scholarly journals Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and Lung by Overlapping but Distinct Molecular Mechanisms

2001 ◽  
Vol 21 (24) ◽  
pp. 8301-8317 ◽  
Author(s):  
Kalpana Ghoshal ◽  
Sarmila Majumder ◽  
Qin Zhu ◽  
John Hunzeker ◽  
Jharna Datta ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Glucocorticoid Receptor ◽  
Influenza A ◽  
Molecular Mechanisms ◽  
Influenza Virus Infection ◽  
Upper Respiratory Tract ◽  
Response Element ◽  
Induction Process ◽  
Ifn Γ

ABSTRACT Metallothionein I (MT-I) and MT-II have been implicated in the protection of cells against reactive oxygen species (ROS), heavy metals, and a variety of pathological and environmental stressors. Here, we show a robust increase in MT-I/MT-II mRNA level and MT proteins in the livers and lungs of C57BL/6 mice exposed to the influenza A/PR8 virus that infects the upper respiratory tract and lungs. Interleukin-6 (IL-6) had a pronounced effect on the induction of these genes in the liver but not the lung. Treatment of the animals with RU-486, a glucocorticoid receptor antagonist, inhibited induction of MT-I/MT-II in both liver and lung, revealing a direct role of glucocorticoid that is increased upon infection in this induction process. In vivo genomic footprinting (IVGF) analysis demonstrated involvement of almost all metal response elements, major late transcription factor/antioxidant response element (MLTF/ARE), the STAT3 binding site on the MT-I upstream promoter, and the glucocorticoid responsive element (GRE1), located upstream of the MT-II gene, in the induction process in the liver and lung. In the lung, inducible footprinting was also identified at a unique gamma interferon (IFN-γ) response element (γ-IRE) and at Sp1 sites. The mobility shift analysis showed activation of STAT3 and the glucocorticoid receptor in the liver and lung nuclear extracts, which was consistent with the IVGF data. Analysis of the newly synthesized mRNA for cytokines in the infected lung by real-time PCR showed a robust increase in the levels of IL-10 and IFN-γ mRNA that can activate STAT3 and STAT1, respectively. A STAT1-containing complex that binds to the γ-IRE in vitro was activated in the infected lung. No major change in MLTF/ARE DNA binding activity in the liver and lung occurred after infection. These results have demonstrated that MT-I and MT-II can be induced robustly in the liver and lung following experimental influenza virus infection by overlapping but distinct molecular mechanisms.

scholarly journals Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung

2016 ◽  
Vol 90 (20) ◽  
pp. 9364-9382 ◽  
Author(s):  
Stephanie C. Talker ◽  
Maria Stadler ◽  
Hanna C. Koinig ◽  
Kerstin H. Mair ◽  
Irene M. Rodríguez-Gómez ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Influenza A ◽  
Vaccine Development ◽  
Influenza Virus Infection ◽  
T Cell Response ◽  
Large Animal ◽  
Ifn Γ

ABSTRACTPigs are natural hosts for influenza A viruses and play a critical role in influenza epidemiology. However, little is known about their influenza-evoked T-cell response. We performed a thorough analysis of both the local and systemic T-cell response in influenza virus-infected pigs, addressing kinetics and phenotype as well as multifunctionality (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and cross-reactivity. A total of 31 pigs were intratracheally infected with an H1N2 swine influenza A virus (FLUAVsw) and consecutively euthanized. Lungs, tracheobronchial lymph nodes, and blood were sampled during the first 15 days postinfection (p.i.) and at 6 weeks p.i.Ex vivoflow cytometry of lung lymphocytes revealed an increase in proliferating (Ki-67+) CD8+T cells with an early effector phenotype (perforin+CD27+) at day 6 p.i. Low frequencies of influenza virus-specific IFN-γ-producing CD4+and CD8+T cells could be detected in the lung as early as 4 days p.i. On consecutive days, influenza virus-specific CD4+and CD8+T cells produced mainly IFN-γ and/or TNF-α, reaching peak frequencies around day 9 p.i., which were up to 30-fold higher in the lung than in tracheobronchial lymph nodes or blood. At 6 weeks p.i., CD4+and CD8+memory T cells had accumulated in lung tissue. These cells showed diverse cytokine profiles andin vitroreactivity against heterologous influenza virus strains, all of which supports their potential to combat heterologous influenza virus infections in pigs.IMPORTANCEPigs not only are a suitable large-animal model for human influenza virus infection and vaccine development but also play a central role in the emergence of new pandemic strains. Although promising candidate universal vaccines are tested in pigs and local T cells are the major correlate of heterologous control, detailed and targeted analyses of T-cell responses at the site of infection are scarce. With the present study, we provide the first detailed characterization of magnitude, kinetics, and phenotype of specific T cells recruited to the lungs of influenza virus-infected pigs, and we could demonstrate multifunctionality, cross-reactivity, and memory formation of these cells. This, and ensuing work in the pig, will strengthen the position of this species as a large-animal model for human influenza virus infection and will immediately benefit vaccine development for improved control of influenza virus infections in pigs.

