-
Science Translational Medicine Jul 2022Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics and from viruses adapted to a variety of animals including...
Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics and from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called "universal" influenza vaccines, do not currently exist but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole-virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is composed of four β-propiolactone-inactivated low-pathogenicity avian IAV subtypes of H1N9, H3N8, H5N1, and H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to control animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.
Topics: Animals; Antibodies, Viral; Ferrets; Horses; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N8 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N3 Subtype; Influenza A Virus, H7N9 Subtype; Influenza Vaccines; Mice; Orthomyxoviridae Infections; Swine
PubMed: 35857640
DOI: 10.1126/scitranslmed.abo2167 -
Viruses Mar 2023An influenza pandemic happens when a novel influenza A virus is able to infect and transmit efficiently to a new, distinct host species. Although the exact timing of... (Review)
Review
An influenza pandemic happens when a novel influenza A virus is able to infect and transmit efficiently to a new, distinct host species. Although the exact timing of pandemics is uncertain, it is known that both viral and host factors play a role in their emergence. Species-specific interactions between the virus and the host cell determine the virus tropism, including binding and entering cells, replicating the viral RNA genome within the host cell nucleus, assembling, maturing and releasing the virus to neighboring cells, tissues or organs before transmitting it between individuals. The influenza A virus has a vast and antigenically varied reservoir. In wild aquatic birds, the infection is typically asymptomatic. Avian influenza virus (AIV) can cross into new species, and occasionally it can acquire the ability to transmit from human to human. A pandemic might occur if a new influenza virus acquires enough adaptive mutations to maintain transmission between people. This review highlights the key determinants AIV must achieve to initiate a human pandemic and describes how AIV mutates to establish tropism and stable human adaptation. Understanding the tropism of AIV may be crucial in preventing virus transmission in humans and may help the design of vaccines, antivirals and therapeutic agents against the virus.
Topics: Animals; Humans; Influenza in Birds; Influenza A virus; Influenza, Human; Birds; Tropism
PubMed: 37112812
DOI: 10.3390/v15040833 -
Journal of Virology Aug 2022The M1 of influenza A virus (IAV) is important for the virus life cycle, especially for the assembly and budding of viruses, which is a multistep process that requires...
The M1 of influenza A virus (IAV) is important for the virus life cycle, especially for the assembly and budding of viruses, which is a multistep process that requires host factors. Identifying novel host proteins that interact with M1 and understanding their functions in IAV replication are of great interest in antiviral drug development. In this study, we identified 19 host proteins in DF1 cells suspected to interact with the M1 protein of an H5N6 virus through immunoprecipitation (IP)/mass spectrometry. Among them, PSMD12, a 26S proteasome regulatory subunit, was shown to interact with influenza M1, acting as a positive host factor in IAV replication in avian and human cells. The data showed that PSMD12 promoted K63-linked ubiquitination of M1 at the K102 site. H5N6 and PR8 with an M1-K102 site mutant displayed a significantly weaker replication ability than the wild-type viruses. Mechanistically, PSMD12 promoted M1-M2 virus-like particle (VLP) release, and an M1-K102 mutation disrupted the formation of supernatant M1-M2 VLPs. An H5N6 M1-K102 site mutation or knockdown PSMD12 disrupted the budding release of the virus in chicken embryo fibroblast (CEF) cells, which was confirmed by transmission electron microscopy. Further study confirmed that M1-K102 site mutation significantly affected the virulence of H5N6 and PR8 viruses in mice. In conclusion, we report the novel host factor PSMD12 which affects the replication of influenza virus by mediating K63-linked ubiquitination of M1 at K102. These findings provide novel insight into the interactions between IAV and host cells, while suggesting an important target for anti-influenza virus drug research. M1 is proposed to play multiple biologically important roles in the life cycle of IAV, which relies largely on host factors. This study is the first one to identify that PSMD12 interacts with M1, mediates K63-linked ubiquitination of M1 at the K102 site, and thus positively regulates influenza virus proliferation. PSMD12 promoted M1-M2 VLP egress, and an M1-K102 mutation affected the M1-M2 VLP formation. Furthermore, we demonstrate the importance of this site to the morphology and budding of influenza viruses by obtaining mutant viruses, and the M1 ubiquitination regulator PSMD12 has a similar function to the M1 K102 mutation in regulating virus release and virus morphology. Additionally, we confirm the reduced virulence of H5N6 and PR8 (H1N1) viruses carrying the M1-K102 site mutation in mice. These findings provide novel insights into IAV interactions with host cells and suggest a valid and highly conserved candidate target for antiviral drug development.
