scholarly journals Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection

2016 ◽  
Author(s):  
Stefanie Duvigneau ◽  
Niharika Sharma-Chawla ◽  
Alessandro Boianelli ◽  
Sabine Stegemann-Koniszewski ◽  
Van Kinh Nguyen ◽  
...  
Keyword(s):  
Influenza A ◽  
Inflammatory Responses ◽  
Influenza Infection ◽  
Bacterial Clearance ◽  
Contributing Factors ◽  
Relative Contribution ◽  
Systemic Dissemination ◽  
Respiratory Conditions ◽  
Bacterial Outgrowth

AbstractIn the course of influenza A virus (IAV) infections, a secondary bacterial infection frequently leads to serious respiratory conditions provoking high hospitalization and death tolls. Although abundant pro-inflammatory responses have been reported as key contributing factors for these severe dual infections, the relative contribution of cytokines remain largely unclear.In the current study, mathematical modelling on in vivo experimental data highlight IFN-γ as a decisive candidate responsible for impaired bacterial clearance, thereby promoting bacterial growth and systemic dissemination during acute IAV infection. Moreover, we found a time-dependent detrimental role of IL-6 in curtailing bacterial outgrowth which was however not as distinct as for IFN-γ. Importantly, our results furthermore challenge current beliefs that the TNF-α response or the increased availability of nutrients modulated by IAV infection have a central role to the bacterial outgrowth. Ultimately, our findings contribute to a detailed understanding of the mechanisms underlying impaired bacterial clearance following influenza infection.

scholarly journals ZMPSTE24 defends against influenza and other pathogenic viruses

2017 ◽  
Vol 214 (4) ◽  
pp. 919-929 ◽  
Author(s):  
Bishi Fu ◽  
Lingyan Wang ◽  
Shitao Li ◽  
Martin E. Dorf
Keyword(s):  
Viral Entry ◽  
Influenza A ◽  
Defense Mechanisms ◽  
Transmembrane Protein ◽  
Influenza Infection ◽  
In Vivo Studies ◽  
Antiviral Protein ◽  
Dna Viruses ◽  
Specific Effector

Zinc metallopeptidase STE24 (ZMPSTE24) is a transmembrane metalloprotease whose catalytic activity is critical for processing lamin A on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum. We now report ZMPSTE24 is a virus-specific effector that restricts enveloped RNA and DNA viruses, including influenza A, Zika, Ebola, Sindbis, vesicular stomatitis, cowpox, and vaccinia, but not murine leukemia or adenovirus. ZMPSTE24-mediated antiviral action is independent of protease activity. Coimmunoprecipitation studies indicate ZMPSTE24 can complex with proteins of the interferon-induced transmembrane protein (IFITM) family. IFITM proteins impede viral entry, and ZMPSTE24 expression is necessary for IFITM antiviral activity. In vivo studies demonstrate ZMPSTE24-deficient mice display higher viral burdens, enhanced cytokine production, and increased mortality after influenza infection. Collectively, these findings identify ZMPSTE24 as an intrinsic broad-spectrum antiviral protein and provide insights into antiviral defense mechanisms.

Influenza A Virus Accelerates Neutrophil Apoptosis and Markedly Potentiates Apoptotic Effects of Bacteria

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2395-2403 ◽  
Author(s):  
Maria Luisa Colamussi ◽  
Mitchell R. White ◽  
Erika Crouch ◽  
Kevan L. Hartshorn
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Fas Ligand ◽  
Inflammatory Responses ◽  
Neutrophil Apoptosis ◽  
Simultaneous Treatment ◽  
E Coli ◽  
Apoptotic Effects ◽  
Bacterial Superinfection

Abstract Neutrophils are recruited into the airway in the early phase of uncomplicated influenza A virus (IAV) infection and during the bacterial superinfections that are a significant cause of morbidity and mortality in IAV-infected subjects. In this report, we show that IAV accelerates neutrophil apoptosis. Unopsonized Escherichia colihad similar effects, although apoptotic effects of opsonized E coli were greater. When neutrophils were treated with both IAV and unopsonized E coli, a marked enhancement of the rate and extent of neutrophil apoptosis occured as compared with that caused by either pathogen alone. Treatment of neutrophils with IAV markedly increased phagocytosis of E coli. Simultaneous treatment of neutrophils with IAV and E coli also elicited greater hydrogen peroxide production than did either pathogen alone. IAV increased neutrophil expression of Fas antigen and Fas ligand, and it also increased release of Fas ligand into the cell supernatant. These findings may have relevance to the understanding of inflammatory responses to IAV in vivo and of bacterial superinfection of IAV-infected subjects.

