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

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

ABSTRACTInfluenza A viruses have regularly jumped to new hosts 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 deep sequence variation of a human H1N1 pandemic virus, a seasonal H3N2 virus, and a H3N2 canine influenza virus during experimental passage. We also compared replication and sequence variation in wild-type mice expressing N-glycolylneuraminic acid (Neu5Gc) with that 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 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.SIGNIFICANCEMice 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 the mutation dynamics depended on the virus examined. In addition, variation in the viral receptor, sialic acid, did not effect influenza evolution in this model. Overall this shows that mice provide a useful animal model for influenza, but that host passage evolution will vary depending on the virus being tested.

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 Origins and Evolutionary Dynamics of H3N2 Canine Influenza Virus

2015 ◽  
Vol 89 (10) ◽  
pp. 5406-5418 ◽  
Author(s):  
Henan Zhu ◽  
Joseph Hughes ◽  
Pablo R. Murcia
Keyword(s):  
Influenza Virus ◽  
North American ◽  
Influenza A ◽  
Influenza Viruses ◽  
Animal Origin ◽  
Influenza A Viruses ◽  
Canine Influenza Virus ◽  
Zoonotic Infections ◽  
Avian Origin ◽  
Canine Influenza

ABSTRACTInfluenza A viruses (IAVs) are maintained mainly in wild birds, and despite frequent spillover infections of avian IAVs into mammals, only a small number of viruses have become established in mammalian hosts. A new H3N2 canine influenza virus (CIV) of avian origin emerged in Asia in the mid-2000s and is now circulating in dog populations of China and South Korea, and possibly in Thailand. The emergence of CIV provides new opportunities for zoonotic infections and interspecies transmission. We examined 14,764 complete IAV genomes together with all CIV genomes publicly available since its first isolation until 2013. We show that CIV may have originated as early as 1999 as a result of segment reassortment among Eurasian and North American avian IAV lineages. We also identified amino acid changes that might have played a role in CIV emergence, some of which have not been previously identified in other cross-species jumps. CIV evolves at a lower rate than H3N2 human influenza viruses do, and viral phylogenies exhibit geographical structure compatible with high levels of local transmission. We detected multiple intrasubtypic and heterosubtypic reassortment events, including the acquisition of the NS segment of an H5N1 avian influenza virus that had previously been overlooked. In sum, our results provide insight into the adaptive changes required by avian viruses to establish themselves in mammals and also highlight the potential role of dogs to act as intermediate hosts in which viruses with zoonotic and/or pandemic potential could originate, particularly with an estimated dog population of ∼700 million.IMPORTANCEInfluenza A viruses circulate in humans and animals. This multihost ecology has important implications, as past pandemics were caused by IAVs carrying gene segments of both human and animal origin. Adaptive evolution is central to cross-species jumps, and this is why understanding the evolutionary processes that shape influenza A virus genomes is key to elucidating the mechanisms underpinning viral emergence. An avian-origin canine influenza virus (CIV) has recently emerged in dogs and is spreading in Asia. We reconstructed the evolutionary history of CIV and show that it originated from both Eurasian and North American avian lineages. We also identified the mutations that might have been responsible for the cross-species jump. Finally, we provide evidence of multiple reassortment events between CIV and other influenza viruses (including an H5N1 avian virus). This is a cause for concern, as there is a large global dog population to which humans are highly exposed.

scholarly journals Emergence and Characterization of a Novel Reassortant Canine Influenza Virus Isolated from Cats

Pathogens ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1320
Author(s):  
Jin Zhao ◽  
Wanting He ◽  
Meng Lu ◽  
Haijian He ◽  
Alexander Lai
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Reassortant Virus ◽  
Human Influenza Virus ◽  
Canine Influenza Virus ◽  
Stray Cats ◽  
Wide Range ◽  
Canine Influenza

