scholarly journals Oseltamivir-Resistant Influenza A Viruses Are Transmitted Efficiently among Guinea Pigs by Direct Contact but Not by Aerosol

2008 ◽  
Vol 82 (20) ◽  
pp. 10052-10058 ◽  
Author(s):  
Nicole M. Bouvier ◽  
Anice C. Lowen ◽  
Peter Palese
Keyword(s):  
Influenza Virus ◽  
Guinea Pigs ◽  
Direct Contact ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Transmission Model ◽  
Resistance Mutations ◽  
In Ovo ◽  
Oseltamivir Resistance

ABSTRACT Influenza viruses resistant to the neuraminidase (NA) inhibitor oseltamivir arise under drug selection pressure both in vitro and in vivo. Several mutations in the active site of the viral NA are known to confer relative resistance to oseltamivir, and influenza viruses with certain oseltamivir resistance mutations have been shown to transmit efficiently among cocaged ferrets. However, it is not known whether NA mutations alter aerosol transmission of drug-resistant influenza virus. Here, we demonstrate that recombinant human influenza A/H3N2 viruses without and with oseltamivir resistance mutations (in which NA carries the mutation E119V or the double mutations E119V I222V) have similar in ovo growth kinetics and infectivity in guinea pigs. These viruses also transmit efficiently by the contact route among cocaged guinea pigs, as in the ferret model. However, in an aerosol transmission model, in which guinea pigs are caged separately, the oseltamivir-resistant viruses transmit poorly or not at all; in contrast, the oseltamivir-sensitive virus transmits efficiently even in the absence of direct contact. The present results suggest that oseltamivir resistance mutations reduce aerosol transmission of influenza virus, which could have implications for public health measures taken in the event of an influenza pandemic.

scholarly journals Two amino acid substitutions in the haemagglutinin of the 2009 pandemic H1N1 virus decrease direct-contact transmission in guinea pigs

2014 ◽  
Vol 95 (12) ◽  
pp. 2612-2617 ◽  
Author(s):  
Liang He ◽  
Kaijun Jiang ◽  
Qiwen Wu ◽  
Zhiqiang Duan ◽  
Haixu Xu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Guinea Pigs ◽  
Direct Contact ◽  
Influenza A ◽  
Influenza Pandemic ◽  
H1n1 Influenza ◽  
Pandemic H1n1 ◽  
Binding Preference ◽  
Contact Transmission

The 2009 pandemic H1N1 influenza A virus spread across the globe and caused the first influenza pandemic of the 21st century. Many of the molecular factors that contributed to the airborne transmission of this pandemic virus have been determined; however, the direct-contact transmission of this virus remains poorly understood. In this study, we report that a combination of two mutations (N159D and Q226R) in the haemagglutinin (HA) protein of the representative 2009 H1N1 influenza virus A/California/04/2009 (CA04) caused a switch in receptor binding preference from the α2,6-sialoglycan to the α2,3-sialoglycan receptor, and decreased the binding intensities for both glycans. In conjunction with a significantly decreased replication efficiency in the nasal epithelium, this limited human receptor binding affinity resulted in inefficient direct-contact transmission of CA04 between guinea pigs. Our findings highlight the role of the HA gene in the transmission of the influenza virus.

scholarly journals Role of Sialic Acid Binding Specificity of the 1918 Influenza Virus Hemagglutinin Protein in Virulence and Pathogenesis for Mice

2009 ◽  
Vol 83 (8) ◽  
pp. 3754-3761 ◽  
Author(s):  
Li Qi ◽  
John C. Kash ◽  
Vivien G. Dugan ◽  
Ruixue Wang ◽  
Guozhong Jin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Binding Specificity ◽  
Influenza Viruses ◽  
Virulence Determinants ◽  
Sialic Acid Binding ◽  
1918 Influenza

