scholarly journals Influenza A Virus Neuraminidase Enhances Meningococcal Adhesion to Epithelial Cells through Interaction with Sialic Acid-Containing Meningococcal Capsules

2009 ◽  
Vol 77 (9) ◽  
pp. 3588-3595 ◽  
Author(s):  
Marie-Anne Rameix-Welti ◽  
Maria Leticia Zarantonelli ◽  
Dario Giorgini ◽  
Corinne Ruckly ◽  
Monica Marasescu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Epithelial Cells ◽  
Influenza A Virus ◽  
Influenza A ◽  
Bacterial Infections ◽  
Control Strategies ◽  
Direct Interaction ◽  
Virus Infections ◽  
Meningococcal Infections

ABSTRACT The underlying mechanisms of the epidemiological association between influenza virus infections and Neisseria meningitidis invasive infections are not fully understood. Here we report that adhesion of N. meningitidis to human Hec-1-B epithelial cells is enhanced by influenza A virus (IAV) infection. A potential role of the viral neuraminidase (NA) in facilitating meningococcal adhesion to influenza virus-infected epithelial cells was examined. Expression of a recombinant IAV NA in Hec-1-B human epithelial cells increased the adhesion of strains of N. meningitidis belonging to the sialic acid-containing capsular serogroups B, C, and W135 but not to the mannosamine phosphate-containing capsular serogroup A. Adhesion enhancement was not observed with an inactive NA mutant or in the presence of an NA inhibitor (zanamivir). Furthermore, purified IAV NA was shown to cleave sialic acid-containing capsular polysaccharides of N. meningitidis. On the whole, our findings suggest that a direct interaction between the NA of IAV and the capsule of N. meningitidis enhances bacterial adhesion to cultured epithelial cells, most likely through cleavage of capsular sialic acid-containing polysaccharides. A better understanding of the association between IAV and invasive meningococcal infections should help to set up improved control strategies against these seasonal dual viral-bacterial infections.

scholarly journals The mechanism of resistance to favipiravir in influenza

2018 ◽  
Vol 115 (45) ◽  
pp. 11613-11618 ◽  
Author(s):  
Daniel H. Goldhill ◽  
Aartjan J. W. te Velthuis ◽  
Robert A. Fletcher ◽  
Pinky Langat ◽  
Maria Zambon ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Viral Fitness ◽  
Virus Infections ◽  
Virus Rna ◽  
Evolution Of Resistance ◽  
Emergence Of Resistance

Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.

scholarly journals In Vitro System for Modeling Influenza A Virus Resistance under Drug Pressure

2010 ◽  
Vol 54 (8) ◽  
pp. 3442-3450 ◽  
Author(s):  
Ashley N. Brown ◽  
James J. McSharry ◽  
Qingmei Weng ◽  
Elizabeth M. Driebe ◽  
David M. Engelthaler ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Mdck Cells ◽  
Influenza Virus Infection ◽  
Infection Model ◽  
Virus Infections ◽  
Drug Pressure

ABSTRACT One of the biggest challenges in the effort to treat and contain influenza A virus infections is the emergence of resistance during treatment. It is well documented that resistance to amantadine arises rapidly during the course of treatment due to mutations in the gene coding for the M2 protein. To address this problem, it is critical to develop experimental systems that can accurately model the selection of resistance under drug pressure as seen in humans. We used the hollow-fiber infection model (HFIM) system to examine the effect of amantadine on the replication of influenza virus, A/Albany/1/98 (H3N2), grown in MDCK cells. At 24 and 48 h postinfection, virus replication was inhibited in a dose-dependent fashion. At 72 and 96 h postinfection, virus replication was no longer inhibited, suggesting the emergence of amantadine-resistant virus. Sequencing of the M2 gene revealed that mutations appeared at between 48 and 72 h of drug treatment and that the mutations were identical to those identified in the clinic for amantadine-resistant viruses (e.g., V27A, A30T, and S31N). Interestingly, we found that the type of mutation was strongly affected by the dose of the drug. The data suggest that the HFIM is a good model for influenza virus infection and resistance generation in humans. The HFIM has the advantage of being a highly controlled system where multiplicity parameters can be directly and accurately controlled and measured.

scholarly journals Influenza Viruses in Mice: Deep Sequencing Analysis of Serial Passage and Effects of Sialic Acid Structural Variation

