In Silico Prediction and Bioactivity Evaluation of Chemical Ingredients Against Influenza A Virus From Isatis tinctoria L

Influenza A virus (IAV) is one of the major causes of seasonal endemic diseases and unpredictable periodic pandemics. Due to the high mutation rate and drug resistance, it poses a persistent threat and challenge to public health. Isatis tinctoria L. (Banlangen, BLG), a traditional herbal medicine widely used in Asian countries, has been reported to possess strong efficacy on respiratory viruses, including IAV. However, its effective anti-IAV components and the mechanism of actions (MOAs) are not yet fully elucidated. In this study, we first summarized the chemical components and corresponding contents in BLG according to current available chemical analysis literature. We then presented a network-based in silico framework for identifying potential drug candidates against IAV from BLG. A total of 269 components in BLG were initially screened by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) evaluation. Thereafter, network predictive models were built via the integration of compound–target networks and influenza virus–host proteins. We highlighted 23 compounds that possessed high potential as anti-influenza virus agents. Through experimental evaluation, six compounds, namely, eupatorin, dinatin, linarin, tryptanthrin, indirubin, and acacetin, exhibited good inhibitory activity against wild-type H1N1 and H3N2. Particularly, they also exerted significant effects on drug-resistant strains. Finally, we explored the anti-IAV MOAs of BLG and showcased the potential biological pathways by systems pharmacology analysis. In conclusion, this work provides important information on BLG regarding its use in the development of anti-IAV drugs, and the network-based prediction framework proposed here also offers a powerfulful strategy for the in silico identification of novel drug candidates from complex components of herbal medicine.

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A novel family of peptides with potent activity against influenza A viruses

Journal of General Virology ◽

10.1099/vir.0.038679-0 ◽

2012 ◽

Vol 93 (5) ◽

pp. 980-986 ◽

Cited By ~ 33

Author(s):

Marlynne Q. Nicol ◽

Yvonne Ligertwood ◽

Matthew N. Bacon ◽

Bernadette M. Dutia ◽

Anthony A. Nash

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Antiviral Agents ◽

Influenza Virus Infection ◽

Influenza A Viruses ◽

Potent Inhibition ◽

Human Immunodeficiency Virus Entry ◽

Drug Resistant Strains

The emergence of drug-resistant strains of influenza virus has catalysed a search for new antiviral agents to supplement or replace existing drugs. Following the success of the human immunodeficiency virus entry blocker Enfuvirtide, there has been a resurgence of interest in peptide-based antivirals. In this paper, we report on the discovery of a novel family of peptides (FluPep, FP) that function as inhibitors of influenza A virus infection. The prototype peptide (FP1, also known as Tkip) interacts with haemagglutinin and inhibits the binding of the virus to cell membranes. Using a plaque-reduction assay, we have demonstrated that a variety of influenza A virus subtypes (including H1N1, H3N2 and H5N1) are inhibited by FluPep and its derivatives at nanomolar concentrations. By truncating FluPep we have identified a minimal sequence of 6 aa that binds to haemagglutinin and inhibits infection. Using a mouse model of intranasal influenza virus infection, we observed potent inhibition of virus infection when peptide is given at the time of virus administration. These data indicate that FluPep is a highly effective anti-influenza agent with the potential to translate to the clinic.

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Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30

Viruses ◽

10.3390/v13020156 ◽

2021 ◽

Vol 13 (2) ◽

pp. 156

Author(s):

Jasmina M. Luczo ◽

Sydney L. Ronzulli ◽

Stephen M. Tompkins

Keyword(s):

Influenza Virus ◽

Nk Cells ◽

Influenza A Virus ◽

Influenza A ◽

Nk Cell ◽

Influenza Virus Infection ◽

Target Cells ◽

Natural Cytotoxicity ◽

Activating Receptors ◽

Natural Cytotoxicity Receptors

Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.

