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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 -
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 -
Proceedings of the National Academy of... Jun 2018Novel reassortant avian influenza H7N9 virus and pandemic 2009 H1N1 (H1N1pdm) virus cause human infections, while avian H7N2 and swine H1N1 virus mainly infect birds and...
Novel reassortant avian influenza H7N9 virus and pandemic 2009 H1N1 (H1N1pdm) virus cause human infections, while avian H7N2 and swine H1N1 virus mainly infect birds and pigs, respectively. There is no robust in vitro model for assessing the infectivity of emerging viruses in humans. Based on a recently established method, we generated long-term expanding 3D human airway organoids which accommodate four types of airway epithelial cells: ciliated, goblet, club, and basal cells. We report differentiation conditions which increase ciliated cell numbers to a nearly physiological level with synchronously beating cilia readily discernible in every organoid. In addition, the differentiation conditions induce elevated levels of serine proteases, which are essential for productive infection of human influenza viruses and low-pathogenic avian influenza viruses. We also established improved 2D monolayer culture conditions for the differentiated airway organoids. To demonstrate the ability of differentiated airway organoids to identify human-infective virus, 3D and 2D differentiated airway organoids are applied to evaluate two pairs of viruses with known distinct infectivity in humans, H7N9/Ah versus H7N2 and H1N1pdm versus an H1N1 strain isolated from swine (H1N1sw). The human-infective H7N9/Ah virus replicated more robustly than the poorly human-infective H7N2 virus; the highly human-infective H1N1pdm virus replicated to a higher titer than the counterpart H1N1sw. Collectively, we developed differentiated human airway organoids which can morphologically and functionally simulate human airway epithelium. These differentiated airway organoids can be applied for rapid assessment of the infectivity of emerging respiratory viruses to human.
Topics: Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H7N2 Subtype; Influenza, Human; Organoids; Respiratory System
PubMed: 29891677
DOI: 10.1073/pnas.1806308115 -
Viruses Mar 2022In recent years, advances in diagnostics and deep sequencing technologies have led to the identification and characterization of novel viruses in cats as protoparviruses... (Review)
Review
In recent years, advances in diagnostics and deep sequencing technologies have led to the identification and characterization of novel viruses in cats as protoparviruses and chaphamaparvoviruses, unveiling the diversity of the feline virome in the respiratory tract. Observational, epidemiological and experimental data are necessary to demonstrate firmly if some viruses are able to cause disease, as this information may be confounded by virus- or host-related factors. Also, in recent years, researchers were able to monitor multiple examples of transmission to felids of viruses with high pathogenic potential, such as the influenza virus strains H5N1, H1N1, H7N2, H5N6 and H3N2, and in the late 2019, the human hypervirulent coronavirus SARS-CoV-2. These findings suggest that the study of viral infections always requires a multi-disciplinary approach inspired by the One Health vision. By reviewing the literature, we provide herewith an update on the emerging viruses identified in cats and their potential association with respiratory disease.
Topics: Animals; COVID-19; Cats; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N2 Subtype; Influenza, Human; Orthomyxoviridae Infections; SARS-CoV-2
PubMed: 35458393
DOI: 10.3390/v14040663 -
Frontiers in Immunology 2021Neuraminidase of influenza A and B viruses plays a critical role in the virus life cycle and is an important target of the host immune system. Here, we highlight the... (Review)
Review
Neuraminidase of influenza A and B viruses plays a critical role in the virus life cycle and is an important target of the host immune system. Here, we highlight the current understanding of influenza neuraminidase structure, function, antigenicity, immunogenicity, and immune protective potential. Neuraminidase inhibiting antibodies have been recognized as correlates of protection against disease caused by natural or experimental influenza A virus infection in humans. In the past years, we have witnessed an increasing interest in the use of influenza neuraminidase to improve the protective potential of currently used influenza vaccines. A number of well-characterized influenza neuraminidase-specific monoclonal antibodies have been described recently, most of which can protect in experimental challenge models by inhibiting the neuraminidase activity or by Fc receptor-dependent mechanisms. The relative instability of the neuraminidase poses a challenge for protein-based antigen design. We critically review the different solutions that have been proposed to solve this problem, ranging from the inclusion of stabilizing heterologous tetramerizing zippers to the introduction of inter-protomer stabilizing mutations. Computationally engineered neuraminidase antigens have been generated that offer broad, within subtype protection in animal challenge models. We also provide an overview of modern vaccine technology platforms that are compatible with the induction of robust neuraminidase-specific immune responses. In the near future, we will likely see the implementation of influenza vaccines that confront the influenza virus with a double punch: targeting both the hemagglutinin and the neuraminidase.