ABSTRACT The 1918 influenza pandemic caused more than 40 million deaths and likely resulted from the introduction and adaptation of a novel avian-like virus. Influenza A virus hemagglutinins are important in host switching and virulence. Avian-adapted influenza virus hemagglutinins bind sialic acid receptors linked via α2-3 glycosidic bonds, while human-adapted hemagglutinins bind α2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with α2-6 or mixed α2-6/α2-3 binding. To characterize the role of the sialic acid binding specificity of the 1918 hemagglutinin, we evaluated in mice chimeric influenza viruses expressing wild-type and mutant hemagglutinin genes from avian and 1918 strains with differing receptor specificities. Viruses expressing 1918 hemagglutinin possessing either α2-6, α2-3, or α2-3/α2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing α2-3 to α2-6 binding specificity did not increase the lethality of an avian-adapted hemagglutinin. Thus, the 1918 hemagglutinin contains murine virulence determinants independent of receptor binding specificity.

scholarly journals Preparing intensive care for the next pandemic influenza

Critical Care ◽  
2019 ◽  
Vol 23 (1) ◽  
Author(s):  
Taylor Kain ◽  
Robert Fowler
Keyword(s):  
Resource Allocation ◽  
Influenza Virus ◽  
Intensive Care ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Large Scale ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Timely Initiation

Abstract Few viruses have shaped the course of human history more than influenza viruses. A century since the 1918–1919 Spanish influenza pandemic—the largest and deadliest influenza pandemic in recorded history—we have learned much about pandemic influenza and the origins of antigenic drift among influenza A viruses. Despite this knowledge, we remain largely underprepared for when the next major pandemic occurs. While emergency departments are likely to care for the first cases of pandemic influenza, intensive care units (ICUs) will certainly see the sickest and will likely have the most complex issues regarding resource allocation. Intensivists must therefore be prepared for the next pandemic influenza virus. Preparation requires multiple steps, including careful surveillance for new pandemics, a scalable response system to respond to surge capacity, vaccine production mechanisms, coordinated communication strategies, and stream-lined research plans for timely initiation during a pandemic. Conservative models of a large-scale influenza pandemic predict more than 170% utilization of ICU-level resources. When faced with pandemic influenza, ICUs must have a strategy for resource allocation as strain increases on the system. There are several current threats, including avian influenza A(H5N1) and A(H7N9) viruses. As humans continue to live in closer proximity to each other, travel more extensively, and interact with greater numbers of birds and livestock, the risk of emergence of the next pandemic influenza virus mounts. Now is the time to prepare and coordinate local, national, and global efforts.

scholarly journals A multiplex real-time PCR assay for detection of oseltamivir-resistant strains of influenza virus

2014 ◽  
Vol 9 (6) ◽  
pp. 628-633
Author(s):  
Dawid Nidzworski ◽  
Joanna Dobkowska ◽  
Marcin Hołysz ◽  
Beata Gromadzka ◽  
Bogusław Szewczyk
Keyword(s):  
Real Time ◽  
Influenza A Virus ◽  
Real Time Pcr ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Neuraminidase Inhibitor ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Influenza A Viruses ◽  
Oseltamivir Resistance

AbstractInfluenza is a contagious disease of humans and animals caused by viruses belonging to the Orthomyxoviridae family. The influenza A virus genome consists of negative sense, single-stranded, segmented RNA. Influenza viruses are classified into subtypes based on two surface antigens known as hemagglutinin (H) and neuraminidase (N). The main problem with influenza A viruses infecting humans is drug resistance, which is caused by antigenic changes. A few antiviral drugs are available, but the most popular is the neuraminidase inhibitor — oseltamivir. The resistance against this drug has probably developed through antigenic drift by a point mutation in one amino acid at position 275 (H275Y). In order to prevent a possible influenza pandemic it is necessary to develop fast diagnostic tests. The aim of this project was to develop a new test for detection of influenza A virus and determination of oseltamivir resistance/sensitivity in humans. Detection and differentiation of oseltamivir resistance/sensitivity of influenza A virus was based on real-time PCR. This test contains two TaqMan probes, which work at different wavelengths. Application of techniques like multiplex real-time PCR has greatly enhanced the capability for surveillance and characterization of influenza viruses. After its potential validation, this test can be used for diagnosis before treatment.

