Identification of a Small Benzamide Inhibitor of Influenza Virus Using a Cell-Based Screening

Chemotherapy ◽  
2016 ◽  
Vol 61 (3) ◽  
pp. 159-166 ◽  
Author(s):  
Woo-Jin Shin ◽  
Ky-Youb Nam ◽  
Nam-Doo Kim ◽  
Sei-Hwan Kim ◽  
Kyoung-Tai No ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Global Pandemic ◽  
Lethal Infection ◽  
Avian Influenza A Virus ◽  
A Cell ◽  
Antiviral Activities

Background: The zoonotic transmission of highly pathogenic avian influenza viruses and the global pandemic of H1N1 influenza in 2009 signified the need for a wider coverage of therapeutic options for the control of influenza. Methods: An in-house compound library was screened using a cytopathic effect inhibition assay. Selected hits were then tested in vivo and used as a core skeleton for derivative synthesis. Results: The hit compound (BMD-2601505) was effective [50% effective concentration (EC50) of 60-70 μM] in reducing the death rate of cells infected with human influenza A and B viruses as well as avian influenza A virus. Furthermore, BMD-2601505 reduced the weight loss and increased the survival after lethal infection. The compound was further modified to enhance its antiviral potency. Results show that one derivative with bromobenzene moiety was most effective (EC50 of 22-37 μM) against the influenza viruses tested. Conclusion: We identified a small benzamide compound exhibiting antiviral activity against influenza viruses. The results warrant further evaluation of antiviral activities against drug-resistant influenza isolates.

scholarly journals Molecular Basis for the Generation in Pigs of Influenza A Viruses with Pandemic Potential

1998 ◽  
Vol 72 (9) ◽  
pp. 7367-7373 ◽  
Author(s):  
Toshihiro Ito ◽  
J. Nelson S. S. Couceiro ◽  
Sørge Kelm ◽  
Linda G. Baum ◽  
Scott Krauss ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Influenza Viruses ◽  
Structural Basis ◽  
Human Populations ◽  
Influenza A Viruses ◽  
Human Virus ◽  
Surface Receptors ◽  
Virus Receptors ◽  
Avian Influenza A Virus

ABSTRACT Genetic and biologic observations suggest that pigs may serve as “mixing vessels” for the generation of human-avian influenza A virus reassortants, similar to those responsible for the 1957 and 1968 pandemics. Here we demonstrate a structural basis for this hypothesis. Cell surface receptors for both human and avian influenza viruses were identified in the pig trachea, providing a milieu conducive to viral replication and genetic reassortment. Surprisingly, with continued replication, some avian-like swine viruses acquired the ability to recognize human virus receptors, raising the possibility of their direct transmission to human populations. These findings help to explain the emergence of pandemic influenza viruses and support the need for continued surveillance of swine for viruses carrying avian virus genes.

scholarly journals Molecular Analysis of H7 Avian Influenza Viruses from Australia and New Zealand: Genetic Diversity and Relationships from 1976 to 2007

2010 ◽  
Vol 84 (19) ◽  
pp. 9957-9966 ◽  
Author(s):  
Dieter Bulach ◽  
Rebecca Halpin ◽  
David Spiro ◽  
Laura Pomeroy ◽  
Daniel Janies ◽  
...  
Keyword(s):  
New Zealand ◽  
Avian Influenza ◽  
Influenza A ◽  
Influenza Viruses ◽  
Full Genome Sequencing ◽  
Influenza A Viruses ◽  
Independent Evolution ◽  
Avian Influenza A Virus ◽  
Geographic Regions ◽  
Genetic Pool