scholarly journals The Role of Alpha/Beta and Gamma Interferons in Development of Immunity to Influenza A Virus in Mice

2000 ◽  
Vol 74 (9) ◽  
pp. 3996-4003 ◽  
Author(s):  
Graeme E. Price ◽  
Anna Gaszewska-Mastarlarz ◽  
Demetrius Moskophidis
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Antibody Responses ◽  
Adaptive Immune ◽  
Ifn Γ ◽  
Alpha Beta

ABSTRACT During influenza virus infection innate and adaptive immune defenses are activated to eliminate the virus and thereby bring about recovery from illness. Both arms of the adaptive immune system, antibody neutralization of free virus and termination of intracellular virus replication by antiviral cytotoxic T cells (CTLs), play pivotal roles in virus elimination and protection from disease. Innate cytokine responses, such as alpha/beta interferon (IFN-α/β) or IFN-γ, can have roles in determining the rate of virus replication in the initial stages of infection and in shaping the initial inflammatory and downstream adaptive immune responses. The effect of these cytokines on the replication of pneumotropic influenza A virus in the respiratory tract and in the regulation of adaptive antiviral immunity was examined after intranasal infection of mice with null mutations in receptors for IFN-α/β, IFN-γ, and both IFNs. Virus titers in the lungs of mice unable to respond to IFNs were not significantly different from congenic controls for both primary and secondary infection. Likewise the mice were comparably susceptible to X31 (H3N2) influenza virus infection. No significant disruption to the development of normal antiviral CTL or antibody responses was observed. In contrast, mice bearing the disrupted IFN-α/β receptor exhibited accelerated kinetics and significantly higher levels of neutralizing antibody activity during primary or secondary heterosubtypic influenza virus infection. Thus, these observations reveal no significant contribution for IFN-controlled pathways in shaping acute or memory T-cell responses to pneumotropic influenza virus infection but do indicate some role for IFN-α/β in the regulation of antibody responses. Recognizing the pivotal role of CTLs and antibody in virus clearance, it is reasonable to assume a redundancy in IFN-mediated antiviral effects in pulmonary influenza. However, IFN-α/β seems to be a valid factor in determining tissue tropism and replicative rates of highly virulent influenza virus strains as reported previously by others, and this aspect is discussed here.

scholarly journals Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus

2015 ◽  
Vol 112 (25) ◽  
pp. 7809-7814 ◽  
Author(s):  
Tadaki Suzuki ◽  
Akira Kawaguchi ◽  
Akira Ainai ◽  
Shin-ichi Tamura ◽  
Ryo Ito ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A ◽  
High Speed ◽  
Influenza Virus Infection ◽  
Secretory Iga ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Iga Antibodies ◽  
Quaternary Structures

