Factors influencing the assessment of lung function in mice with influenza‐induced lung disease

Please cite this paper as: Larcombe et al. (2012) Factors influencing the assessment of lung function in mice with influenza‐induced lung disease. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12034. Background  The constant‐phase model (CPM) is commonly fit to respiratory system input impedance (Z _rs) to estimate lung mechanics. Driving signal frequencies and the method of model fitting may influence the results, especially in cases of severe lung disease or under severe bronchoconstriction. Objective  To illustrate the effects of different CPM fits to Z _rs data using a mouse model of influenza‐induced lung disease. Methods  BALB/c mice infected with influenza (or control) were challenged with methacholine. The CPM was fitted to Z _rs, measured between 0·25 and 19·625 Hz, using both unweighted and weighted fits. The effect of different lowest frequencies was assessed. Results and Conclusions  For influenza‐infected mice, the unweighted fit was poor, and airway resistance (R _aw) was often biologically impossible. The weighted fit provided more realistic estimates of R _aw. Different model fits and minimal frequencies had little effect on tissue mechanics.     

Role of monokine induced by interferon-γ in liver injury induced by hepatitis B virus in mice

The chemokine monokine induced by interferon-γ (Mig) is involved in the recruitment of inflammatory cells and liver injury during hepatitis B virus (HBV) infection. HBV protein X contributes to Mig expression in vitro by activation of nuclear factor (NF)-κB; however, the molecular mechanisms by which HBV induces Mig expression in vivo are unknown. In this paper, we established a mouse model for HBV study by tail vein injection of HBV genome-containing adenovirus vectors. Host immune response to the secreted hepatitis B surface antigen and e antigen was detected and serum alanine aminotransferase (ALT) was elevated at different time points. We also demonstrated that peripheral and intrahepatic Mig expression was increased after Ad-HBV infection. This was followed by inflammatory cell migration and formation of inflammatory foci in the liver. In addition, NF-κB p65 subunit translocated from the cytoplasm to the nucleus, and phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were to some extent phosphorylated after HBV injection. Following tail vein injection of Mig siRNA/in vivo-jetPEI-Gal complex, Mig expression was partially suppressed, inflammatory cell migration was inhibited, serum level of ALT were reduced. In conclusion, through NF-κB activation, HBV induced Mig expression in vivo, which recruited peripheral inflammatory cells to the liver and resulted in liver damage. Phosphorylation of phosphoinositide 3-kinase/Akt, ERK and JNK but not p38 might involved in the molecular mechanisms underlying HBV induced Mig expression in vivo.     

Inactivated influenza virus vaccine is efficient and reduces IL‐4 and IL‐6 in allergic asthma mice

Background

Allergic asthma is a globally respiratory inflammatory disease. Influenza virus is a respiratory pathogen that causes yearly epidemics and results in high rates of morbidity and mortality. Patients with allergic asthma had a more severe symptom and a higher mortality when they were infected with influenza virus. Hence, influenza vaccination is recommended for patients with asthma.

Objectives

We evaluated the efficacy and effects of influenza vaccination on allergic asthma in a mouse model.

Methods

Ovalbumin‐immunized mice were inoculated with inactivated influenza virus A/Puerto Rico/8/34 (PR8) as vaccines and morbidity or mortality and allergic asthma features of these mice were analyzed.

Results

Mice inoculated with inactivated PR8 induced high levels of anti‐PR8 IgG2a and upregulation of Toll‐like receptor (TLR) 7. Vaccinated allergic mice were healthy when they were challenged with live influenza virus while none of non‐vaccinated allergic mice survived. Furthermore, inactivated influenza virus vaccine induced neither extra airway inflammation nor asthma features such as IgE, airway hyper‐reactivity, and eosinophilia in allergic mice. Particularly, decreased frequency of immune cell infiltrated airways and Th2 cytokines IL‐4 and IL‐6 production in the bronchoalveolar lavage fluid were noted in vaccinated allergic mice. These results suggested that inactivated influenza virus vaccine is efficient to protect allergic mice from further influenza infection, and it does not exacerbate but reduces IL‐4 and IL‐6 of allergic asthma.

Conclusion

Influenza vaccination is essential and efficient for allergic subjects to protect influenza virus infection.     