Cats are susceptible to a wide range of influenza A viruses (IAV). Furthermore, cats can serve as an intermediate host, and transfer avian influenza virus (AIV) H7N2 to a veterinarian. In this report, a novel reassortant influenza virus, designated A/feline/Jiangsu/HWT/2017 (H3N2), and abbreviated as FIV-HWT-2017, was isolated from nasal swab of a symptomatic cat in Jiangsu province, China. Sequence analysis indicated that, whilst the other seven genes were most similar to the avian-origin canine influenza viruses (CIV H3N2) isolated in China, the NS gene was more closely related to the circulating human influenza virus (H3N2) in the region. Therefore, FIV-HWT-2017 is a reassortant virus. In addition, some mutations were identified, and they were similar to a distinctive CIV H3N2 clade. Whether these cats were infected with the reassortant virus was unknown, however, this random isolation of a reassortant virus indicated that domestic or stray cats were “mixing vessel” for IAV cannot be ruled out. An enhanced surveillance for novel influenza virus should include pet and stray cats.

scholarly journals In VitroSusceptibility of Canine Influenza A (H3N8) Virus to Nitazoxanide and Tizoxanide

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Laura V. Ashton ◽  
Robert L. Callan ◽  
Sangeeta Rao ◽  
Gabriele A. Landolt
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
The United States ◽  
Canine Influenza Virus ◽  
Valuable Adjunct ◽  
Canine Influenza ◽  
The Impact ◽  
H3n8 Virus

Infection of dogs with canine influenza virus (CIV) is considered widespread throughout the United States following the first isolation of CIV in 2004. While vaccination against influenza A infection is a common and important practice for disease control, antiviral therapy can serve as a valuable adjunct in controlling the impact of the disease. In this study, we examined the antiviral activity of nitazoxanide (NTZ) and tizoxanide (TIZ) against three CIV isolatesin vitro. NTZ and TIZ inhibited virus replication of all CIVs with 50% and 90% inhibitory concentrations ranging from 0.17 to 0.21 μMand from 0.60 to 0.76 μM, respectively. These results suggest that NTZ and TIZ are effective against CIV and may be useful for treatment of canine influenza in dogs but further investigation of thein vivoefficacy against CIV as well as the drug's potential for toxicity in dogs is needed.

scholarly journals Functional Comparison of Mx1 from Two Different Mouse Species Reveals the Involvement of Loop L4 in the Antiviral Activity against Influenza A Viruses

2015 ◽  
Vol 89 (21) ◽  
pp. 10879-10890 ◽  
Author(s):  
Judith Verhelst ◽  
Jan Spitaels ◽  
Cindy Nürnberger ◽  
Dorien De Vlieger ◽  
Tine Ysenbaert ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Influenza A Virus ◽  
Mus Musculus ◽  
Influenza A ◽  
Common Mechanism ◽  
Mus Spretus ◽  
Influenza A Viruses ◽  
Content Type ◽  
Mouse Species

ABSTRACTThe interferon-inducedMx1gene is an important part of the mammalian defense against influenza viruses.Mus musculusMx1 inhibits influenza A virus replication and transcription by suppressing the polymerase activity of viral ribonucleoproteins (vRNPs). Here, we compared the anti-influenza virus activity of Mx1 fromMus musculusA2G with that of its ortholog fromMus spretus. We found that the antiviral activity ofM. spretusMx1 was less potent than that ofM. musculusMx1. Comparison of theM. musculusMx1 sequence with theM. spretusMx1 sequence revealed 25 amino acid differences, over half of which were present in the GTPase domain and 2 of which were present in loop L4. However, thein vitroGTPase activity of Mx1 from the two mouse species was similar. Replacement of one of the residues in loop L4 inM. spretusMx1 by the corresponding residue of A2G Mx1 increased its antiviral activity. We also show that deletion of loop L4 prevented the binding of Mx1 to influenza A virus nucleoprotein and, hence, abolished the antiviral activity of mouse Mx1. These results indicate that loop L4 of mouse Mx1 is a determinant of antiviral activity. Our findings suggest that Mx proteins from different mammals use a common mechanism to inhibit influenza A viruses.IMPORTANCEMx proteins are evolutionarily conserved in vertebrates and inhibit a wide range of viruses. Still, the exact details of their antiviral mechanisms remain largely unknown. Functional comparison of theMxgenes from two species that diverged relatively recently in evolution can provide novel insights into these mechanisms. We show that bothMus musculusA2G Mx1 andMus spretusMx1 target the influenza virus nucleoprotein. We also found that loop L4 in mouse Mx1 is crucial for its antiviral activity, as was recently reported for primate MxA. This indicates that human and mouse Mx proteins, which have diverged by 75 million years of evolution, recognize and inhibit influenza A viruses by a common mechanism.