Topics: Animals; Antiviral Agents; Cell Line; Chick Embryo; Fibroblasts; Host-Pathogen Interactions; Humans; Influenza A Virus, H1N1 Subtype; Influenza A virus; Mice; Mutation; Proteasome Endopeptidase Complex; Ubiquitination; Viral Matrix Proteins; Virulence; Virus Replication
PubMed: 35861516
DOI: 10.1128/jvi.00786-22 -
Viruses Aug 2020We are in the midst of a pandemic where the infective agent has been identified, but how it causes mild disease in some and fatally severe disease in other infected...
We are in the midst of a pandemic where the infective agent has been identified, but how it causes mild disease in some and fatally severe disease in other infected individuals remains a mystery [...].
Topics: Animals; Host-Pathogen Interactions; Humans; Influenza A virus; Influenza, Human; Mutation; Orthomyxoviridae Infections
PubMed: 32784813
DOI: 10.3390/v12080870 -
Viruses Jan 2021Highly pathogenic avian influenza (HPAI) outbreaks in wild birds and poultry are no longer a rare phenomenon in Europe. In the past 15 years, HPAI outbreaks-in... (Review)
Review
Highly pathogenic avian influenza (HPAI) outbreaks in wild birds and poultry are no longer a rare phenomenon in Europe. In the past 15 years, HPAI outbreaks-in particular those caused by H5 viruses derived from the A/Goose/Guangdong/1/1996 lineage that emerged in southeast Asia in 1996-have been occuring with increasing frequency in Europe. Between 2005 and 2020, at least ten HPAI H5 incursions were identified in Europe resulting in mass mortalities among poultry and wild birds. Until 2009, the HPAI H5 virus outbreaks in Europe were caused by HPAI H5N1 clade 2.2 viruses, while from 2014 onwards HPAI H5 clade 2.3.4.4 viruses dominated outbreaks, with abundant genetic reassortments yielding subtypes H5N1, H5N2, H5N3, H5N4, H5N5, H5N6 and H5N8. The majority of HPAI H5 virus detections in wild and domestic birds within Europe coincide with southwest/westward fall migration and large local waterbird aggregations during wintering. In this review we provide an overview of HPAI H5 virus epidemiology, ecology and evolution at the interface between poultry and wild birds based on 15 years of avian influenza virus surveillance in Europe, and assess future directions for HPAI virus research and surveillance, including the integration of whole genome sequencing, host identification and avian ecology into risk-based surveillance and analyses.
Topics: Animal Migration; Animals; Animals, Wild; Birds; Europe; Influenza A virus; Influenza in Birds
PubMed: 33573231
DOI: 10.3390/v13020212 -
International Journal of Molecular... Mar 2022The Influenza A virus (IAV) is a severe respiratory pathogen. C1q is the first subcomponent of the complement system's classical pathway. C1q is composed of 18...
The Influenza A virus (IAV) is a severe respiratory pathogen. C1q is the first subcomponent of the complement system's classical pathway. C1q is composed of 18 polypeptide chains. Each of these chains contains a collagen-like region located at the N terminus, and a C-terminal globular head region organized as a heterotrimeric structure (ghA, ghB and ghC). This study was aimed at investigating the complement activation-independent modulation by C1q and its individual recombinant globular heads against IAV infection. The interaction of C1q and its recombinant globular heads with IAV and its purified glycoproteins was examined using direct ELISA and far-Western blotting analysis. The effect of the complement proteins on IAV replication kinetics and immune modulation was assessed by qPCR. The IAV entry inhibitory properties of C1q and its recombinant globular heads were confirmed using cell binding and luciferase reporter assays. C1q bound IAV virions via HA, NA and M1 IAV proteins, and suppressed replication in H1N1, while promoting replication in H3N2-infected A549 cells. C1q treatment further triggered an anti-inflammatory response in H1N1 and pro-inflammatory response in H3N2-infected cells as evident from differential expression of TNF-α, NF-κB, IFN-α, IFN-β, IL-6, IL-12 and RANTES. Furthermore, C1q treatment was found to reduce luciferase reporter activity of MDCK cells transfected with H1N1 pseudotyped lentiviral particles, indicative of an entry inhibitory role of C1q against infectivity of IAV. These data appear to demonstrate the complement-independent subtype specific modulation of IAV infection by locally produced C1q.
Topics: Complement C1q; Complement System Proteins; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza, Human
PubMed: 35328462
DOI: 10.3390/ijms23063045 -
Journal of Virology Jun 2015Influenza A viruses display a broad cellular tropism within the respiratory tracts of mammalian hosts. Uncovering the relationship between tropism and virus immunity,... (Review)
Review
Influenza A viruses display a broad cellular tropism within the respiratory tracts of mammalian hosts. Uncovering the relationship between tropism and virus immunity, pathogenesis, and transmission will be critical for the development of therapeutic interventions. Here we discuss recent developments of several recombinant strains of influenza A virus. These viruses have inserted reporters to track tropism, microRNA target sites to restrict tropism, or barcodes to assess transmission dynamics, expanding our understanding of pathogen-host interactions.
