The cellular immunophenotype expression of influenza A virus and influenza B virus infection in children

ABSTRACT Protection from influenza virus infection is canonically associated with antibodies that neutralize the virus by blocking the interaction between the viral hemagglutinin and host cell receptors. However, protection can also be conferred by other mechanisms, including antibody-mediated effector functions. Here, we report the characterization of 22 broadly cross-reactive, nonneutralizing antibodies specific for influenza B virus hemagglutinin. The majority of these antibodies recognized influenza B viruses isolated over the period of 73 years and bind the conserved stalk domain of the hemagglutinin. A proportion of the characterized antibodies protected mice from both morbidity and mortality after challenge with a lethal dose of influenza B virus. Activity in an antibody-dependent cell-mediated cytotoxicity reporter assay correlated strongly with protection, suggesting that Fc-dependent effector function determines protective efficacy. The information regarding mechanism of action and epitope location stemming from our characterization of these antibodies will inform the design of urgently needed vaccines that could induce broad protection against influenza B viruses. IMPORTANCE While broadly protective antibodies against the influenza A virus hemagglutinin have been well studied, very limited information is available for antibodies that broadly recognize influenza B viruses. Similarly, the development of a universal or broadly protective influenza B virus vaccine lags behind the development of such a vaccine for influenza A virus. More information about epitope location and mechanism of action of broadly protective influenza B virus antibodies is required to inform vaccine development. In addition, protective antibodies could be a useful tool to treat or prevent influenza B virus infection in pediatric cohorts or in a therapeutic setting in immunocompromised individuals in conjugation with existing treatment avenues.

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Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection

Journal of Virology ◽

10.1128/jvi.00549-16 ◽

2016 ◽

Vol 90 (14) ◽

pp. 6263-6275 ◽

Cited By ~ 17

Author(s):

Jingwen Jiang ◽

Jing Li ◽

Wenhui Fan ◽

Weinan Zheng ◽

Meng Yu ◽

...

Keyword(s):

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Molecular Mechanisms ◽

Rna Binding ◽

Influenza B Virus ◽

Influenza B ◽

Type I ◽

Ns1 Protein ◽

B Virus

ABSTRACTInfluenza A and B virus infections both cause a host innate immunity response. Here, we report that the robust production of type I and III interferons (IFNs), IFN-stimulated genes, and proinflammatory factors can be induced by influenza B virus rather than influenza A virus infection in alveolar epithelial (A549) cells during early infection. This response is mainly dependent on the retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway. Infection by influenza B virus promotes intense Lys63-linked ubiquitination of RIG-I, resulting in cytokine eruption. It is known that the influenza A virus NS1 protein (NS1-A) interacts with RIG-I and TRIM25 to suppress the activation of RIG-I-mediated signaling. However, the present results indicate that the influenza B virus NS1 protein (NS1-B) is unable to interact with RIG-I but engages in the formation of a RIG-I/TRIM25/NS1-B ternary complex. Furthermore, we demonstrate that the N-terminal RNA-binding domain (RBD) of NS1-B is responsible for interaction with TRIM25 and that this interaction blocks the inhibitory effect of the NS1-B C-terminal effector domain (TED) on RIG-I ubiquitination. Our findings reveal a novel mechanism for the host cytokine response to influenza B virus infection through regulatory interplay between host and viral proteins.IMPORTANCEInfluenza B virus generally causes local mild epidemics but is occasionally lethal to individuals. Existing studies describe the broad characteristics of influenza B virus epidemiology and pathology. However, to develop better prevention and treatments for the disease, determining the concrete molecular mechanisms of pathogenesis becomes pivotal to understand how the host reacts to the challenge of influenza B virus. Thus, we aimed to characterize the host innate immune response to influenza B virus infection. Here, we show that vigorous Lys63-linked ubiquitination of RIG-I and cytokine eruption dependent on RIG-I-mediated signal transduction are induced by virus infection. Additionally, TRIM25 positively regulates RIG-I-mediated signaling by ablating the inhibitory function of NS1-B on RIG-I ubiquitination.

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Acute Respiratory Disease at a Chinese Military Recruitment Training Center: Three-Year Consecutive Investigation

Infection International ◽

10.1515/ii-2017-0084 ◽

2014 ◽

Vol 3 (3) ◽

pp. 108-113

Author(s):

Jun-fei Zhang ◽

Jian Fang ◽

Hai-yan Song ◽

Wei-li Wu ◽

Bo Liu ◽

...