ABSTRACT Full-genome sequencing of 11 Australian and 1 New Zealand avian influenza A virus isolate (all subtype H7) has enabled comparison of the sequences of each of the genome segments to those of other subtype H7 avian influenza A viruses. The inference of phylogenetic relationships for each segment has been used to develop a model of the natural history of these viruses in Australia. Phylogenetic analysis of the hemagglutinin segment indicates that the Australian H7 isolates form a monophyletic clade. This pattern is consistent with the long-term, independent evolution that is, in this instance, associated with geographic regions. On the basis of the analysis of the other H7 hemagglutinin sequences, three other geographic regions for which similar monophyletic clades have been observed were confirmed. These regions are Eurasia plus Africa, North America, and South America. Analysis of the neuraminidase sequences from the H7N1, H7N3, and H7N7 genomes revealed the same region-based relationships. This pattern of independent evolution of Australian isolates is supported by the results of analysis of each of the six remaining genomic segments. These results, in conjunction with the occurrence of five different combinations of neuraminidase subtypes (H7N2, H7N3, H7N4, H7N6, H7N7) among the 11 Australian isolates, suggest that the maintenance host(s) is nearly exclusively associated with Australia. The single lineage of Australian H7 hemagglutinin sequences, despite the occurrence of multiple neuraminidase types, suggests the existence of a genetic pool from which a variety of reassortants arise rather than the presence of a small number of stable viral clones. This pattern of evolution is likely to occur in each of the regions mentioned above.

scholarly journals Pathogenesis and Transmission Assessments of Two H7N8 Influenza A Viruses Recently Isolated from Turkey Farms in Indiana Using Mouse and Ferret Models

2016 ◽  
Vol 90 (23) ◽  
pp. 10936-10944 ◽  
Author(s):  
Xiangjie Sun ◽  
Jessica A. Belser ◽  
Joanna A. Pulit-Penaloza ◽  
Hui Zeng ◽  
Amanda Lewis ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Influenza Viruses ◽  
Avian Influenza Viruses ◽  
Highly Pathogenic ◽  
Pathogenic Avian Influenza ◽  
Domestic Poultry ◽  
Commercial Turkey

ABSTRACTAvian influenza A H7 viruses have caused multiple outbreaks in domestic poultry throughout North America, resulting in occasional infections of humans in close contact with affected birds. In early 2016, the presence of H7N8 highly pathogenic avian influenza (HPAI) viruses and closely related H7N8 low-pathogenic avian influenza (LPAI) viruses was confirmed in commercial turkey farms in Indiana. These H7N8 viruses represent the first isolation of this subtype in domestic poultry in North America, and their virulence in mammalian hosts and the potential risk for human infection are largely unknown. In this study, we assessed the ability of H7N8 HPAI and LPAI viruses to replicatein vitroin human airway cells andin vivoin mouse and ferret models. Both H7N8 viruses replicated efficientlyin vitroandin vivo, but they exhibited substantial differences in disease severity in mammals. In mice, while the H7N8 LPAI virus largely remained avirulent, the H7N8 HPAI virus exhibited greater infectivity, virulence, and lethality. Both H7N8 viruses replicated similarly in ferrets, but only the H7N8 HPAI virus caused moderate weight loss, lethargy, and mortality. The H7N8 LPAI virus displayed limited transmissibility in ferrets placed in direct contact with an inoculated animal, while no transmission of H7N8 HPAI virus was detected. Our results indicate that the H7N8 avian influenza viruses from Indiana are able to replicate in mammals and cause severe disease but with limited transmission. The recent appearance of H7N8 viruses in domestic poultry highlights the need for continued influenza surveillance in wild birds and close monitoring of the potential risk to human health.IMPORTANCEH7 influenza viruses circulate in wild birds in the United States, but when the virus emerges in domestic poultry populations, the frequency of human exposure and the potential for human infections increases. An H7N8 highly pathogenic avian influenza (HPAI) virus and an H7N8 low-pathogenic avian influenza (LPAI) virus were recently isolated from commercial turkey farms in Indiana. To determine the risk that these influenza viruses pose to humans, we assessed their pathogenesis and transmissionin vitroand in mammalian models. We found that the H7N8 HPAI virus exhibited enhanced virulence, and although transmission was only observed with the H7N8 LPAI virus, the ability of this H7 virus to transmit in a mammalian host and quickly evolve to a more virulent strain is cause for concern. Our findings offer important insight into the potential for emerging H7 avian influenza viruses to acquire the ability to cause disease and transmit among mammals.