Circulating platelet-neutrophil complexes are important for subsequent neutrophil activation and migration

2010 ◽  
Vol 109 (3) ◽  
pp. 758-767 ◽  
Author(s):  
Kristin N. Kornerup ◽  
Gary P. Salmon ◽  
Simon C. Pitchford ◽  
Wai L. Liu ◽  
Clive P. Page
Keyword(s):  
Inflammatory Responses ◽  
Functional Expression ◽  
Neutrophil Activation ◽  
Neutrophil Recruitment ◽  
Current Therapy ◽  
Adequate Treatment ◽  
Relative Contribution ◽  
Inflammatory Conditions ◽  
Inflammatory Stimuli

Previous studies in our laboratory have shown that platelets are essential for the migration of eosinophils into the lungs of allergic mice, and that this is dependent on the functional expression of platelet P-selectin. We sought to investigate whether the same is true for nonallergic, acute inflammatory stimuli administered to distinct anatomic compartments. Neutrophil trafficking was induced in two models, namely zymosan-induced peritonitis and LPS-induced lung inflammation, and the platelet dependence of these responses investigated utilizing mice rendered thrombocytopenic. The relative contribution of selectins was also investigated. The results presented herein clearly show that platelet depletion (>90%) significantly inhibits neutrophil recruitment in both models. In addition, we show that P-selectin glycoprotein ligand-1, but not P-selectin, is essential for neutrophil recruitment in mice in vivo, thus suggesting the existence of different regulatory mechanisms for the recruitment of leukocyte subsets in response to allergic and nonallergic stimuli. Further studies in human blood demonstrate that low-dose prothrombotic and pro-inflammatory stimuli (CCL17 or CCL22) synergize to induce platelet and neutrophil activation, as well as the formation of platelet-neutrophil conjugates. We conclude that adhesion between platelets and neutrophils in vivo is an important event in acute inflammatory responses. Targeting this interaction may be a successful strategy for inflammatory conditions where current therapy fails to provide adequate treatment.

Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

2005 ◽  
Vol 289 (1) ◽  
pp. L111-L124 ◽  
Author(s):  
Sabine Teske ◽  
Andrea A. Bohn ◽  
Jean F. Regal ◽  
Joshua J. Neumiller ◽  
B. Paige Lawrence
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Neutrophil Function ◽  
Aryl Hydrocarbon ◽  
Potent Agonist

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

scholarly journals Histone H4 potentiates neutrophil inflammatory responses to influenza A virus: Down-modulation by H4 binding to C-reactive protein and Surfactant protein D

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247605
Author(s):  
I-Ni Hsieh ◽  
Mitchell White ◽  
Marloes Hoeksema ◽  
Xavier Deluna ◽  
Kevan Hartshorn
Keyword(s):  
Influenza A Virus ◽  
Respiratory Burst ◽  
Influenza A ◽  
Inflammatory Responses ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Histone H4 ◽  
C Reactive Protein ◽  
Reactive Protein

Neutrophils participate in the early phase of the innate response to uncomplicated influenza A virus (IAV) infection but also are a major component in later stages of severe IAV or COVID 19 infection where neutrophil extracellular traps (NETs) and associated cell free histones are highly pro-inflammatory. It is likely that IAV interacts with histones during infection. We show that histone H4 binds to IAV and aggregates viral particles. In addition, histone H4 markedly potentiates IAV induced neutrophil respiratory burst responses. Prior studies have shown reactive oxidants to be detrimental during severe IAV infection. C reactive protein (CRP) and surfactant protein D (SP-D) rise during IAV infection. We now show that both of these innate immune proteins bind to histone H4 and significantly down regulate respiratory burst and other responses to histone H4. Isolated constructs composed only of the neck and carbohydrate recognition domain of SP-D also bind to histone H4 and partially limit neutrophil responses to it. These studies indicate that complexes formed of histones and IAV are a potent neutrophil activating stimulus. This finding could account for excess inflammation during IAV or other severe viral infections. The ability of CRP and SP-D to bind to histone H4 may be part of a protective response against excessive inflammation in vivo.