Keyword(s):

Virus Infection ◽

Respiratory Disease ◽

Influenza A Virus ◽

Legionella Pneumophila ◽

Influenza A ◽

Influenza B Virus ◽

Influenza B ◽

Training Center ◽

Acute Respiratory Disease ◽

B Virus

Abstract Background Military recruits are at a higher risk of acute respiratory disease (ARD) and the causative agents might change over time, which needs to be investigated. Methods The nasopharyngeal swabs and blood samples were consecutively collected from conscripts for three years in a military training center. The real-time fluorescent quantitative PCR assays were conducted for 15 species of common respiratory pathogens; the serum anti-Legionella pneumophila antibodies were detected by indirect immunofluorescence (IIF) assay, and serum anti-Microplasma pneumoniae antibodies, serum anti-influenza B virus and anti-influenza A virus-IgM and IgG were detected by ELISA. Results The prevalences of ARD were 59.3% (108/182) in 2008, 23.3% (50/215) in 2009, and 19.6% (40/204) in 2010. Among the patients with ARD from 2008 to 2010, the influenza B virus infection accounted for 45.4%, 30.0% and 55.0%, and seasonal influenza A virus infection for 8.3%, 8.0% and 5.0%, respectively; the positive rates of serum anti-Legionella pneumophila and anti-Microplasma pneumoniae antibodies in recruits was lower than 10% each year respectively in the three years without diagnostic significance. Conclusion The early appropriate diagnosis and treatment of ARD in military personnel will ensure the power strength of armed forces.

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RIG-I Signaling Is Essential for Influenza B Virus-Induced Rapid Interferon Gene Expression

Journal of Virology ◽

10.1128/jvi.01576-15 ◽

2015 ◽

Vol 89 (23) ◽

pp. 12014-12025 ◽

Cited By ~ 25

Author(s):

Sanna M. Mäkelä ◽

Pamela Österlund ◽

Veera Westenius ◽

Sinikka Latvala ◽

Michael S. Diamond ◽

...

Keyword(s):

Gene Expression ◽

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Innate Immune ◽

Influenza B Virus ◽

Influenza B ◽

Immune Recognition ◽

B Virus ◽

Irf3 Activation

ABSTRACTInfluenza B virus causes annual epidemics and, along with influenza A virus, accounts for substantial disease and economic burden throughout the world. Influenza B virus infects only humans and some marine mammals and is not responsible for pandemics, possibly due to a very low frequency of reassortment and a lower evolutionary rate than that of influenza A virus. Influenza B virus has been less studied than influenza A virus, and thus, a comparison of influenza A and B virus infection mechanisms may provide new insight into virus-host interactions. Here we analyzed the early events in influenza B virus infection and interferon (IFN) gene expression in human monocyte-derived macrophages and dendritic cells. We show that influenza B virus induces IFN regulatory factor 3 (IRF3) activation and IFN-λ1 gene expression with faster kinetics than does influenza A virus, without a requirement for viral protein synthesis or replication. Influenza B virus-induced activation of IRF3 required the fusion of viral and endosomal membranes, and nuclear accumulation of IRF3 and viral NP occurred concurrently. In comparison, immediate early IRF3 activation was not observed in influenza A virus-infected macrophages. Experiments with RIG-I-, MDA5-, and RIG-I/MDA5-deficient mouse fibroblasts showed that RIG-I is the critical pattern recognition receptor needed for the influenza B virus-induced activation of IRF3. Our results show that innate immune mechanisms are activated immediately after influenza B virus entry through the endocytic pathway, whereas influenza A virus avoids early IRF3 activation and IFN gene induction.IMPORTANCERecently, a great deal of interest has been paid to identifying the ligands for RIG-I under conditions of natural infection, as many previous studies have been based on transfection of cells with different types of viral or synthetic RNA structures. We shed light on this question by analyzing the earliest step in innate immune recognition of influenza B virus by human macrophages. We show that influenza B virus induces IRF3 activation, leading to IFN gene expression after viral RNPs (vRNPs) are released into the cytosol and are recognized by RIG-I receptor, meaning that the incoming influenza B virus is already able to activate IFN gene expression. In contrast, influenza A (H3N2) virus failed to activate IRF3 at very early times of infection, suggesting that there are differences in innate immune recognition between influenza A and B viruses.