scholarly journals Genetic and serologic surveillance of canine (CIV) and equine (EIV) influenza virus in Nuevo León State, México

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8239
Author(s):  
Claudia B. Plata-Hipólito ◽  
Sibilina Cedillo-Rosales ◽  
Nelson Obregón-Macías ◽  
Carlos E. Hernández-Luna ◽  
Cristina Rodríguez-Padilla ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Companion Animals ◽  
Enzyme Linked Immunosorbent Assay ◽  
Nuevo Leon ◽  
Stray Dogs ◽  
Matrix Gene ◽  
Nuevo León ◽  
Canine Influenza

Background Despite the uncontrolled distribution of the Influenza A virus through wild birds, the detection of canine influenza virus and equine influenza virus in Mexico was absent until now. Recently, outbreaks of equine and canine influenza have been reported around the world; the virus spreads quickly among animals and there is potential for zoonotic transmission. Methods Amplification of the Influenza A virus matrix gene from necropsies, nasal and conjunctival swabs from trash service horses and pets/stray dogs was performed through RT-PCR. The seroprevalence was carried out through Sandwich enzyme-linked immunosorbent assay system using the M1 recombinant protein and polyclonal antibodies anti-M1. Results The matrix gene was amplified from 13 (19.11%) nasal swabs, two (2.94%) conjunctival swabs and five (7.35%) lung necropsies, giving a total of 20 (29.41%) positive samples in a pet dog population. A total of six (75%) positive samples of equine nasal swab were amplified. Sequence analysis showed 96–99% identity with sequences of Influenza A virus matrix gene present in H1N1, H1N2 and H3N2 subtypes. The phylogenetic analysis of the sequences revealed higher identity with matrix gene sequences detected from zoonotic isolates of subtype H1N1/2009. The detection of anti-M1 antibodies in stray dogs showed a prevalence of 123 (100%) of the sampled population, whereas in horses, 114 (92.68%) positivity was obtained. Conclusion The results unveil the prevalence of Influenza A virus in the population of horses and dogs in the state of Nuevo Leon, which could indicate a possible outbreak of equine and Canine Influenza in Mexico. We suggest that the prevalence of Influenza virus in companion animals be monitored to investigate its epizootic and zoonotic potential, in addition to encouraging the regulation of vaccination in these animal species in order to improve their quality of life.

scholarly journals Role of the PB2 627 Domain in Influenza A Virus Polymerase Function

2017 ◽  
Vol 91 (7) ◽  
Author(s):  
Benjamin E. Nilsson ◽  
Aartjan J. W. te Velthuis ◽  
Ervin Fodor
Keyword(s):  
Influenza Virus ◽  
Rna Polymerase ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza A Viruses ◽  
Viral Polymerase ◽  
Virus Rna ◽  
Rna Genome ◽  
Transcription And Replication