Secretory IgA (S-IgA) antibodies, the major contributors to humoral mucosal immunity to influenza virus infection, are polymeric Igs present in many external secretions. In the present study, the quaternary structures of human S-IgA induced in nasal mucosa after administration of intranasal inactivated influenza vaccines were characterized in relation to neutralization potency against influenza A viruses. Human nasal IgA antibodies have been shown to contain at least five quaternary structures. Direct and real-time visualization of S-IgA using high-speed atomic force microscopy (AFM) demonstrated that trimeric and tetrameric S-IgA had six and eight antigen-binding sites, respectively, and that these structures exhibited large-scale asynchronous conformational changes while capturing influenza HA antigens in solution. Furthermore, trimeric, tetrameric, and larger polymeric structures, which are minor fractions in human nasal IgA, displayed increased neutralizing potency against influenza A viruses compared with dimeric S-IgA, suggesting that the larger polymeric than dimeric forms of S-IgA play some important roles in protection against influenza A virus infection in the human upper respiratory tract.

scholarly journals Salivary Blockade Protects the Lower Respiratory Tract of Mice from Lethal Influenza Virus Infection

2017 ◽  
Vol 91 (14) ◽  
Author(s):  
Karen Ivinson ◽  
Georgia Deliyannis ◽  
Leanne McNabb ◽  
Lara Grollo ◽  
Brad Gilbertson ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Influenza A ◽  
Lethal Dose ◽  
Laboratory Mouse ◽  
Influenza Virus Infection ◽  
Upper Respiratory Tract ◽  
Upper Respiratory

ABSTRACT It is possible to model the progression of influenza virus from the upper respiratory tract to the lower respiratory tract in the mouse using viral inoculum delivered in a restricted manner to the nose. In this model, infection with the A/Udorn/307/72 (Udorn) strain of virus results ultimately in high viral titers in both the trachea and lungs. In contrast, the A/Puerto Rico/8/34 (PR8) strain causes an infection that is almost entirely limited to the nasal passages. The factors that govern the progression of virus down the respiratory tract are not well understood. Here, we show that, while PR8 virus grows to high titers in the nose, an inhibitor present in the saliva blocks further progression of infection to the trachea and lungs and renders an otherwise lethal dose of virus completely asymptomatic. In vitro, the salivary inhibitor was capable of potent neutralization of PR8 virus and an additional 20 strains of type A virus and two type B strains that were tested. The exceptions were Udorn virus and the closely related H3N2 strains A/Port Chalmers/1/73 and A/Victoria/3/75. Characterization of the salivary inhibitor showed it to be independent of sialic acid and other carbohydrates for its function. This and other biochemical properties, together with its virus strain specificity and in vivo function, indicate that the mouse salivary inhibitor is a previously undescribed innate inhibitory molecule that may have evolved to provide pulmonary protection of the species from fatal influenza virus infection. IMPORTANCE Influenza A virus occasionally jumps from aquatic birds, its natural host, into mammals to cause outbreaks of varying severity, including pandemics in humans. Despite the laboratory mouse being used as a model to study influenza virus pathogenesis, natural outbreaks of influenza have not been reported in the species. Here, we shed light on one mechanism that might allow mice to be protected from influenza in the wild. We show that virus deposited in the mouse upper respiratory tract will not progress to the lower respiratory tract due to the presence of a potent inhibitor of the virus in saliva. Containing inhibitor-sensitive virus to the upper respiratory tract renders an otherwise lethal infection subclinical. This knowledge sheds light on how natural inhibitors may have evolved to improve survival in this species.

Impact of influenza virus during pregnancy: from disease severity to vaccine efficacy

2020 ◽  
Vol 15 (7) ◽  
pp. 441-453
Author(s):  
Ana Vazquez-Pagan ◽  
Rebekah Honce ◽  
Stacey Schultz-Cherry
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Immune Responses ◽  
Pregnant Women ◽  
Disease Severity ◽  
Influenza A ◽  
Antiviral Treatment ◽  
Influenza Virus Infection ◽  
Severe Influenza ◽  
The Impact

Pregnant women are among the individuals at the highest risk for severe influenza virus infection. Infection of the mother during pregnancy increases the probability of adverse fetal outcomes such as small for gestational age, preterm birth and fetal death. Animal models of syngeneic and allogeneic mating can recapitulate the increased disease severity observed in pregnant women and are used to define the mechanism(s) of that increased severity. This review focuses on influenza A virus pathogenesis, the unique immunological landscape during pregnancy, the impact of maternal influenza virus infection on the fetus and the immune responses at the maternal–fetal interface. Finally, we summarize the importance of immunization and antiviral treatment in this population and highlight issues that warrant further investigation.