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

Journal of Medical Virology ◽

10.1002/jmv.27400 ◽

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

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Clinical Investigations. Comparison of Directigen Flu A+B with Real Time PCR in the Diagnosis of Influenza / Сравнение Иммунохроматографического Метода (Directigen Flu A+B) И Теста RT-PCR При Инфекциях Гриппа

Folia Medica ◽

10.1515/folmed-2015-0027 ◽

2015 ◽

Vol 57 (2) ◽

pp. 104-110 ◽

Cited By ~ 4

Author(s):

Golubinka Bosevska ◽

Nikola Panovski ◽

Elizabeta Janceska ◽

Vladimir Mikik ◽

Irena Kondova Topuzovska ◽

...

Keyword(s):

Real Time ◽

Influenza A Virus ◽

Real Time Pcr ◽

Influenza A ◽

Age Groups ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

B Virus ◽

Nose And Throat

AbstractEarly diagnosis and treatment of patients with influenza is the reason why physicians need rapid high-sensitivity influenza diagnostic tests that require no complex lab equipment and can be performed and interpreted within 15 min. The Aim of this study was to compare the rapid Directigen Flu A+B test with real time PCR for detection of influenza viruses in the Republic of Macedonia. MATERIALS AND METHODS: One-hundred-eight respiratory samples (combined nose and throat swabs) were routinely collected for detection of influenza virus during influenza seasons. Forty-one patients were pediatric cases and 59 were adult. Their mean age was 23 years. The patients were allocated into 6 age groups: 0 - 4 yrs, 5 - 9 yrs, 10 - 14 yrs, 15 - 19 yrs, 20-64 yrs and > 65 yrs. Each sample was tested with Directigen Flu A+B and CDC real time PCR kit for detection and typisation/subtypisation of influenza according to the lab diagnostic protocol. RESULTS: Directigen Flu A+B identified influenza A virus in 20 (18.5%) samples and influenza B virus in two 2 (1.9%) samples. The high specificity (100%) and PPV of Directigen Flu A+B we found in our study shows that the positive results do not need to be confirmed. The overall sensitivity of Directigen Flu A+B is 35.1% for influenza A virus and 33.0% for influenza B virus. The sensitivity for influenza A is higher among children hospitalized (45.0%) and outpatients (40.0%) versus adults. CONCLUSION: Directigen Flu A+B has relatively low sensitivity for detection of influenza viruses in combined nose and throat swabs. Negative results must be confirmed.

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Serum High-Mobility-Group Box 1 as a Biomarker and a Therapeutic Target during Respiratory Virus Infections

mBio ◽

10.1128/mbio.00246-18 ◽

2018 ◽

Vol 9 (2) ◽

Cited By ~ 16

Author(s):

Mira C. Patel ◽

Kari Ann Shirey ◽

Marina S. Boukhvalova ◽

Stefanie N. Vogel ◽

Jorge C. G. Blanco

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza A ◽

Influenza Virus Infection ◽

High Mobility ◽

Influenza B Virus ◽

Influenza B ◽

Lung Pathology ◽

B Virus ◽

Cotton Rats

ABSTRACT Host-derived “danger-associated molecular patterns” (DAMPs) contribute to innate immune responses and serve as markers of disease progression and severity for inflammatory and infectious diseases. There is accumulating evidence that generation of DAMPs such as oxidized phospholipids and high-mobility-group box 1 (HMGB1) during influenza virus infection leads to acute lung injury (ALI). Treatment of influenza virus-infected mice and cotton rats with the Toll-like receptor 4 (TLR4) antagonist Eritoran blocked DAMP accumulation and ameliorated influenza virus-induced ALI. However, changes in systemic HMGB1 kinetics during the course of influenza virus infection in animal models and humans have yet to establish an association of HMGB1 release with influenza virus infection. To this end, we used the cotton rat model that is permissive to nonadapted strains of influenza A and B viruses, respiratory syncytial virus (RSV), and human rhinoviruses (HRVs). Serum HMGB1 levels were measured by an enzyme-linked immunosorbent assay (ELISA) prior to infection until day 14 or 18 post-infection. Infection with either influenza A or B virus resulted in a robust increase in serum HMGB1 levels that decreased by days 14 to 18. Inoculation with the live attenuated vaccine FluMist resulted in HMGB1 levels that were significantly lower than those with infection with live influenza viruses. RSV and HRVs showed profiles of serum HMGB1 induction that were consistent with their replication and degree of lung pathology in cotton rats. We further showed that therapeutic treatment with Eritoran of cotton rats infected with influenza B virus significantly blunted serum HMGB1 levels and improved lung pathology, without inhibiting virus replication. These findings support the use of drugs that block HMGB1 to combat influenza virus-induced ALI. IMPORTANCE Influenza virus is a common infectious agent causing serious seasonal epidemics, and there is urgent need to develop an alternative treatment modality for influenza virus infection. Recently, host-derived DAMPs, such as oxidized phospholipids and HMGB1, were shown to be generated during influenza virus infection and cause ALI. To establish a clear link between influenza virus infection and HMGB1 as a biomarker, we have systematically analyzed temporal patterns of serum HMGB1 release in cotton rats infected with nonadapted strains of influenza A and B viruses and compared these patterns with a live attenuated influenza vaccine and infection by other respiratory viruses. Towards development of a new therapeutic modality, we show herein that blocking serum HMGB1 levels by Eritoran improves lung pathology in influenza B virus-infected cotton rats. Our study is the first report of systemic HMGB1 as a potential biomarker of severity in respiratory virus infections and confirms that drugs that block virus-induced HMGB1 ameliorate ALI.