The effect of bacille Calmette-Guérin vaccine strain and route of administration on induced immune responses in vaccinated infants

Vaccination with Mycobacterium bovis bacille Calmette-Guerin (BCG) has variable efficacy in preventing tuberculosis. Both BCG strain and route of administration have been implicated in determining efficacy; however, these variables are not considered in current clinical recommendations for vaccine choice. We evaluated antigen-specific immunity after percutaneous or intradermal administration of Japanese BCG or intradermal administration of Danish BCG. Ten weeks after vaccination of neonates, percutaneous Japanese BCG had induced significantly higher frequencies of BCG-specific interferon- gamma -producing CD4(+) and CD8(+) T cells in BCG-stimulated whole blood than did intradermal Danish BCG. Similarly, percutaneous vaccination with Japanese BCG resulted in significantly greater secretion of the T helper 1-type cytokines interferon- gamma, tumor necrosis factor- alpha , and interleukin-2; significantly lower secretion of the T helper 2-type cytokine interleukin-4; and greater CD4(+) and CD8(+) T cell proliferation. Thus, BCG strain and route of neonatal vaccination confer different levels of immune activation, which may affect the efficacy of the vaccine.     

Viral and host genetic factors influence encephalomyocarditis virus—induced polymyositis in adult mice

Recent research findings implicate picornaviruses in the etiology of human polymyositis/dermatomyositis and suggest that genetic factors play a role in susceptibility to these diseases. We compared 2 variants of encephalomyocarditis (EMC) virus for their ability to induce polymyositis in adult mice, and evaluated what role the genetic background of the host plays in the degree of myositis induced. While BALB/c mice developed minimal myositis when infected with a diabetogenic variant (EMC-D), the same strain inoculated with a newly isolated myopathic variant (EMC-221A) developed viral dose—dependent elevations in muscle-associated enzymes, bilateral limb muscle weakness, and the histopathologic changes of severe polymyositis. Mice with different genetic backgrounds showed significantly different susceptibilities to EMC-221A. These data suggest that the severity of polymyositis induced by EMC virus is influenced by both the viral and host genomes.     

Insulin expression in livers of diabetic mice mediated by hydrodynamics-based administration

AIM:Transfer and expression of insulin gene in vivo arean alternative strategy to improve glycemic control in type1 diabetes.Hydrodynamics-based procedure has beenproved to be very efficient to transfer naked DNA to mouselivers.The basal hepatic insulin production mediated bythis rapid tail vein injection was studied to determine itseffect on the resumption of glycemic control in type 1diabetic mice.METHODS:Engineered insulin cDNA was inserted intoplasmid vectors under a CMV promoter,and transferred intoSTZ induced diabetic mice by hydrodynamic procedure.Glucose levels,body weight of treated mice,insulin levels,immunohistology of the liver,and quantity of insulin mRNAin the liver were assayed to identify the improvement ofhyperglycemic complication after plasmid administration.Sleeping Beauty,a transposon system,was also used toprolong the insulin expression in the liver.RESULTS:After plasmid administration,Plasma insulin wassignificantly increased in the diabetic mice and the liverswere insulin-positive by immunostaining.At the same timethe hyperglycemic complication was improved,The bloodglucose levels of mice were reduced to normal.Glucosetolerance of the treated diabetic mice was improved,Bodyweight loss was also ameliorated.The rapid tail vein injectiondid not cause any fatal result.CONCLUSION:Our results suggested that insulin genecould be efficiently transferred into the livers of diabeticmice via rapid tail vein injection and it resulted in high levelof insulin expression.The basal hepatic insulin productionmediated by hydrodynamics-based administration improvedthe glycemic control in type 1 diabetes dramatically andameliorated diabetic syndromes.Hydrodynamics-basedadministration offers a simple and efficient way in the studyof gene therapy for type 1 diabetes.     

Prior infection of pigs with a recent human H3N2 influenza virus confers minimal cross‐protection against a European swine H3N2 virus

Background

H3N2 influenza viruses circulating in humans and European pigs originate from the pandemic A/Hong Kong/68 virus. Because of slower antigenic drift in swine, the antigenic divergence between swine and human viruses has been increasing. It remains unknown to what extent this results in a reduced cross‐protection between recent human and swine H3N2 influenza viruses.

Objectives

We examined whether prior infection of pigs with an old [A/Victoria/3/75 (A/Vic/75)] or a more recent [A/Wisconsin/67/05 (A/Wis/05)] human H3N2 virus protected against a European swine H3N2 virus [sw/Gent/172/08 (sw/Gent/08)]. Genetic and antigenic relationships between sw/Gent/08 and a selection of human H3N2 viruses were also assessed.