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Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Viruses ◽

10.3390/v13020234 ◽

2021 ◽

Vol 13 (2) ◽

pp. 234

Author(s):

Sarah Al-Beltagi ◽

Cristian Alexandru Preda ◽

Leah V. Goulding ◽

Joe James ◽

Juan Pu ◽

...

Keyword(s):

Influenza Virus ◽

Respiratory Syncytial Virus ◽

Influenza A Virus ◽

Broad Spectrum ◽

Influenza A ◽

Respiratory Viruses ◽

Influenza Viruses ◽

Virus Challenge ◽

2009 H1n1 ◽

Syncytial Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

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STUDIES ON INFLUENZA VIRUS

Journal of Experimental Medicine ◽

10.1084/jem.73.5.581 ◽

1941 ◽

Vol 73 (5) ◽

pp. 581-599 ◽

Cited By ~ 18

Author(s):

Edwin H. Lennette ◽

Frank L. Horsfall

Keyword(s):

Influenza Virus ◽

Chick Embryo ◽

Influenza A Virus ◽

Influenza A ◽

Complement Fixation ◽

Soluble Antigen ◽

Swine Virus ◽

Specific Fixation ◽

Mouse Lungs

Influenza complement fixation tests designed for use with ferret serum are described. Complement-fixing antigens derived from influenza ferret lungs were unsatisfactory due to their low content of soluble antigen; those prepared from mouse lungs or developing chick embryo membranes proved to be better antigenically and were reliable when the various reagents in the test were properly adjusted to eliminate non-specific fixation of complement. The results of cross complement fixation tests indicated that the soluble antigens of the PR8 and W.S. strains of influenza A virus were closely similar, if not identical. They indicated also that the soluble antigen of swine virus possessed components present in the antigens of the human strains of virus.

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Attaching Zanamivir to a Polymer Markedly Enhances Its Activity Against Drug-resistant Strains of Influenza a Virus

Journal of Pharmaceutical Sciences ◽

10.1002/jps.22338 ◽

2011 ◽

Vol 100 (3) ◽

pp. 831-835 ◽

Cited By ~ 29

Author(s):

Alisha K. Weight ◽

Jayanta Haldar ◽

Luis Álvarez de Cienfuegos ◽

Larisa V. Gubareva ◽

Terrence M. Tumpey ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Drug Resistant ◽

Resistant Strains ◽

Drug Resistant Strains

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Development of Neuraminidase Subtype-Specific Reference Antisera by Recombinant Protein Expressed in Baculovirus

Clinical and Vaccine Immunology ◽

10.1128/cvi.00385-12 ◽

2012 ◽

Vol 20 (2) ◽

pp. 140-145 ◽

Cited By ~ 3

Author(s):

Kyu-Jun Lee ◽

Jun-Gu Choi ◽

Hyun-Mi Kang ◽

Kwang-Il Kim ◽

Choi-Kyu Park ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Influenza A Virus ◽

Diagnostic Tests ◽

Influenza A ◽

Recombinant Baculovirus ◽

Cross Reactivity ◽

Specific Reference ◽

Simple Method ◽

Avian Influenza A Virus

ABSTRACTOutbreaks of avian influenza A virus infection, particularly the H5N1 strains that have affected birds and some humans for the past 15 years, have highlighted the need for increased surveillance and disease control. Such measures require diagnostic tests to detect and characterize the different subtypes of influenza virus. In the current study, a simple method for producing reference avian influenza virus antisera to be used in diagnostic tests was developed. Antisera of nine avian influenza A virus neuraminidases (NA) used for NA subtyping were produced using a recombinant baculovirus. The recombinant NA (rNA) proteins were expressed in Sf9 insect cells and inoculated intramuscularly into specific-pathogen-free chickens with the ISA70 adjuvant. The NA inhibition antibody titers of the rNA antiserum were in the ranges of 5 to 8 and 6 to 9 log2units after the primary and boost immunizations, respectively. The antisera were subtype specific, showing low cross-reactivity against every other NA subtype using the conventional thiobarbituric acid NA inhibition assay. These results suggest that this simple method for producing reference NA antisera without purification may be useful for the diagnosis and surveillance of influenza virus.