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Comparative Outcomes of Adults Hospitalized With Seasonal Influenza A or B Virus Infection: Application of the 7-Category Ordinal Scale

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz053 ◽

2019 ◽

Vol 6 (3) ◽

Cited By ~ 7

Author(s):

Yeming Wang ◽

Guohui Fan ◽

Peter Horby ◽

Fredrick Hayden ◽

Qian Li ◽

...

Keyword(s):

Virus Infection ◽

Clinical Improvement ◽

Influenza A ◽

Cox Model ◽

Normal Activity ◽

Ordinal Scale ◽

Influenza B Virus ◽

Influenza B ◽

B Virus ◽

The Difference

Abstract Background The objective of this study was to investigate the difference in disease severity between influenza A and B among hospitalized adults using a novel ordinal scale and existing clinical outcome end points. Methods A prospective, observational study was conducted over the 2016–2018 influenza seasons in a central hospital. The primary outcome was the rate of clinical improvement, defined as a decline of 2 categories from admission on a 7-category ordinal scale that ranges from 1 (discharged with normal activity) to 7 (death), or hospital discharge up to day 28. Results In total, 574 eligible patients were enrolled, including 369 (64.3%) influenza A cases and 205 (35.7%) influenza B cases. The proportion of patients with a worse ordinal scale at admission was higher in influenza A than influenza B (P = .0005). Clinical improvement up to 28 days occurred in 82.4% of patients with influenza A and 90.7% of patients with influenza B (P = .0067). The Cox model indicated that influenza B patients had a higher clinical improvement probability than influenza A cases (adjusted hazard ratio [HR], 1.266; 95% confidence interval [CI], 1.019–1.573; P = .0335). A similar pattern was observed in weaning oxygen supplement (adjusted HR, 1.285; 95% CI, 1.030–1.603; P = .0261). In-hospital mortality for influenza A was marginally higher than influenza B (11.4% vs 6.8%; P = .0782). Conclusions Our findings indicated that hospitalized patients with influenza A were more ill and had delayed clinical improvement compared with those with influenza B virus infection.

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STUDIES ON THE MECHANISM OF ADAPTATION OF INFLUENZA VIRUS TO MICE

Journal of Experimental Medicine ◽

10.1084/jem.86.5.357 ◽

1947 ◽

Vol 86 (5) ◽

pp. 357-366 ◽

Cited By ~ 53

Author(s):

George K. Hirst

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

High Titer ◽

Strain Difference ◽

Mouse Lung ◽

Influenza B Virus ◽

Influenza B ◽

Difference Problem ◽

B Virus ◽

Repeated Passage

1. When strains of influenza A virus which have been isolated in chick embryos are introduced into the mouse lung, the virus multiplies readily and achieves initially a titer which is as high as is even obtained, even after repeated passage. The high initial titer of virus may be unaccompanied by any lethal or visible pathogenic effects; but with four or five mouse passages the agent becomes lethal in high titer and causes extensive pulmonary consolidation, though its capacity to multiply in the lung has not increased. In one example the adaptation to mouse lung was accompanied by increasing capacity to agglutinate guinea pig red cells without a corresponding increase in agglutinating power for chicken cells. Influenza B virus, in preliminary tests, did not behave in a similar fashion. 2. The adaptation of influenza A virus to mice is accompanied by changes in antigenic pattern, as detected by cross-tests with the agglutination inhibition method. Two strains, initially similar, with passage, changed in pattern along divergent paths so that they became not only unlike the parent strains but unlike each other. This finding has important implications for the interpretation of the strain difference problem in human influenza.

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