Results

After challenge with sw/Gent/08, all challenge controls had high virus titers in the entire respiratory tract at 3 days post‐challenge and nasal virus excretion for 5–6 days. Prior infection with sw/Gent/08 or A/Vic/75 offered complete virological protection against challenge. Pigs previously inoculated with A/Wis/05 showed similar virus titers in the respiratory tract as challenge controls, but the mean duration of nasal shedding was 1·3 days shorter. Unlike sw/Gent/08‐ and A/Vic/75‐inoculated pigs, A/Wis/05‐inoculated pigs lacked cross‐reactive neutralizing antibodies against sw/Gent/08 before challenge, but they showed a more rapid antibody response to sw/Gent/08 than challenge controls after challenge. Cross‐protection and serological responses correlated with genetic and antigenic differences.

Conclusions

Infection immunity to a recent human H3N2 virus confers minimal cross‐protection against a European swine H3N2 virus. We discuss our findings with regard to the recent zoonotic infections of humans in the United States with a swine‐origin H3N2 variant virus.     

Application of protection motivation theory in epidemic prevention in patients with respiratory diseases under the COVID‐19 pandemic: A cross‐sectional study

Objective

This study aimed to investigate the effects of nursing intervention based on protection motivation theory (PMT) on patients with respiratory diseases in the context of the Coronavirus Disease 2019 (COVID-19) pandemic.

Methods

A total of 74 patients with respiratory diseases who were hospitalized from June 2020 to February 2021 were enrolled and stratified into a control group (n = 37) and an experimental group (n = 37) according to a stratified random sampling method. The control group adopted a routine nursing intervention program of the respiratory department, whereas the experimental group received a PMT-based nursing intervention program on the basis of the control group. Chronic Disease Self-Management Study Measures (CDSMS) and Self-Efficacy for Managing Chronic Diseases 6-item Scale (SECD6) were used to evaluate the effect of PMT intervention before intervention, after 1 week, and after 4 weeks of intervention. The levels of forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC and peak expiratory flow (PEF) were measured to evaluate pulmonary function.

Results

Before the intervention, there were no significant differences in the scores of CDSMS and SECD6 scales and liver function indexes between the two groups (p > 0.05). After 1 and 4 weeks of intervention, the scores of CDSMS and SECD6 scales of the experimental group were significantly higher than those of the control group (p < 0.0001). The indexes of pulmonary function of the experimental group were improved, but there was no significant difference compared with the control group (p > 0.05).

Conclusion

Nursing intervention based on PMT contributes to the improvement of self-management behaviors and self-efficacy, which is conducive to the prognoses of patients.     

Expression of Th2 cytokines decreases the development of and improves Behçet's disease-like symptoms induced by herpes simplex virus in mice

In the etiology of Beh?et's disease (BD), viral infection has long been postulated as a contributing factor, and viral involvement has been demonstrated. However, viral infection alone is not sufficient to explain the pathogenesis of BD, and some evidence suggests that immunologic abnormalities are also important. To study the possible role of immune regulation in the development of BD-like symptoms induced by herpes simplex virus inoculation in ICR mice, macrophages were deleted by use of liposome-encapsulated clodronate (lip-Cl(2)MDP). Treatment with lip-Cl(2)MDP suppressed the development of BD-like symptoms, and this suppression was correlated with the induction of interleukin-4 expression in mouse spleens. When the Th2 adjuvant ovalbumin (OVA)-alum was injected into mice with BD-like symptoms, their cutaneous symptoms improved. Adoptive transfer with splenocytes from OVA-alum-injected mice also resulted in improvement. These findings suggest that up-regulated Th2 cytokine expression can attenuate the development of and improve some BD-like symptoms.     

Original Article: Peroxisome proliferator‐activated receptor and AMP‐activated protein kinase agonists protect against lethal influenza virus challenge in mice

Please cite this paper as: Moseley et al. (2010) Peroxisome proliferator‐activated receptor and AMP‐activated protein kinase agonists protect against lethal influenza virus challenge in mice. Influenza and Other Respiratory Viruses 4(5), 307–311.Background  A novel influenza A (H1N1) virus was isolated from humans in North America and has developed into the first pandemic of the 21st century. Reports of a global shortage of antiviral drugs, the evolution of drug‐resistant influenza virus variants, and a 6‐month delay in vaccine availability underline the need to develop new therapeutics that may be widely distributed during future pandemics.Methods  In an effort to discover alternatives to the conventional therapeutic strategies available, we screened several classes of immunomodulatory agents possessing the potential to mitigate the effects of influenza virus‐induced immunopathology.Results  Here, we provide preliminary evidence that two classes of drugs, peroxisome proliferator‐activated receptor‐γ agonists and AMP‐activated protein kinase agonists, provide protection in mice infected with highly pathogenic and pandemic strains of influenza virus.Conclusions  The extensive production in the developed world, combined with the significant degree of protection described here, establishes these drugs as a potential therapeutic option that may be broadly implemented to combat serious disease caused by future influenza epidemics or pandemics.     