scholarly journals Oseltamivir susceptibility in south-western France during the 2007-8 and 2008-9 influenza epidemics and the ongoing influenza pandemic 2009

2009 ◽  
Vol 14 (38) ◽  
Author(s):  
S Burrel ◽  
L Roncin ◽  
M E Lafon ◽  
H Fleury
Keyword(s):  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Neuraminidase Inhibitors ◽  
Influenza A Viruses ◽  
Oseltamivir Resistance ◽  
The Past ◽  
Influenza A H1n1 ◽  
Recent Emergence

The recent emergence of seasonal influenza A(H1N1) strains resistant to oseltamivir makes it necessary to monitoring carefully the susceptibility of human influenza viruses to neuraminidase inhibitors. We report the prevalence of the oseltamivir resistance among influenza A viruses circulating in south-western France over the past three years: seasonal influenza A(H1N1), seasonal influenza A(H3N2), and the influenza A(H1N1)v viruses associated with the ongoing 2009 pandemic. The main result of the study is the absence of oseltamivir resistance in the pandemic H1N1 strains studied so far (n=129).

scholarly journals Structural insight into the mechanism of neuraminidase inhibitor-resistant mutations in human-infecting H10N8 Influenza A virus

2018 ◽  
Author(s):  
Babayemi O. Oladejo ◽  
Yuhai Bi ◽  
Christopher J. Vavricka ◽  
Chunrui Li ◽  
Yan Chai ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Drug Resistance ◽  
Influenza Virus ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Fatal Case ◽  
Influenza Virus Infection ◽  
Full Potential ◽  
Drug Resistant ◽  
Oseltamivir Resistance

AbstractThe emergence of drug resistance in avian influenza virus (AIV) is a serious concern for public health. Neuraminidase (NA) isolated from a fatal case of avian-origin H10N8 influenza virus infection was found to carry a drug-resistant mutation, NA-Arg292Lys (291 in N8 numbering). In order to understand the full potential of H10N8 drug resistance, the virus was first passaged in the presence of the most commonly used neuraminidase inhibitors (NAIs), oseltamivir and zanamivir. As expected, the Arg292Lys substitution was detected after oseltamivir treatment, however a novel Val116Asp substitution (114 in N8 numbering) was selected by zanamivir treatment. Next generation sequencing (NGS) confirmed that the mutations arose early (after passages 1-3) and became dominant in the presence of the NAI inhibitors. Extensive crystallographic studies revealed that N8-Arg292Lys resistance results mainly from loss of interactions with the inhibitor carboxylate, while rotation of Glu276 was not impaired as observed in the N9-Arg292Lys, a group 2 NA structure. In the case of Val116Asp, the binding mode between oseltamivir and zanamivir is different. Asp151 forms stabilized hydrogen bond to guanidine group of zanamivir, which may compensate the resistance caused by Val116Asp. By contrast, the amino group of oseltamivir is too short to maintain this hydrogen bond, which result in resistant. Moreover, the oseltamivir-zanamivir hybrid inhibitor MS-257 displays higher effectiveness to Val116Asp than oseltamivir, which support this notion.Author SummaryAside from vaccination, NAIs are currently the only alternative for the clinical treatment and prophylaxis of influenza. Understanding the mechanisms of resistance is critical to guide in drug development. In this study, two drug-resistant NA substitutions, Val116Asp and Arg292Lys, were discovered from oseltamivir and zanamivir treatment of H10N8 virus. Crystal structural analyses revealed two distinct mechanisms of these two resistant mutations and provide the explanation for the difference in susceptibility of different NAIs. Zanamivir and laninamivir were more effective against the resistant variants than oseltamivir, and Arg292Lys results in more serious oseltamivir resistance in N9 than N8 subtype. This study is well-correlated to influenza pandemic/epidemic pre-warning, as the discovery of inhibitor resistant viruses will help for new drug preparedness.