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Brian R. Wasik ◽  
Ian E. H. Voorhees ◽  
Karen N. Barnard ◽  
Brynn K. Alford-Lawrence ◽  
Wendy S. Weichert ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Influenza A Virus ◽  
Deep Sequencing ◽  
Influenza A ◽  
Natural Host ◽  
H1n1 Pandemic ◽  
Influenza A Viruses ◽  
Canine Influenza Virus ◽  
Canine Influenza

ABSTRACT Influenza A viruses have regularly jumped to new host species to cause epidemics or pandemics, an evolutionary process that involves variation in the viral traits necessary to overcome host barriers and facilitate transmission. Mice are not a natural host for influenza virus but are frequently used as models in studies of pathogenesis, often after multiple passages to achieve higher viral titers that result in clinical disease such as weight loss or death. Here, we examine the processes of influenza A virus infection and evolution in mice by comparing single nucleotide variations of a human H1N1 pandemic virus, a seasonal H3N2 virus, and an H3N2 canine influenza virus during experimental passage. We also compared replication and sequence variation in wild-type mice expressing N-glycolylneuraminic acid (Neu5Gc) with those seen in mice expressing only N-acetylneuraminic acid (Neu5Ac). Viruses derived from plasmids were propagated in MDCK cells and then passaged in mice up to four times. Full-genome deep sequencing of the plasmids, cultured viruses, and viruses from mice at various passages revealed only small numbers of mutational changes. The H3N2 canine influenza virus showed increases in frequency of sporadic mutations in the PB2, PA, and NA segments. The H1N1 pandemic virus grew well in mice, and while it exhibited the maintenance of some minority mutations, there was no clear evidence for adaptive evolution. The H3N2 seasonal virus did not establish in the mice. Finally, there were no clear sequence differences associated with the presence or absence of Neu5Gc. IMPORTANCE Mice are commonly used as a model to study the growth and virulence of influenza A viruses in mammals but are not a natural host and have distinct sialic acid receptor profiles compared to humans. Using experimental infections with different subtypes of influenza A virus derived from different hosts, we found that evolution of influenza A virus in mice did not necessarily proceed through the linear accumulation of host-adaptive mutations, that there was variation in the patterns of mutations detected in each repetition, and that the mutation dynamics depended on the virus examined. In addition, variation in the viral receptor, sialic acid, did not affect influenza virus evolution in this model. Overall, our results show that while mice provide a useful animal model for influenza virus pathology, host passage evolution will vary depending on the specific virus tested.

scholarly journals Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors

2015 ◽  
Vol 59 (10) ◽  
pp. 6007-6016 ◽  
Author(s):  
Alice W. Tsai ◽  
Colleen F. McNeil ◽  
Joshua R. Leeman ◽  
Hamilton B. Bennett ◽  
Kwame Nti-Addae ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Therapeutic Agents ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Whole Body ◽  
Infection Model ◽  
Virus Infections

ABSTRACTThrough antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellentin vitroandin vivoproperties have been identified. To evaluate thein vivoefficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.

scholarly journals A single dose vaccination with an elastase-dependent H1N1 live attenuated swine influenza virus protects pigs from challenge with 2009 pandemic H1N1 virus

2014 ◽  
Vol 64 (1) ◽  
pp. 10-23
Author(s):  
Aleksandar Mašić ◽  
Niziti Woldeab ◽  
Carissa Embury-Hyatt ◽  
Yan Zhou ◽  
Shawn Babiuk
Keyword(s):  
Influenza Virus ◽  
Single Dose ◽  
Influenza A Virus ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Swine Influenza Virus ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
Virus Infections ◽  
Intranasal Route

Abstract The 2009 outbreak of H1N1 influenza A viruses in humans underscored the importance of pigs in influenza A virus evolution and the emergence of novel viruses with pandemic potential. In addition, influenza A virus infections continued to cause production losses in the agricultural industry resulting in a significant drop of profit. The primary method to control influenza A virus infections in pigs is through vaccination. Previously we demonstrated that two doses of an elastase-dependent live attenuated swine influenza virus administered by either the intratracheal or intranasal route can provide a high degree of protection in pigs against challenge with both homologous and different heterologous swine influenza viruses. Here we report the protection efficacy of a single dose elastase-dependent live attenuated swine influenza virus administered by the intranasal route against challenge with homologous subtypic H1N1 2009 pandemic swine-like influenza virus. Protection was observed in the absence of neutralizing antibodies specific for H1N1 2009 in sera.