Antitumor immunopreventive effect in mice induced by DNA vaccine encoding a fusion protein of α-fetoprotein and CTLA4

AIM:To develop a tumor DNA vaccine encoding a fusionprotein of murine AFP and CTLA4,and to study its ability toinduce specific CTL response and its protective effect againstAFP-producing tumor.METHODS:Murine a-fetoprotein (mAFP) gene was clonedfrom total RNA of Hepa1-6 cells by RT-PCR.A DNA vaccinewas constructed by fusion murine α-fetoprotein gene andextramembrane domain of murine CTLA4 gene.The DNAvaccine was identified by restriction enzyme analysis,sequencing and expression.EL-4 (mAFP) was developedby stable transfection of EL-4 cells with pmAFR Thefrequency of cells producing IFN-γ in splenocytes harvestedfrom the immunized mice was measured by ELISPOT.Miceimmunized with DNA vaccine were inoculated with EL-4(mAFP) cells in back to observe the protective effect ofimmunization on tumor.On the other hand,blood sampleswere collected from the immunized mice to check thefunctions of liver and kidney.RESULTS:1.8 kb mAFP cDNA was cloned from total RNAof Hepa1-6 cells by RT-PCR.The DNA vaccine encoding afusion protein of mAFP-CTLA4 was constructed andconfirmed by restriction enzyme analysis,sequencing andexpression.The expression of mAFP mRNA in EL-4 (mAFP)was confirmed by RT-PCR.The ELISPOT results showedthat the number of IFN-γ-producing cells in pmAFP-CTLA4group was significantly higher than that in pmAFP,pcDNA3.1and PBS group.The tumor volume in pmAFP-CTLA4 groupwas significantly smaller than that in pmAFP,pcDNA3.1 andPBS group,respectively.The hepatic and kidney functionsin each group were not altered.CONCLUSION:AFP-CTLA4 DNA vaccine can stimulatepotent specific CTL responses and has distinctive antitumoreffect on AFP-producing tumor.The vaccine has no impacton the function of mouse liver and kidney.     

Antitumor immunopreventive effect in mice induced by DNA vaccine encoding a fusion protein of α-fetoprotein and CTLA4

AIM:To develop a tumor DNA vaccine encoding a fusion protein of murine AFP and CTLA4,and to study its ability to induce specific CTL response and its protective effect against AFP-producing tumor.METHODS:Murine α-fetoprotein (mAFP) gene was cloned from total RNA of Hepal-6 cells by RT-PCR.A DNA vaccine was constructed by fusion murine α-fetoprotein gene and extramembrane domain of murine CTLA4 gene.The DNA vaccine was identified by restriction enzyme analysis,sequencing and expression.EL-4 (mAFP) was developed by stable transfection of EL-4 cells with pmAFP.The frequency of cells producing IFN-γ in splenocytes harvested from the immunized mice was measured by ELISPOT.Mice immunized with DNA vaccine were inoculated with EL-4(mAFP) cells in back to observe the protective effect of immunization on tumor. On the other hand,blood samples were collected from the immunized mice to check the functions of liver and kidney.RESULTS:1.8kb mAFP cDNA was cloned from total RNA of Hepal-6 cells by RT-PCR.The DNA vaccine encoding a fusion protein of mAFP-CTLA4 was constructed and confirmed by restriction enzyme analysis,sequencing and expression.The expression of mAFP mRNA in EL-4 (mAFP) was confirmed by RT-PCR.The ELISPOT results showedthat the number of IFN-γ-producing cells in pmAFP-CTLA4 group was significantly higher than that in pmAFP,pcDNA3.1 and PBS group.The tumor volume in pmAFP-CTLA4 group was significantly smaller than that in pmAFP,pcDNA3.1 and PBS group, respectively. The hepatic and kidney functions in each group were not altered.CONCLUSION: AFP-CTLA4 DNA vaccine can stimulate potent specific CTL responses and has distinctive antitumor effect on AFP-producing tumor.The vaccine has no impact on the function of mouse liver and kidney.     

Effectiveness of seasonal influenza vaccine in preventing medically attended influenza infection in England and Wales during the 2010/2011 season: a primary care‐based cohort study

Background

Estimates of seasonal influenza vaccine effectiveness (VE) are affected by factors such as the strain of the current circulating influenza virus and characteristics of the host.