scholarly journals Modern application and prospects of the stable isotopes  method for studying avian influenza A virus transmission   in migratory birds

2019 ◽  
Vol 14 (3) ◽  
pp. 92-100
Author(s):  
O. R. Druzyaka ◽  
A. V. Druzyaka ◽  
M. A. Gulyaeva ◽  
F. Huettmann ◽  
A. M. Shestopalov
Keyword(s):  
Stable Isotopes ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Bird Migration ◽  
Migratory Birds ◽  
Influenza Viruses ◽  
Migration Routes ◽  
Viral Pathogen ◽  
Avian Influenza A Virus

Aim. The circulation and transmission of pathogens is a global biological phenomenon that is closely associated with bird migration. This analysis was carried out with  the aim of understanding and assessing the prospects of using the stable isotope  method to study the circulation and transmission of the avian influenza A virus via  migratory birds. Discussion. Insufficient data on the distances of migration of infected birds and their  interpopulational relationships leaves open the question of the transmission of highly pathogenic influenza viruses (HSV) in the wild bird population. A deeper study of  the role of migrations in the spread of HSV may possibly allow the more effective  investigation of the transmission of the viral pathogen between individuals at migration stopover sites and the clarification of global migration routes. New methodological approaches are providing a more complete picture of the geography and phenology of migrations, as well as of the consequences of migratory behavior for species biology. The study of the quantitative component of migratory flows based on  the analysis of the content of stable isotopes (SIMS) in bird tissues seems very promising. This method is being applied to the solution of various environmental issues,  including the study of animal migrations.   Conclusion. Based on data from the scientific literature, it is shown that SIMS is  promising for the clarification of bird migration routes and the quantification of their  intensity. The resolving power of the method is sufficient to determine the migration  pathways of carriers of viral pathogens on the scale of zoogeographic subdomains  and in even further detail. However, to date, there have been few such studies: in  Russia they have not been conducted at all. The increased use of the SIMS methodology may possibly reveal new ways in which viral infections are spread via birds.  

scholarly journals Generation of a Highly Pathogenic Avian Influenza A Virus from an Avirulent Field Isolate by Passaging in Chickens

2001 ◽  
Vol 75 (9) ◽  
pp. 4439-4443 ◽  
Author(s):  
Toshihiro Ito ◽  
Hideo Goto ◽  
Eiji Yamamoto ◽  
Hiroko Tanaka ◽  
Mutsuko Takeuchi ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Field Isolate ◽  
Influenza Viruses ◽  
Highly Pathogenic ◽  
Avian Influenza A Virus ◽  
Highly Virulent ◽  
Type Sequence ◽  
Wild Waterfowl ◽  
Selection Of

ABSTRACT Highly virulent avian influenza viruses can arise from avirulent strains maintained in poultry, but evidence to support their generation from viruses in wild birds is lacking. The most likely mechanism for the acquisition of virulence by benign avian viruses is the introduction of mutations by error-prone RNA polymerase, followed by the selection of virulent viruses. To investigate whether this mechanism could apply to wild waterfowl, we studied an avirulent wild-swan virus that replicates poorly in chickens. After 24 consecutive passages by air sac inoculation, followed by five passages in chicken brain, the avirulent virus became highly pathogenic in chickens, producing a 100% mortality rate. Sequence analysis at the hemmaglutinin cleavage site of the original isolate revealed a typical avirulence type of sequence, R-E-T-R, which progressed incrementally to a typical virulence type of sequence, R-R-K-K-R, during repeated passages in chickens. These results demonstrate that avirulent viruses maintained in wild waterfowl in nature and bearing the consensus avirulence type sequence R-E-T-R have the potential to become highly pathogenic while circulating in chickens.