scholarly journals A Novel Sulfonated Derivative of β-Cyclodextrin Effectively Inhibits Influenza A Virus Infection in vitro and in vivo

Acta Naturae ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 20-30 ◽  
Author(s):  
E. P. Goncharova ◽  
Y. A. Kostyro ◽  
A. V. Ivanov ◽  
M. A. Zenkova
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
High Efficiency ◽  
Influenza Infection ◽  
Lethal Infection ◽  
Novel Drugs ◽  
Infected Cells ◽  
Low Toxicity

The development of novel drugs against the influenza virus with high efficiency and low toxicity is an urgent and important task. Previous reports have demonstrated that compounds based on sulfo derivatives of oligo- and polysaccharides possess high antiviral activity. In this study, we have examined the ability of a novel sulfonated derivative of -cyclodextrin (KS-6469) to inhibit the influenza virus A/WSN/33 (H1N1) infection in vitro and in vivo. The antiviral potential of KS-6469 against the influenza virus was evaluated in Madin-Darby Canine Kidney epithelial cells treated with serially diluted KS-6469. We found out that KS-6469 completely inhibited viral reproduction after treatment of the infected cells with the compound for 48 h. Our data show that double intranasal treatment of mice with KS-6469 fully protected the animals from a lethal infection and significantly decreased the viral titers in the lungs of the infected animals. Thus, the novel sulfonated -cyclodextrin derivative KS-6469 is a promising candidate for the development of antiviral drugs for preventing and treating the influenza infection.

scholarly journals TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2

2020 ◽  
Vol 11 (12) ◽  
pp. 894-914
Author(s):  
Nan Sun ◽  
Li Jiang ◽  
Miaomiao Ye ◽  
Yihan Wang ◽  
Guangwen Wang ◽  
...  
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Influenza Infection ◽  
Type I ◽  
Subsequent Formation ◽  
Antiviral Immune Response ◽  
Signaling Complex ◽  
Deficient Mice

AbstractTripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-I-mediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63- or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.

scholarly journals Manganese exposure in juvenile C57BL/6 mice increases glial inflammatory responses in the substantia nigra following infection with H1N1 influenza virus

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245171
Author(s):  
Collin M. Bantle ◽  
C. Tenley French ◽  
Jason E. Cummings ◽  
Shankar Sadasivan ◽  
Kevin Tran ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Glial Cells ◽  
Dopaminergic Neurons ◽  
Influenza A ◽  
Inflammatory Responses ◽  
Influenza Infection ◽  
Significant Loss ◽  
Neurological Deficits ◽  
Substantia Nigra Pars Compacta ◽  
Juvenile Development

Infection with Influenza A virus can lead to the development of encephalitis and subsequent neurological deficits ranging from headaches to neurodegeneration. Post-encephalitic parkinsonism has been reported in surviving patients of H1N1 infections, but not all cases of encephalitic H1N1 infection present with these neurological symptoms, suggesting that interactions with an environmental neurotoxin could promote more severe neurological damage. The heavy metal, manganese (Mn), is a potential interacting factor with H1N1 because excessive exposure early in life can induce long-lasting effects on neurological function through inflammatory activation of glial cells. In the current study, we used a two-hit model of neurotoxin-pathogen exposure to examine whether exposure to Mn during juvenile development would induce a more severe neuropathological response following infection with H1N1 in adulthood. To test this hypothesis, C57BL/6 mice were exposed to MnCl2 in drinking water (50 mg/kg/day) for 30 days from days 21–51 postnatal, then infected intranasally with H1N1 three weeks later. Analyses of dopaminergic neurons, microglia and astrocytes in basal ganglia indicated that although there was no significant loss of dopaminergic neurons within the substantia nigra pars compacta, there was more pronounced activation of microglia and astrocytes in animals sequentially exposed to Mn and H1N1, as well as altered patterns of histone acetylation. Whole transcriptome Next Generation Sequencing (RNASeq) analysis was performed on the substantia nigra and revealed unique patterns of gene expression in the dual-exposed group, including genes involved in antioxidant activation, mitophagy and neurodegeneration. Taken together, these results suggest that exposure to elevated levels of Mn during juvenile development could sensitize glial cells to more severe neuro-immune responses to influenza infection later in life through persistent epigenetic changes.