Objective

The objective of this study was to provide VE estimates for the 2010/2011 seasonal trivalent influenza vaccine (TIV) in preventing medically attended influenza in England and Wales for the season 2010/2011.

Methods

A cohort study design was employed using electronic health records extracted from 104 GP practices in the Royal College of General Practitioners (RCGP) primary care sentinel network. Endpoints included influenza‐like illness (ILI), lower respiratory tract infection (LTRI) as well as PCR‐confirmed influenza from patients swabbed from practices participating in a swabbing scheme. Adjustment was made for age, month, underlying chronic condition, region and number of consultations in the 12 months prior to the study period. In addition to the cohort analysis, a nested test‐negative case–control analysis (TNCC) was carried out using the swab‐negative results as controls.

Results

In the cohort analysis, VE against LRTI was −0·5% [95% CI: (−7·0%, 7·5%)], against ILI was 37·8% [95% CI: (32·3%, 43·0%)] and against PCR‐confirmed influenza was 50·0% [95% CI:(25·9%, 65·6%)] for type A and 44·4% [95% CI: (10·1%, 65·6%)] for type B. Using the TNCC design, the type A VE was 56·5% [95% CI: (30·4%, 72·7%)] and for type B was 54·0% [95% CI: (21·0%, 73·3%)].

Conclusions

This study shows that the 2010/2011 TIV provided moderate protection against the circulating influenza strains for the 2010/2011 season. It also suggests that VE against the less specific diagnosis of ILI can be found, but less specific endpoints such as LRTI are not useful.     

Original Article: Highly conserved cross‐reactive CD4+ T‐cell HA‐epitopes of seasonal and the 2009 pandemic influenza viruses

Please cite this paper as: Duvvuri et al. (2010) Highly conserved cross‐reactive CD4+ T‐cell HA‐epitopes of seasonal and the 2009 pandemic influenza viruses. Influenza and Other Respiratory Viruses 4(5), 249–258.Background The relatively mild nature of the 2009 influenza pandemic (nH1N1) highlights the overriding importance of pre‐existing immune memory. The absence of cross‐reactive antibodies to nH1N1 in most individuals suggests that such attenuation may be attributed to pre‐existing cellular immune responses to epitopes shared between nH1N1 virus and previously circulating strains of inter‐pandemic influenza A viruses.Results We sought to identify potential CD4+ T cell epitopes and predict the level of cross‐reactivity of responding T cells. By performing large‐scale major histocompatibility complex II analyses on Hemagglutinin (HA) proteins, we investigated the degree of T‐cell cross‐reactivity between seasonal influenza A (sH1N1, H3N2) from 1968 to 2009 and nH1N1 strains. Each epitope was examined against all the protein sequences that correspond to sH1N1, H3N2, and nH1N1. T‐cell cross‐reactivity was estimated to be 52%, and maximum conservancy was found between sH1N1 and nH1N1 with a significant correlation (P < 0·05).Conclusions  Given the importance of cellular responses in kinetics of influenza infection in humans, our findings underscore the role of T‐cell assays for understanding the inter‐pandemic variability in severity and for planning treatment methods for emerging influenza viruses.     

Mortality burden of the 2009‐10 influenza pandemic in the United States: improving the timeliness of influenza severity estimates using inpatient mortality records

Background

Delays in the release of national vital statistics hinder timely assessment of influenza severity, especially during pandemics. Inpatient mortality records could provide timelier estimates of influenza‐associated mortality.

Methods

We compiled weekly age‐specific deaths for various causes from US State Inpatient Databases (1990–2010) and national vital statistics (1990–2009). We calculated influenza‐attributable excess deaths by season based on Poisson regression models driven by indicators of respiratory virus activity, seasonality, and temporal trends.

Results

Extrapolations of excess mortality from inpatient data fell within 11% and 17% of vital statistics estimates for pandemic and seasonal influenza, respectively, with high year‐to‐year correlation (Spearman''s rho = 0·87–0·90, P < 0·001, n = 19). We attribute 14 800 excess respiratory and cardiac deaths (95% CI: 10 000–19 650) to pandemic influenza activity during April 2009–April 2010, 79% of which occurred in people under 65 years.

Conclusions

Modeling inpatient mortality records provides useful estimates of influenza severity in advance of national vital statistics release, capturing both the magnitude and the age distribution of pandemic and epidemic deaths. We provide the first age‐ and cause‐specific estimates of the 2009 pandemic mortality burden using traditional ‘excess mortality’ methods, confirming the unusual burden of this virus in young populations. Our inpatient‐based approach could help monitor mortality trends in other infectious diseases.