scholarly journals In vitro demonstration of neural transmission of avian influenza A virus

2005 ◽  
Vol 86 (4) ◽  
pp. 1131-1139 ◽  
Author(s):  
Kazuya Matsuda ◽  
Takuma Shibata ◽  
Yoshihiro Sakoda ◽  
Hiroshi Kida ◽  
Takashi Kimura ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A Virus ◽  
Intermediate Filaments ◽  
Influenza A ◽  
Pseudorabies Virus ◽  
Influenza Viruses ◽  
Avian Influenza A Virus ◽  
Neural Transmission ◽  
The Central Nervous System

Neural involvement following infections of influenza viruses can be serious. The neural transport of influenza viruses from the periphery to the central nervous system has been indicated by using mouse models. However, no direct evidence for neuronal infection has been obtained in vitro and the mechanisms of neural transmission of influenza viruses have not been reported. In this study, the transneural transmission of a neurotropic influenza A virus was examined using compartmentalized cultures of neurons from mouse dorsal root ganglia, and the results were compared with those obtained using the pseudorabies virus, a virus with well-established neurotransmission. Both viruses reached the cell bodies of the neurons via the axons. This is the first report on axonal transport of influenza A virus in vitro. In addition, the role of the cytoskeleton (microtubules, microfilaments and intermediate filaments) in the neural transmission of influenza virus was investigated by conducting cytoskeletal perturbation experiments. The results indicated that the transport of avian influenza A virus in the neurons was independent of microtubule integrity but was dependent on the integrity of intermediate filaments, whereas pseudorabies virus needed both for neural spread.

scholarly journals The Impact of the Closure of the Live Poultry Market due to COVID-19 on the Avian Influenza Virus in Nanchang, Jiangxi Province, China

2021 ◽  
Author(s):  
Jin Guo ◽  
Wentao Song ◽  
Xiansheng Ni ◽  
Kun Zhou ◽  
Jingwen Wu ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Influenza Viruses ◽  
Jiangxi Province ◽  
Detection Rates ◽  
Before And After ◽  
Avian Influenza A Virus ◽  
Positive Rate ◽  
Live Poultry ◽  
The Impact

This article aims to understand the changes in the detection rates of H5, H7, and H9 subtypes of avian influenza viruses (AIVs) in the live poultry markets (LPMs) in Nanchang City, Jiangxi Province, before and after the outbreak of the COVID-19. From 2019 to 2020, we monitored the LPM and collected specimens, using real-time reverse transcription polymerase chain reaction technology to detect the nucleic acid of type A AIV in the samples. The H5, H7, and H9 subtypes of influenza viruses were further classified for positive results. We analyzed 1,959 samples before and after the outbreak and found that the positive rates of avian influenza A virus (39.69%) and H9 subtype (30.66%) after the outbreak were significantly higher than before the outbreak (26.84% and 20.90%, respectively; P < 0.001). In various LPMs, the positive rate of H9 subtypes has increased significantly (P ≤ 0.001). Positive rates of the H9 subtype in duck, fecal, daub, and sewage samples, but not chicken samples, have increased to varying degrees. This study shows that additional measures are needed to strengthen the control of AIVs now that LPMs have reopened after the relaxing of COVID-19–related restrictions.

scholarly journals In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein

2017 ◽  
Vol 214 (5) ◽  
pp. 1239-1248 ◽  
Author(s):  
Christoph M. Deeg ◽  
Ebrahim Hassan ◽  
Pascal Mutz ◽  
Lara Rheinemann ◽  
Veronika Götz ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Transgenic Mice ◽  
Influenza A ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Avian Influenza Viruses ◽  
Species Barrier ◽  
Human Virus ◽  
Adaptive Mutations