A Fungal Cu/Zn-Containing Superoxide Dismutase Enhances the Therapeutic Efficacy of a Plant Polyphenol Extract in Experimental Influenza Virus Infection

2010 ◽  
Vol 65 (5-6) ◽  
pp. 419-428 ◽  
Author(s):  
Julia Serkedjieva ◽  
Tsvetanka Stefanova ◽  
Ekaterina Krumova
Keyword(s):  
Superoxide Dismutase ◽  
Influenza Virus ◽  
Virus Infection ◽  
Protective Effect ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Protective Role ◽  
Combined Application ◽  
Combined Use ◽  
Experimental Influenza

The combined protective effect of a polyphenol-rich extract, isolated from Geranium sanguineum L. (PC), and a novel naturally glycosylated Cu/Zn-containing superoxide dismutase, produced from the fungal strain Humicula lutea 103 (HL-SOD), in the experimental influenza A virus infection (EIVI) in mice, induced with the virus A/Aichi/2/68 (H3N2), was investigated. The combined application of HL-SOD and PC in doses, which by themselves do not defend significantly mice in EIVI, resulted in a synergistically increased protection, determined on the basis of protective indices and amelioration of lung injury. Lung weights and consolidation as well as infectious lung virus titers were all decreased significantly parallel to the reduction of the mortality rates; lung indices were raised. The excessive production of reactive oxygen species (ROS) by alveolar macrophages (aMØ) as well as the elevated levels of the lung antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), induced by EIVI, were brought to normal. For comparative reasons the combined protective effect of PC and vitamin C was investigated. The obtained results support the combined use of antioxidants for the treatment of influenza virus infection and in general indicate the beneficial protective role of combinations of viral inhibitors of natural origin with diverse modes of action.

scholarly journals Chimeric Hemagglutinin-Based Live-Attenuated Vaccines Confer Durable Protective Immunity against Influenza A Viruses in a Preclinical Ferret Model

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 40
Author(s):  
Wen-Chun Liu ◽  
Raffael Nachbagauer ◽  
Daniel Stadlbauer ◽  
Shirin Strohmeier ◽  
Alicia Solórzano ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Antibody Responses ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Humoral And Cellular Immunity ◽  
Stalk Domain ◽  
One Year

Epidemic or pandemic influenza can annually cause significant morbidity and mortality in humans. We developed novel chimeric hemagglutinin (cHA)-based universal influenza virus vaccines, which contain a conserved HA stalk domain from a 2009 pandemic H1N1 (pH1N1) strain combined with globular head domains from avian influenza A viruses. Our previous reports demonstrated that prime-boost sequential immunizations induced robust antibody responses directed toward the conserved HA stalk domain in ferrets. Herein, we further followed vaccinated animals for one year to compare the efficacy and durability of these vaccines in the preclinical ferret model of influenza. Although all cHA-based immunization regimens induced durable HA stalk-specific and heterosubtypic antibody responses in ferrets, sequential immunization with live-attenuated influenza virus vaccines (LAIV-LAIV) conferred the best protection against upper respiratory tract infection by a pH1N1 influenza A virus. The findings from this study suggest that our sequential immunization strategy for a cHA-based universal influenza virus vaccine provides durable protective humoral and cellular immunity against influenza virus infection.