The In Vivo Source of Type I and Type III IFNs is Pathogen Dependent

2021 ◽  
Author(s):  
Marvin J. Sandoval ◽  
Hsiang-Chi Tseng ◽  
Heidi P. Risman ◽  
Sergey Smirnov ◽  
Qing Li ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Virus Infection ◽  
Respiratory Tract ◽  
Influenza A ◽  
Influenza Infection ◽  
Type I ◽  
Protective Effects ◽  
Type Iii

Type I (-α, β) and type III (-λ) interferons (IFNs) are produced in response to virus infection and upregulate a largely overlapping set of IFN stimulated genes which mediate the protective effects of these antiviral cytokines. In vitro studies have demonstrated the redundancy of these two cytokine families which activate the same transcription factor, IFN stimulated gene factor 3 (ISGF3), via distinct ligands and receptors. However, in vivo, these IFN types do have distinct functions based on receptor distribution, but also ligand availability. Using a newly generated IFN-λ reporter mouse strain we have observed that both type I and type III IFNs are produced in response to respiratory tract infection by Newcastle disease virus (NDV) and influenza A virus (IAV). In the case of NDV these IFNs are synthesized by different cell types. Type I IFNs are produced primarily by alveolar macrophages, type III IFNs are made only by epithelial cells, and production of either is dependent on MAVS. While epithelial cells of the respiratory tract represent the primary target of IAV infection, we found that they did not significantly contribute to IFN-λ production, and IFN-λ protein levels were largely unaffected in the absence of MAVS. Instead we found that pDCs, a cell type known for robust IFN-α production via TLR/MyD88 signaling, were the major producers of IFN-λ during IAV infection, with pDC depletion during influenza infection resulting in significantly reduced levels of both IFN-α and IFN-λ. In addition, we were able to demonstrate that pDCs rely on type I IFN for optimal IFN-λ production. These studies therefore demonstrate that the in vivo producers of Type III IFNs in response to respiratory virus infection are pathogen dependent, a finding which may explain the varying levels of cytokine production induced by different viral pathogens.

Influenza A Virus Accelerates Neutrophil Apoptosis and Markedly Potentiates Apoptotic Effects of Bacteria

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2395-2403 ◽  
Author(s):  
Maria Luisa Colamussi ◽  
Mitchell R. White ◽  
Erika Crouch ◽  
Kevan L. Hartshorn
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Fas Ligand ◽  
Inflammatory Responses ◽  
Neutrophil Apoptosis ◽  
Simultaneous Treatment ◽  
E Coli ◽  
Apoptotic Effects ◽  
Bacterial Superinfection

Neutrophils are recruited into the airway in the early phase of uncomplicated influenza A virus (IAV) infection and during the bacterial superinfections that are a significant cause of morbidity and mortality in IAV-infected subjects. In this report, we show that IAV accelerates neutrophil apoptosis. Unopsonized Escherichia colihad similar effects, although apoptotic effects of opsonized E coli were greater. When neutrophils were treated with both IAV and unopsonized E coli, a marked enhancement of the rate and extent of neutrophil apoptosis occured as compared with that caused by either pathogen alone. Treatment of neutrophils with IAV markedly increased phagocytosis of E coli. Simultaneous treatment of neutrophils with IAV and E coli also elicited greater hydrogen peroxide production than did either pathogen alone. IAV increased neutrophil expression of Fas antigen and Fas ligand, and it also increased release of Fas ligand into the cell supernatant. These findings may have relevance to the understanding of inflammatory responses to IAV in vivo and of bacterial superinfection of IAV-infected subjects.

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