Authors: Jaekeun Park, Sharon L Fong Legaspi, Louis M Schwartzman...

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

Review

Authors: Umarqayum AbuBakar, Lina Amrani, Farah Ayuni Kamarulzaman...

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

Authors: Xianfeng Hui, Lei Cao, Ting Xu...

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

Authors: Sunil K Lal

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

Review

Authors: Edward J Dubovi

Canine influenza, as a recognized clinical entity in dogs, has a relatively brief history. The presence of specific subtypes of influenza virus capable of being transmitted from dog to dog is at present geographically limited to the United States and Korea. As surveillance intensifies to meet the concerns of the human population on pandemic influenza viruses, more cases of influenza virus in dogs are certain to be detected. Each infection offers an opportunity for a unique variant to emerge and continue the evolution of influenza virus as a species-crossing pathogen.

Topics: Animals; Dog Diseases; Dogs; Humans; Influenza A virus; Orthomyxoviridae Infections; Prevalence; Species Specificity; Zoonoses

PubMed: 20933136
DOI: 10.1016/j.cvsm.2010.07.005

Meta-Analysis

Authors: Evelien A Germeraad, Pim Sanders, Thomas J Hagenaars...

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

Authors: Alessandra Silva Dias, Amy L Vincent Baker, Rodney B Baker...

Inactivated influenza A virus (IAV) vaccines help reduce clinical disease in suckling piglets, although endemic infections still exist. The objective of this study was to evaluate the detection of IAV in suckling and nursery piglets from IAV-vaccinated sows from farms with endemic IAV infections. Eight nasal swab collections were obtained from 135 two-week-old suckling piglets from four farms every other week from March to September 2013. Oral fluid samples were collected from the same group of nursery piglets. IAV RNA was detected in 1.64% and 31.01% of individual nasal swabs and oral fluids, respectively. H1N2 was detected most often, with sporadic detection of H1N1 and H3N2. Whole-genome sequences of IAV isolated from suckling piglets revealed an H1 hemagglutinin (HA) from the 1B.2.2.2 clade and N2 neuraminidase (NA) from the 2002A clade. The internal gene constellation of the endemic H1N2 was TTTTPT with a pandemic lineage matrix. The HA gene had 97.59% and 97.52% nucleotide and amino acid identities, respectively, to the H1 1B.2.2.2 used in the farm-specific vaccine. A similar H1 1B.2.2.2 was detected in the downstream nursery. These data demonstrate the low frequency of IAV detection in suckling piglets and downstream nurseries from farms with endemic infections in spite of using farm-specific IAV vaccines in sows.

Topics: Animals; Swine; Swine Diseases; Orthomyxoviridae Infections; Influenza A virus; Influenza Vaccines; Phylogeny; Farms; Animals, Suckling; Vaccination; Endemic Diseases; Influenza A Virus, H1N1 Subtype; RNA, Viral; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H1N2 Subtype; Genome, Viral

PubMed: 38675967
DOI: 10.3390/v16040626

Authors: Praveen M Varghese, Uday Kishore, Reena Rajkumari...

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

Review

Authors: Jessica K Fiege, Ryan A Langlois

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

Authors: Taeyong Kwon, Bianca L Artiaga, Chester D McDowell...

Proteolytic activation of the haemagglutinin (HA) glycoprotein by host cellular proteases is pivotal for influenza A virus (IAV) infectivity. Highly pathogenic avian influenza viruses possess the multibasic cleavage site of the HA which is cleaved by ubiquitous proteases, such as furin; in contrast, the monobasic HA motif is recognized and activated by trypsin-like proteases, such as the transmembrane serine protease 2 (TMPRSS2). Here, we aimed to determine the effects of TMPRSS2 on the replication of pandemic H1N1 and H3N2 subtype IAVs in the natural host, the pig. The use of the CRISPR/Cas 9 system led to the establishment of homozygous gene edited (GE) knockout (KO) pigs. Delayed IAV replication was demonstrated in primary respiratory cells of KO pigs . IAV infection resulted in a significant reduction of virus shedding in the upper respiratory tract, and lower virus titers and pathological lesions in the lower respiratory tract of KO pigs as compared to wild-type pigs. Our findings support the commercial use of GE pigs to mitigate influenza A virus infection in pigs, as an alternative approach to prevent zoonotic influenza A transmissions from pigs to humans.

Topics: Animals; Swine; Orthomyxoviridae Infections; Gene Editing; Serine Endopeptidases; Virus Replication; Influenza A Virus, H3N2 Subtype; CRISPR-Cas Systems; Swine Diseases; Influenza A Virus, H1N1 Subtype; Humans; Virus Shedding; Influenza A virus; Gene Knockout Techniques

PubMed: 39083026
DOI: 10.1080/22221751.2024.2387449