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REACTIONS BETWEEN INFLUENZA VIRUS AND A COMPONENT OF ALLANTOIC FLUID

Journal of Experimental Medicine ◽

10.1084/jem.88.4.463 ◽

1948 ◽

Vol 88 (4) ◽

pp. 463-484 ◽

Cited By ~ 22

Author(s):

Paul H. Hardy ◽

Frank L. Horsfall

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Influenza A ◽

Allantoic Fluid ◽

Partial Dissociation

Evidence is presented which shows that there is a component present in normal allantoic fluid, probably mucoprotein in nature, capable of combining with influenza A virus (PR8), and that following combination between this component and the virus only partial dissociation of the complex occurs. Evidence is also presented which strongly suggests that the component is present in virus-infected allantoic fluid in which it is in part combined with the virus and in part free although altered by viral action. The probability that the component is present as well in highly purified preparations of influenza virus, and its effect upon various reactions obtained with this agent are discussed.

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Functional Analysis of PA Binding by Influenza A Virus PB1: Effects on Polymerase Activity and Viral Infectivity

Journal of Virology ◽

10.1128/jvi.75.17.8127-8136.2001 ◽

2001 ◽

Vol 75 (17) ◽

pp. 8127-8136 ◽

Cited By ~ 78

Author(s):

Daniel R. Perez ◽

Ruben O. Donis

Keyword(s):

Amino Acids ◽

Influenza Virus ◽

Amino Acid ◽

Viral Replication ◽

Influenza A Virus ◽

Influenza A ◽

Amino Acid Sequences ◽

Influenza Viruses ◽

Virus Growth ◽

Transcription And Replication

ABSTRACT Influenza A virus expresses three viral polymerase (P) subunits—PB1, PB2, and PA—all of which are essential for RNA and viral replication. The functions of P proteins in transcription and replication have been partially elucidated, yet some of these functions seem to be dependent on the formation of a heterotrimer for optimal viral RNA transcription and replication. Although it is conceivable that heterotrimer subunit interactions may allow a more efficient catalysis, direct evidence of their essentiality for viral replication is lacking. Biochemical studies addressing the molecular anatomy of the P complexes have revealed direct interactions between PB1 and PB2 as well as between PB1 and PA. Previous studies have shown that the N-terminal 48 amino acids of PB1, termed domain α, contain the residues required for binding PA. We report here the refined mapping of the amino acid sequences within this small region of PB1 that are indispensable for binding PA by deletion mutagenesis of PB1 in a two-hybrid assay. Subsequently, we used site-directed mutagenesis to identify the critical amino acid residues of PB1 for interaction with PA in vivo. The first 12 amino acids of PB1 were found to constitute the core of the interaction interface, thus narrowing the previous boundaries of domain α. The role of the minimal PB1 domain α in influenza virus gene expression and genome replication was subsequently analyzed by evaluating the activity of a set of PB1 mutants in a model reporter minigenome system. A strong correlation was observed between a functional PA binding site on PB1 and P activity. Influenza viruses bearing mutant PB1 genes were recovered using a plasmid-based influenza virus reverse genetics system. Interestingly, mutations that rendered PB1 unable to bind PA were either nonviable or severely growth impaired. These data are consistent with an essential role for the N terminus of PB1 in binding PA, P activity, and virus growth.

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

10.21203/rs.3.rs-54705/v2 ◽

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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Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1609316113 ◽

2016 ◽

Vol 113 (42) ◽

pp. 11931-11936 ◽

Cited By ~ 88

Author(s):

Wenqian He ◽

Gene S. Tan ◽

Caitlin E. Mullarkey ◽

Amanda J. Lee ◽

Mannie Man Wai Lam ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Neutralizing Antibodies ◽

Influenza A ◽

Critical Role ◽

Host Cells ◽

Viral Glycoprotein ◽

Effector Functions ◽

Dependent Cell

The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising “universal” influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.

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