ABSTRACT The RNA genome of influenza A viruses is transcribed and replicated by the viral RNA-dependent RNA polymerase, composed of the subunits PA, PB1, and PB2. High-resolution structural data revealed that the polymerase assembles into a central polymerase core and several auxiliary highly flexible, protruding domains. The auxiliary PB2 cap-binding and the PA endonuclease domains are both involved in cap snatching, but the role of the auxiliary PB2 627 domain, implicated in host range restriction of influenza A viruses, is still poorly understood. In this study, we used structure-guided truncations of the PB2 subunit to show that a PB2 subunit lacking the 627 domain accumulates in the cell nucleus and assembles into a heterotrimeric polymerase with PB1 and PA. Furthermore, we showed that a recombinant viral polymerase lacking the PB2 627 domain is able to carry out cap snatching, cap-dependent transcription initiation, and cap-independent ApG dinucleotide extension in vitro, indicating that the PB2 627 domain of the influenza virus RNA polymerase is not involved in core catalytic functions of the polymerase. However, in a cellular context, the 627 domain is essential for both transcription and replication. In particular, we showed that the PB2 627 domain is essential for the accumulation of the cRNA replicative intermediate in infected cells. Together, these results further our understanding of the role of the PB2 627 domain in transcription and replication of the influenza virus RNA genome. IMPORTANCE Influenza A viruses are a major global health threat, not only causing disease in both humans and birds but also placing significant strains on economies worldwide. Avian influenza A virus polymerases typically do not function efficiently in mammalian hosts and require adaptive mutations to restore polymerase activity. These adaptations include mutations in the 627 domain of the PB2 subunit of the viral polymerase, but it still remains to be established how these mutations enable host adaptation on a molecular level. In this report, we characterize the role of the 627 domain in polymerase function and offer insights into the replication mechanism of influenza A viruses.

scholarly journals Temperature-Sensitive Live-Attenuated Canine Influenza Virus H3N8 Vaccine

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Aitor Nogales ◽  
Laura Rodriguez ◽  
Caroline Chauché ◽  
Kai Huang ◽  
Emma C. Reilly ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Respiratory Pathogen ◽  
Temperature Sensitive ◽  
Wild Type ◽  
Canine Influenza Virus ◽  
Canine Influenza ◽  
Better Than

ABSTRACT Canine influenza is a respiratory disease of dogs caused by canine influenza virus (CIV). CIV subtypes responsible for influenza in dogs include H3N8, which originated from the transfer of H3N8 equine influenza virus to dogs; and the H3N2 CIV, which is an avian-origin virus that adapted to infect dogs. Influenza infections are most effectively prevented through vaccination to reduce transmission and future infection. Currently, only inactivated influenza vaccines (IIVs) are available for the prevention of CIV in dogs. However, the efficacy of IIVs is suboptimal, and novel approaches are necessary for the prevention of disease caused by this canine respiratory pathogen. Using reverse genetics techniques, we have developed a live-attenuated CIV vaccine (LACIV) for the prevention of H3N8 CIV. The H3N8 LACIV replicates efficiently in canine cells at 33°C but is impaired at temperatures of 37 to 39°C and was attenuated compared to wild-type H3N8 CIV in vivo and ex vivo. The LACIV was able to induce protection against H3N8 CIV challenge with a single intranasal inoculation in mice. Immunogenicity and protection efficacy were better than that observed with a commercial CIV H3N8 IIV but provided limited cross-reactive immunity and heterologous protection against H3N2 CIV. These results demonstrate the feasibility of implementing a LAIV approach for the prevention and control of H3N8 CIV in dogs and suggest the need for a new LAIV for the control of H3N2 CIV. IMPORTANCE Two influenza A virus subtypes has been reported in dogs in the last 16 years: the canine influenza viruses (CIV) H3N8 and H3N2 of equine and avian origins, respectively. To date, only inactivated influenza vaccines (IIVs) are available to prevent CIV infections. Here, we report the generation of a recombinant, temperature-sensitive H3N8 CIV as a live-attenuated influenza vaccine (LAIV), which was attenuated in mice and dog tracheal, explants compared to CIV H3N8 wild type. A single dose of H3N8 LACIV showed immunogenicity and protection against a homologous challenge that was better than that conferred with an H3N8 IIV, demonstrating the feasibility of implementing a LAIV approach for the improved control of H3N8 CIV infections in dogs.

