed infection resulted in more severe and prolonged exacerbations of NLA.

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High-Density Blood Transcriptomics Reveals Precision Immune Signatures of SARS-CoV-2 Infection in Hospitalized Individuals

Frontiers in Immunology ◽

10.3389/fimmu.2021.694243 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jeremy W. Prokop ◽

Nicholas L. Hartog ◽

Dave Chesla ◽

William Faber ◽

Chanise P. Love ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Viral Infections ◽

Secretory Granules ◽

Mitotic Cell ◽

Hospitalized Patients ◽

High Density ◽

Type I ◽

Secondary Infections ◽

Blood Transcriptomics

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient’s clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.

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Differential Induction of Type I and Type III Interferons by Swine and Human Origin H1N1 Influenza A Viruses in Porcine Airway Epithelial Cells

PLoS ONE ◽

10.1371/journal.pone.0138704 ◽

2015 ◽

Vol 10 (9) ◽

pp. e0138704 ◽

Cited By ~ 5

Author(s):

Venkatramana D. Krishna ◽

Erin Roach ◽

Nathan A. Zaidman ◽

Angela Panoskaltsis-Mortari ◽

Jessica H. Rotschafer ◽

...

Keyword(s):

Epithelial Cells ◽

Influenza A ◽

H1n1 Influenza ◽

Airway Epithelial Cells ◽

Type I ◽

Airway Epithelial ◽

Human Origin ◽

Influenza A Viruses ◽

Type Iii ◽

Differential Induction

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Genetic Polymorphisms of Toll-like receptors 2 and 9 as Susceptibility Factors for the Development of Ankylosing Spondylitis and Psoriatic Arthritis

Journal of Immunology Research ◽

10.1155/2019/1492092 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Camila F. Oliveira-Toré ◽

Amarilis G. Moraes ◽

Gabriela F. Martinez ◽

Janisleya S. F. Neves ◽

Luciana C. Macedo ◽

...

Keyword(s):

Immune Response ◽

Psoriatic Arthritis ◽

Ankylosing Spondylitis ◽

Genetic Polymorphisms ◽

Inflammatory Responses ◽

Strong Association ◽

Adaptive Immune Response ◽

Inflammatory Rheumatic Diseases ◽

Toll Like Receptors ◽

Immunological Mechanisms

Introduction. Ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are classified as spondyloarthritis (SpA), a group of inflammatory rheumatic diseases with complex genetic etiology. Toll-like receptors (TLRs) have an important role in the mechanism of innate immunity and may influence inflammatory responses. Polymorphisms in TLR genes that lead to changes in these receptors or that interfere with the transcription rates of mRNA TLR may be involved in the chronic inflammatory immune response observed in SpA. Currently, there is a lack of studies associating genetic polymorphisms in TLRs and SpA. Objective. Therefore, this case-control study is aimed at analyzing the influence of the respective SNPs on TLR2 rs5743708, TLR6 rs5743810, and TLR9 rs5743836 and rs187084 in the immunopathogenesis of SpA. Methods. The polymorphisms genotyped by PCR-RFLP were TLR2 rs5743708, TLR6 rs5743810, and TLR9 rs5743836 and rs187084. The HLA-B∗27 was performed by PCR-SSP. Results. Logistic regression analysis showed a strong association between SNPs in TLR2 and TLR9 and susceptibility to SpA (OR=12.56; CI=6.5-25.9 and OR=1.62; CI=1.20-2.21, respectively). No association was observed among HLA-B∗27 and TLR polymorphisms (p=0.72), nor among BASDAI and TLR polymorphisms (p=0.85). Discussion. Our findings suggest that polymorphisms in TLR2 and TLR9 genes may contribute to the immunopathogenesis of the SpA. The rs187084, rs5743836, and rs5743708 polymorphisms were associated with the risk of SpA development, in this study, and lead to significant changes in the innate and adaptive immune response profile, as well as the maintenance of the regulation of immunological mechanisms. Conclusion. The polymorphism rs5743708 for the TLR2 and the rs187084_rs5743836 TLR9 haplotypes appear to be involved in the development of clinical forms of SpA and can be a possible therapeutic target for the spondyloarthritis.

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Mast Cell Responses to Viruses and Pathogen Products

International Journal of Molecular Sciences ◽

10.3390/ijms20174241 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4241 ◽

Cited By ~ 21

Author(s):

Jean S. Marshall ◽

Liliana Portales-Cervantes ◽

Edwin Leong

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Immune Responses ◽

Viral Infection ◽

Viral Infections ◽

Inflammatory Responses ◽

Local Source ◽

Type I ◽

Viral Challenge ◽

Cell Responses

Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings. However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts. There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge. These cells are a major and under-appreciated local source of type I and III interferons following viral challenge. However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections. Progress in combating infection and boosting effective immunity requires a better understanding of mast cell responses to viral infection and the pathogen products and receptors we can employ to modify such responses. In this review, we outline some of the key known responses of mast cells to viral infection and their major responses to pathogen products. We have placed an emphasis on data obtained from human mast cells and aim to provide a framework for considering the complex interactions between mast cells and pathogens with a view to exploiting this knowledge therapeutically. Long-lived resident mast cells and their responses to viruses and pathogen products provide excellent opportunities to modify local immune responses that remain to be fully exploited in cancer immunotherapy, vaccination, and treatment of infectious diseases.

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