scholarly journals Quantifying homologous and heterologous antibody titre rises after influenza virus infection

2016 ◽  
Vol 144 (11) ◽  
pp. 2306-2316 ◽  
Author(s):  
G. FREEMAN ◽  
R. A. P. M. PERERA ◽  
E. NGAN ◽  
V. J. FANG ◽  
S. CAUCHEMEZ ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Antibody Titre ◽  
Influenza A ◽  
Haemagglutination Inhibition ◽  
Influenza Virus Infection ◽  
Virus Infections ◽  
Influenza A H1n1 ◽  
Antibody Titres

SUMMARYMost influenza virus infections are associated with mild disease. One approach to estimate the occurrence of influenza virus infections in individuals is via repeated measurement of humoral antibody titres. We used baseline and convalescent antibody titres measured by haemagglutination inhibition (HI) and viral neutralization (VN) assays against influenza A(H1N1), A(H3N2) and B viruses to investigate the characteristics of antibody rises following virologically confirmed influenza virus infections in participants in a community-based study. Multivariate models were fitted in a Bayesian framework to characterize the distribution of changes in antibody titres following influenza A virus infections. In 122 participants with PCR-confirmed influenza A virus infection, homologous antibody titres rose by geometric means of 1·2- to 10·2-fold after infection with A(H1N1), A(H3N2) and A(H1N1)pdm09. Significant cross-reactions were observed between A(H1N1)pdm09 and seasonal A(H1N1). Antibody titre rises for some subtypes and assays varied by age, receipt of oseltamivir treatment, and recent receipt of influenza vaccination. In conclusion, we provided a quantitative description of the mean and variation in rises in influenza virus antibody titres following influenza virus infection. The multivariate patterns in boosting of antibody titres following influenza virus infection could be taken into account to improve estimates of cumulative incidence of infection in seroepidemiological studies.

scholarly journals Berberine Hampers Influenza A Replication through Inhibition of MAPK/ERK Pathway

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 344 ◽  
Author(s):  
Paweł Botwina ◽  
Katarzyna Owczarek ◽  
Zenon Rajfur ◽  
Marek Ochman ◽  
Maciej Urlik ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Influenza A Virus ◽  
Cell Lines ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Airway Epithelial Cells ◽  
Type I ◽  
Erk Pathway ◽  
Human Airway

Background: Berberine (BBR) is an isoquinoline alkaloid which exhibits a variety of biological and therapeutic properties, and has been reported by some to block replication of the influenza virus. However, contradictory results have also been presented, and the mechanistic explanation is lacking. Methods: A panel of cell lines (Madin–Darby canine kidney (MDCK), adenocarcinoma human alveolar basal epithelial cells (A549), lung epithelial type I (LET1)) and primary human airway epithelial cells (HAE) susceptible to influenza virus infection were infected with a seasonal influenza A virus in the presence or absence of BBR. Cytotoxicity towards cell lines was measured using XTT assay. The yield of the virus was analyzed using RT-qPCR. To study the molecular mechanism of BBR, confocal microscopy and Western blot analyses of cellular fractions were applied. Results and conclusions: Our results show cell-type-dependent anti-influenza properties of BBR in vitro which suggests that the compound acts on the cell and not the virus. Importantly, BBR hampers influenza replication in primary human airway epithelium 3D cultures that mimic the natural replication site of the virus. Studies show that the influenza A virus upregulates the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway and hijacks this pathway for nucleolar export of the viral ribonucleoprotein. Our results suggest that BBR interferes with this process and hampers influenza A replication.

scholarly journals STUDIES ON INFLUENZA INFECTION IN FERRETS BY MEANS OF FLUORESCEIN-LABELLED ANTIBODY

1955 ◽  
Vol 101 (6) ◽  
pp. 677-686 ◽  
Author(s):  
Ch'ien Liu
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Infection ◽  
Fluorescent Staining ◽  
Green Fluorescence ◽  
Viral Antigens ◽  
The Cross

Yellow-green fluorescence representing viral antigens was detected in both the nucleus and cytoplasm of epithelial cells of the respiratory tract in ferrets infected with influenza virus. This nuclear fluorescence was the chief manifestation of cross-fluorescent staining reactions among three strains of influenza A virus studied, PR8, Farrington, and Fm1. Absorption experiments with influenza viral V and soluble S antigens showed that S antigen was responsible for the presence of fluorescence in the nucleus and for the cross-staining reactions among these strains.

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