Severe Influenza Virus Infection in Children Admitted to the PICU: Comparison of Influenza A and Influenza B Virus Infection

2021 ◽  
Author(s):  
Pınar YAZICI ÖZKAYA ◽  
Eşe Eda TURANLI ◽  
Hamdi METİN ◽  
Ayça Aydın UYSAL ◽  
Candan ÇİÇEK ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza B Virus ◽  
Influenza B ◽  
Severe Influenza ◽  
B Virus

scholarly journals IFITM3 protects the heart during influenza virus infection

2019 ◽  
Author(s):  
Adam D. Kenney ◽  
Temet M. McMichael ◽  
Alexander Imas ◽  
Nicholas M. Chesarino ◽  
Lizhi Zhang ◽  
...  
Keyword(s):  
Heart Rate ◽  
Influenza Virus ◽  
Virus Infection ◽  
Cardiac Dysfunction ◽  
Influenza A ◽  
Transmembrane Protein ◽  
Influenza Virus Infection ◽  
Small Animal ◽  
Heart Tissue ◽  
Underlying Mechanisms

AbstractInfluenza virus primarily targets the lungs, but dissemination and damage to heart tissue is also known to occur in severe infections. Despite this knowledge, influenza virus-induced cardiac pathogenesis and its underlying mechanisms have been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding interferon-induced transmembrane protein 3 (IFITM3), an antiviral restriction factor, are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to other aspects of pathogenesis, including cardiac dysfunction, is unknown. We now show that IFITM3 deficiency in a newly generated knockout (KO) mouse model exacerbates illness and mortality following influenza A virus infection. Enhanced pathogenesis correlated with increased replication of virus in the lungs, spleens, and hearts of KO mice relative to wildtype (WT) mice. IFITM3 KO mice exhibited normal cardiac function at baseline, but developed severely aberrant electrical activity upon infection, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals. In contrast, WT mice exhibited a mild decrease in heart rate without irregularity of RR intervals. Heightened cardiac virus titers and electrical dysfunction in KO animals was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Our findings reveal an essential role for IFITM3 in controlling influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model to study virus-induced cardiac dysfunction.

scholarly journals Routine blood parameters are helpful for early identification of influenza infection in children

2020 ◽  
Author(s):  
Ronghe Zhu ◽  
Cuie Chen ◽  
Qiu Wang ◽  
Xixi Zhang ◽  
Chaosheng Lu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Early Identification ◽  
Influenza A ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Cutoff Value ◽  
Routine Blood ◽  
Influenza A Virus Infection

Abstract Purpose Routine blood parameters, such as the lymphocyte (LYM) count, platelet (PLT) count, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), LYM*PLT and mean platelet volume-to-platelet ratio (MPV/PLT), are widely used to predict the prognosis of infectious diseases. We aimed to explore the value of these parameters in the early identification of influenza virus infection in children.Methods We conducted a single-center, retrospective, observational study of fever with influenza-like symptoms in pediatric outpatients from different age groups and evaluated the predictive value of various routine blood parameters measured within 48 hours of the onset of fever for influenza virus infection.Results The LYM count, PLT count, LMR and LYM*PLT were lower, and the NLR and MPV/PLT were higher in children with an influenza infection (PCR-confirmed and symptomatic). The LYM count, LMR and LYM*PLT in the influenza infection group were lower in the 1- to 6-year-old subgroup, and the LMR and LYM*PLT in the influenza infection group were lower in the >6-year-old subgroup. In the 1- to 6-year-old subgroup, the cutoff value of the LMR for predicting influenza A virus infection was 3.75, the sensitivity was 81.87%, the specificity was 84.31%, and the area under the curve (AUC) was 0.886; the cutoff value of the LMR for predicting influenza B virus infection was 3.71, the sensitivity was 73.58%, the specificity was 84.31%, and the AUC was 0.843. In the >6-year-old subgroup, the cutoff value of the LMR for predicting influenza A virus infection was 3.05, the sensitivity was 89.27%, the specificity was 89.61%, and the AUC was 0.949; the cutoff value of the LMR for predicting influenza B virus infection was 2.88, the sensitivity was 83.19%, the specificity was 92.21%, and the AUC was 0.924.Conclusions Routine blood tests are simple, inexpensive and easy to perform, and they are useful for the early identification of influenza virus infection in children. The LMR had the strongest predictive value for influenza virus infection in children older than 1 year, particularly influenza A virus infection.

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