Topics: Animals; Genes, Reporter; Host-Pathogen Interactions; Humans; Influenza A virus; Molecular Biology; Viral Tropism; Virology
PubMed: 25855737
DOI: 10.1128/JVI.00462-15 -
Viruses Jun 2020The world's first natural avian-origin H6N1 influenza A virus infection case in dogs was confirmed in Taiwan in 2014. The H6N1 virus in chickens has been endemic in...
The world's first natural avian-origin H6N1 influenza A virus infection case in dogs was confirmed in Taiwan in 2014. The H6N1 virus in chickens has been endemic in Taiwan since 1972. Whether the dog H6N1 virus has interspecies transmission potential is the key issue we aim to understand. Following one virus passage in embryonated eggs and two further passages in MDCK cells, we obtained two virus derivatives, E01EE (PB1 739E and PB2 627E) and E01GK (PB1 739G and PB2 627K), respectively. The pathogenicity of E01EE and E01GK was investigated using plaque assay, growth dynamic analysis and cell viability quantification in cells from different animal species. The impact of amino acid mutation on PB1 739 and PB2 627 on viral ribonucleoprotein (RNP) activity was also analyzed. Further mouse infection experiments were performed. The results showed that both E01EE and E01GK decreased cell relative viability of canine MDCK cells, human A549 cells and chicken DF1 cells. E01Gk caused greater cellular harm in MDCK and A549 cells and had significantly higher virus titers in all of the cells compared to E01EE. The PB2 627K but not PB1 739G was the critical mutation that influenced the viral RNP activity. Both E01EE and E01GK caused mice pneumonia and considerable virus shedding, especially E01GK. This report verifies PB2 E627K mutation in virulence and spotlights the potential for the dog H6N1 virus to extend interspecies transmission.
Topics: Animals; Cell Culture Techniques; Dog Diseases; Dogs; Humans; Influenza A virus; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred BALB C; Mutation; Orthomyxoviridae Infections; Taiwan; Virus Replication
PubMed: 32629810
DOI: 10.3390/v12070704 -
Viruses Sep 2019Understanding virus shedding patterns of avian influenza virus (AIV) in poultry is important for understanding host-pathogen interactions and developing effective... (Meta-Analysis)
Meta-Analysis
Understanding virus shedding patterns of avian influenza virus (AIV) in poultry is important for understanding host-pathogen interactions and developing effective control strategies. Many AIV strains were studied in challenge experiments in poultry, but no study has combined data from those studies to identify general AIV shedding patterns. These systematic review and meta-analysis were performed to summarize qualitative and quantitative information on virus shedding levels and duration for different AIV strains in experimentally infected poultry species. Methods were designed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four electronic databases were used to collect literature. A total of 1155 abstract were screened, with 117 studies selected for the qualitative analysis and 71 studies for the meta-analysis. A large heterogeneity in experimental methods was observed and the quantitative analysis showed that experimental variables such as species, virus origin, age, inoculation route and dose, affect virus shedding (mean, peak and duration) for highly pathogenic AIV (HPAIV), low pathogenic AIV (LPAIV) or both. In conclusion, this study highlights the need to standardize experimental procedures, it provides a comprehensive summary of the shedding patterns of AIV strains by infected poultry and identifies the variables that influence the level and duration of AIV shedding.
Topics: Animals; Host-Pathogen Interactions; Influenza A virus; Influenza in Birds; Poultry; Poultry Diseases; Virus Shedding
PubMed: 31480744
DOI: 10.3390/v11090812 -
Viruses Oct 2016Viruses are obligatory cellular parasites. Their mission is to enter a host cell, to transfer the viral genome, and to replicate progeny whilst diverting cellular... (Review)
Review
Viruses are obligatory cellular parasites. Their mission is to enter a host cell, to transfer the viral genome, and to replicate progeny whilst diverting cellular immunity. The role of ubiquitin is to regulate fundamental cellular processes such as endocytosis, protein degradation, and immune signaling. Many viruses including influenza A virus (IAV) usurp ubiquitination and ubiquitin-like modifications to establish infection. In this focused review, we discuss how ubiquitin and unanchored ubiquitin regulate IAV host cell entry, and how histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase with ubiquitin-binding activity, mediates IAV capsid uncoating. We also discuss the roles of ubiquitin in innate immunity and its implications in the IAV life cycle.
Topics: Animals; Histone Deacetylases; Host-Pathogen Interactions; Humans; Immunity, Innate; Influenza A virus; Ubiquitin; Virus Internalization; Virus Uncoating
PubMed: 27783058
DOI: 10.3390/v8100293