scholarly journals Key Molecular Factors in Hemagglutinin and PB2 Contribute to Efficient Transmission of the 2009 H1N1 Pandemic Influenza Virus

2012 ◽  
Vol 86 (18) ◽  
pp. 9666-9674 ◽  
Author(s):  
Ying Zhang ◽  
Qianyi Zhang ◽  
Yuwei Gao ◽  
Xijun He ◽  
Huihui Kong ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Guinea Pigs ◽  
Influenza Pandemic ◽  
Swine Influenza Virus ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
Human Virus ◽  
2009 H1n1 ◽  
Droplet Transmission

Animal influenza viruses pose a clear threat to public health. Transmissibility among humans is a prerequisite for a novel influenza virus to cause a human pandemic. A novel reassortant swine influenza virus acquired sustained human-to-human transmissibility and caused the 2009 influenza pandemic. However, the molecular aspects of influenza virus transmission remain poorly understood. Here, we show that an amino acid in hemagglutinin (HA) is important for the 2009 H1N1 influenza pandemic virus (2009/H1N1) to bind to human virus receptors and confer respiratory droplet transmissibility in mammals. We found that the change from glutamine (Q) to arginine (R) at position 226 of HA, which causes a switch in receptor-binding preference from human α-2,6 to avian α-2,3 sialic acid, resulted in a virus incapable of respiratory droplet transmission in guinea pigs and reduced the virus's ability to replicate in the lungs of ferrets. The change from alanine (A) to threonine (T) at position 271 of PB2 also abolished the virus's respiratory droplet transmission in guinea pigs, and this mutation, together with the HA Q226R mutation, abolished the virus's respiratory droplet transmission in ferrets. Furthermore, we found that amino acid 271A of PB2 plays a key role in virus acquisition of the mutation at position 226 of HA that confers human receptor recognition. Our results highlight the importance of both the PB2 and HA genes on the adaptation and transmission of influenza viruses in humans and provide important insights for monitoring and evaluating the pandemic potential of field influenza viruses.

SARS-CoV-2 and Influenza A virus Co-infections in Ferrets

2021 ◽  
Author(s):  
Ying Huang ◽  
Amanda L. Skarlupka ◽  
Hyesun Jang ◽  
Uriel Blas-Machado ◽  
Nathan Holladay ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Direct Contact ◽  
Human Population ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Severe Disease ◽  
Influenza Viruses ◽  
Single Infection ◽  
Influenza A Viruses ◽  
Severe Morbidity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal influenza viruses are co-circulating in the human population. However, only a few cases of viral co-infection with these two viruses have been documented in humans with some people having severe disease and others mild disease. In order to examine this phenomenon, ferrets were co-infected with SARS-CoV-2 and human seasonal influenza A viruses (IAVs) (H1N1 or H3N2) and were compared to animals that received each virus alone. Ferrets were either immunologically naïve to both viruses or vaccinated with the 2019-2020 split-inactivated influenza virus vaccine. Co-infected naive ferrets lost significantly more body weight than ferrets infected with each virus alone and induced more severe inflammation in both the nose and lungs than ferrets single-infected with each virus. Co-infected naïve animals had predominantly higher IAV titers than SARS-CoV-2 titers, and IAVs efficiently transmitted to the co-housed ferrets by direct contact. Comparatively, SARS-CoV-2 failed to transmit to the ferrets that co-housed with co-infected ferrets by direct contact. Moreover, vaccination significantly reduced IAVs virus titers and shortened the viral shedding, but did not completely block influenza virus direct contact transmission. Notably, vaccination significantly ameliorated the influenza associated disease by protecting vaccinated animals from severe morbidity after IAV single infection or IAV and SARS-CoV-2 co-infection, suggesting that seasonal influenza virus vaccination is pivotal to prevent severe disease induced by IAVs and SARS-CoV-2 co-infection during the COVID-19 pandemic. Importance Influenza A viruses cause severe morbidity and mortality during each influenza virus season. The emergence of SARS-CoV-2 infection in the human population offers the opportunity to potential co-infections of both viruses. The development of useful animal models to asses pathogenesis, transmission, and viral evolution of these viruses as the co-infect a host is of critical importance for the development of vaccines and therapeutics. The ability to prevent the most severe effects of viral co-infections can be studied using effect co-infection ferret models described in this report.