Zoonotic transmission of influenza A viruses can give rise to devastating pandemics, but currently it is impossible to predict the pandemic potential of circulating avian influenza viruses. Here, we describe a new mouse model suitable for such risk assessment, based on the observation that the innate restriction factor MxA represents an effective species barrier that must be overcome by zoonotic viruses. Our mouse lacks functional endogenous Mx genes but instead carries the human MX1 locus as a transgene. Such transgenic mice were largely resistant to highly pathogenic avian H5 and H7 influenza A viruses, but were almost as susceptible to infection with influenza viruses of human origin as nontransgenic littermates. Influenza A viruses that successfully established stable lineages in humans have acquired adaptive mutations which allow partial MxA escape. Accordingly, an engineered avian H7N7 influenza virus carrying a nucleoprotein with signature mutations typically found in human virus isolates was more virulent in transgenic mice than parental virus, demonstrating that a few amino acid changes in the viral target protein can mediate escape from MxA restriction in vivo. Similar mutations probably need to be acquired by emerging influenza A viruses before they can spread in the human population.

scholarly journals Comparison of serum treatments to remove nonspecific inhibitors from chicken sera for the hemagglutination inhibition test with inactivated H5N1 and H9N2 avian Influenza A virus subtypes

2012 ◽  
Vol 24 (5) ◽  
pp. 954-958 ◽  
Author(s):  
Hye-Ryoung Kim ◽  
Kyoung-Ki Lee ◽  
Yong-Kuk Kwon ◽  
Min-Su Kang ◽  
Oun-Kyung Moon ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A Virus ◽  
Hemagglutination Inhibition ◽  
Influenza A ◽  
Influenza Viruses ◽  
Avian Influenza Viruses ◽  
Chicken Serum ◽  
Hemagglutination Inhibition Test ◽  
Avian Influenza A Virus ◽  
Cell Adsorption

The hemagglutination inhibition (HI) assay is the standard diagnostic test for detection of antibodies to avian influenza viruses. It is well known that chicken serum does not require additional serum pretreatment to remove nonspecific inhibitors (NSIs). However, NSIs were recognized in certain Korean local breeds. In the present study, various treatments were compared to remove such NSIs. Heat treatment, red blood cell adsorption, and kaolin treatment did not remove NSIs effectively, and treatment with periodate only partly eliminated the NSIs. Receptor destroying enzyme (RDE) treatment appeared to effectively remove NSIs from chicken sera, regardless of breeds. It is proposed that RDE treatment should be included in the HI tests for serological diagnosis of avian Influenza A virus.

scholarly journals Comparison of the transmission characteristics of low and high pathogenicity avian influenza A virus (H5N2)

2003 ◽  
Vol 131 (2) ◽  
pp. 1003-1013 ◽  
Author(s):  
J. A. VAN DER GOOT ◽  
M. C. M. DE JONG ◽  
G. KOCH ◽  
M. VAN BOVEN
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Influenza Viruses ◽  
Infectious Period ◽  
Transmission Characteristics ◽  
Final Size ◽  
Highly Pathogenic ◽  
Avian Influenza A Virus ◽  
Previous Infection ◽  
Means Of Transmission

Low pathogenicity avian influenza A strains (LPAI) of the H5 and H7 type are noted for their ability to transform into highly pathogenic counterparts (HPAI). Here we compare the transmission characteristics in poultry of LPAI H5N2 (A/Chicken/Pennsylvania/83) and corresponding HPAI virus by means of transmission experiments. In the experiments, five inoculated animals are placed in a cage with five contact animals, and the infection chain is monitored by taking blood samples, and samples from the trachea and cloaca. The data are analysed by final size methods and a generalized linear model. The results show that HPAI virus is more infectious and induces a longer infectious period than LPAI. In fact, fully susceptible animals are invariably infected when confronted with HPAI virus and die within six days after infection. Animals previously infected with LPAI virus, on the other hand, survive an infection with HPAI virus or escape infection all together. This implies that a previous infection with LPAI virus effectively reduces susceptibility of the host to infection and decreases transmission of HPAI virus. We discuss the implications of these conclusions for the control and evolution of avian influenza viruses.

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