Long-term survival of influenza A viruses in aquatic invertebrate zoocultures

2021 ◽  
Vol 1 (3) ◽  
pp. 34-41
Author(s):  
S. L. Nesterchuk ◽  
◽  
V. A. Ostapenko ◽  
Keyword(s):  
Influenza Virus ◽  
Daphnia Magna ◽  
Influenza A Virus ◽  
Influenza A ◽  
The Body ◽  
Aquatic Invertebrate ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Term Survival ◽  
Chicken Embryos

In experiments to infect aquatic invertebrates in the zooculture, we used influenza A viruses, namely, to infect crustaceans Daphnia magna Straus, 1826 – human influenza virus, Hong Kong strain 1569/79 (H3N2), and to infect molluscs Anodonta cygnea Linné, 1758 – influenza virus A birds, Strain Rostok 1/34 (Hav1Neq1) – the so-called true bird plague virus. As a result of a series of experiments, found that influenza A viruses persist in the water for no more than 3 days, while in the gills and mantle of molluscs the virus is isolated on chicken embryos for at least another 35 days after contact with virus-containing water (a total of 70 individuals were studied). From the body Daphnia magna, to isolate the human influenza A virus on chicken embryos was possible within 14 days after infection through water (examined 6,800 individuals), by the method of immunofluorescence the influenza virus was determined in the intestines of crustaceans during the entire period of observation – 70 days from the time of infection. Influenza A viruses do not have a harmful effect on crustaceans or molluscs, infected animals also develop and reproduce, as well as individuals of control groups. Interesting is the fact that we have established the possibility of the loss of agglutination of red blood cells of chickens as a result of the reproduction of the human influenza A virus in the body of invertebrate Daphnia magna, which indicates a change in the viral protein hemagglutinin. The use of aquatic invertebrate zooculture can help in the study of the circulation of influenza A viruses in nature, as well as in the study of the variability of influenza A viruses.

scholarly journals MicroRNA-Based Attenuation of Influenza Virus across Susceptible Hosts

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Barbara M. Waring ◽  
Louisa E. Sjaastad ◽  
Jessica K. Fiege ◽  
Elizabeth J. Fay ◽  
Ismarc Reyes ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Mdck Cells ◽  
Vaccine Safety ◽  
Human Populations ◽  
Significant Morbidity ◽  
Influenza A Viruses ◽  
Live Attenuated Vaccines ◽  
Zoonotic Infections

ABSTRACTInfluenza A virus drives significant morbidity and mortality in humans and livestock. Annual circulation of the virus in livestock and waterfowl contributes to severe economic disruption and increases the risk of zoonotic transmission of novel strains into the human population, where there is no preexisting immunity. Seasonal vaccinations in humans help prevent infection and can reduce symptoms when infection does occur. However, current vaccination regimens available for livestock are limited in part due to safety concerns regarding reassortment/recombination with circulating strains. Therefore, inactivated vaccines are used instead of the more immunostimulatory live attenuated vaccines. MicroRNAs (miRNAs) have been used previously to generate attenuated influenza A viruses for use as a vaccine. Here, we systematically targeted individual influenza gene mRNAs using the same miRNA to determine the segment(s) that yields maximal attenuation potential. This analysis demonstrated that targeting of NP mRNA most efficiently ablates replication. We further increased the plasticity of miRNA-mediated attenuation of influenza A virus by exploiting a miRNA, miR-21, that is ubiquitously expressed across influenza-susceptible hosts. In order to construct this targeted virus, we used CRISPR/Cas9 to eliminate the universally expressed miR-21 from MDCK cells. miR-21-targeted viruses were attenuated in human, mouse, canine, and avian cells and drove protective immunity in mice. This strategy has the potential to enhance the safety of live attenuated vaccines in humans and zoonotic reservoirs.IMPORTANCEInfluenza A virus circulates annually in both avian and human populations, causing significant morbidity, mortality, and economic burden. High incidence of zoonotic infections greatly increases the potential for transmission to humans, where no preexisting immunity or vaccine exists. There is a critical need for new vaccine strategies to combat emerging influenza outbreaks. MicroRNAs were used previously to attenuate influenza A viruses. We propose the development of a novel platform to produce live attenuated vaccines that are highly customizable, efficacious across a broad species range, and exhibit enhanced safety over traditional vaccination methods. This strategy exploits a microRNA that is expressed abundantly in influenza virus-susceptible hosts. By eliminating this ubiquitous microRNA from a cell line, targeted viruses that are attenuated across susceptible strains can be generated. This approach greatly increases the plasticity of the microRNA targeting approach and enhances vaccine safety.

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