scholarly journals In vivo reassortment of influenza viruses.

2014 ◽  
Vol 61 (3) ◽  
Author(s):  
Kinga Urbaniak ◽  
Iwona Markowska-Daniel
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Genetic Material ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Individual Gene ◽  
Different Strains ◽  
The Individual

The genetic material of influenza A virus consists of eight negative-sense RNA segments. Under suitable conditions, the segmented structure of the viral genome allows an exchange of the individual gene segments between different strains, causing formation of new reassorted viruses. For reassortment to occur, co-infection with two or more influenza virus strains is necessary. The reassortment is an important evolutionary mechanism which can result in antigenic shifts that modify host range, pathology, and transmission of the influenza A viruses. In this process, the influenza virus strain with epidemic and/or pandemic potential can be created. Cases of this kind were in 1957 (Asian flu), 1968 (Hong Kong flu) and recently in 2009 (Mexico). Viruses containing genes of avian, swine, and/or human origin are widespread around the world, for example the triple reassortant H1N1 virus causing the 2009 influenza pandemic in 2009 that has become a seasonal virus. The aim of the study is to present the mechanism of reassortment and the results of experimental co-infection with different influenza viruses.

scholarly journals A Broad and Potent H1-Specific Human Monoclonal Antibody Produced in Plants Prevents Influenza Virus Infection and Transmission in Guinea Pigs

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 167 ◽  
Author(s):  
Jun-Gyu Park ◽  
Chengjin Ye ◽  
Michael S. Piepenbrink ◽  
Aitor Nogales ◽  
Haifeng Wang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Influenza Virus ◽  
Guinea Pigs ◽  
Influenza A ◽  
Human Monoclonal Antibody ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Antigenic Drift

Although seasonal influenza vaccines block most predominant influenza types and subtypes, humans still remain vulnerable to waves of seasonal and new potential pandemic influenza viruses for which no immunity may exist because of viral antigenic drift and/or shift. Previously, we described a human monoclonal antibody (hMAb), KPF1, which was produced in human embryonic kidney 293T cells (KPF1-HEK) with broad and potent neutralizing activity against H1N1 influenza A viruses (IAV) in vitro, and prophylactic and therapeutic activities in vivo. In this study, we produced hMAb KPF1 in tobacco plants (KPF1-Antx) and demonstrated how the plant-produced KPF1-Antx hMAb possesses similar biological activity compared with the mammalian-produced KPF1-HEK hMAb. KPF1-Antx hMAb showed broad binding to recombinant HA proteins and H1N1 IAV, including A/California/04/2009 (pH1N1) in vitro, which was comparable to that observed with KPF1-HEK hMAb. Importantly, prophylactic administration of KPF1-Antx hMAb to guinea pigs prevented pH1N1 infection and transmission in both prophylactic and therapeutic experiments, substantiating its clinical potential to prevent and treat H1N1 infections. Collectively, this study demonstrated, for the first time, a plant-produced influenza hMAb with in vitro and in vivo activity against influenza virus. Because of the many advantages of plant-produced hMAbs, such as rapid batch production, low cost, and the absence of mammalian cell products, they represent an alternative strategy for the production of immunotherapeutics for the treatment of influenza viral infections, including emerging seasonal and/or pandemic strains.

Sign in / Sign up

Export Citation Format

Share Document