Topics: Antibodies, Viral; Antigenic Drift and Shift; Antigens, Viral; Catalytic Domain; Cross Protection; Evolution, Molecular; Humans; Immunogenicity, Vaccine; Influenza Vaccines; Influenza, Human; Alphainfluenzavirus; Betainfluenzavirus; Mutation; Nanoparticles; Neuraminidase; Vaccines, Synthetic; Viral Proteins
PubMed: 34868073
DOI: 10.3389/fimmu.2021.786617 -
Frontiers in Cellular and Infection... 2023Lung infections in Influenza-Like Illness (ILI) are triggered by a variety of respiratory viruses. All human pandemics have been caused by the members of two major virus... (Review)
Review
Lung infections in Influenza-Like Illness (ILI) are triggered by a variety of respiratory viruses. All human pandemics have been caused by the members of two major virus families, namely (influenza A viruses (IAVs); subtypes H1N1, H2N2, and H3N2) and (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2). These viruses acquired some adaptive changes in a known intermediate host including domestic birds (IAVs) or unknown intermediate host (SARS-CoV-2) following transmission from their natural reservoirs (e.g. migratory birds or bats, respectively). Verily, these acquired adaptive substitutions facilitated crossing species barriers by these viruses to infect humans in a phenomenon that is known as zoonosis. Besides, these adaptive substitutions aided the variant strain to transmit horizontally to other contact non-human animal species including pets and wild animals (zooanthroponosis). Herein we discuss the main zoonotic and reverse-zoonosis events that occurred during the last two pandemics of influenza A/H1N1 and SARS-CoV-2. We also highlight the impact of interspecies transmission of these pandemic viruses on virus evolution and possible prophylactic and therapeutic interventions. Based on information available and presented in this review article, it is important to close monitoring viral zoonosis and viral reverse zoonosis of pandemic strains within a One-Health and One-World approach to mitigate their unforeseen risks, such as virus evolution and resistance to limited prophylactic and therapeutic interventions.
Topics: Animals; Humans; Influenza, Human; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Zoonoses; Animals, Wild; Chiroptera; Influenza A virus; SARS-CoV-2
PubMed: 38249300
DOI: 10.3389/fcimb.2023.1232772 -
Vaccine Sep 2008Influenza A viruses exist within their natural host, aquatic birds, in a number of antigenic subtypes. Only a few of these subtypes have successfully crossed into other... (Review)
Review
Influenza A viruses exist within their natural host, aquatic birds, in a number of antigenic subtypes. Only a few of these subtypes have successfully crossed into other avian and mammalian hosts. This brief review will focus on just three examples of viruses that have successfully passed between species; avian H5NI1 and H9N2 viruses and H3N2 viruses which have transmitted from aquatic birds to humans and then to swine. Although there are a number of other subtypes that have also transmitted successfully between species, these three selected examples have spread and evolved in different ways, exemplifying the complexity of influenza A virus epidemiology.
Topics: Animals; Birds; Humans; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H9N2 Subtype; Influenza in Birds; Influenza, Human; Orthomyxoviridae Infections; Swine
PubMed: 19230163
DOI: 10.1016/j.vaccine.2008.07.064 -
Nature Reviews. Microbiology Dec 2021The SARS-CoV-2 pandemic has seen a notable global reduction in influenza cases of both influenza A and B viruses. In particular, the B/Yamagata lineage has not been... (Review)
Review
The SARS-CoV-2 pandemic has seen a notable global reduction in influenza cases of both influenza A and B viruses. In particular, the B/Yamagata lineage has not been isolated from April 2020 to August 2021, suggesting that this influenza lineage may have become extinct, which may provide opportunities for improving availability and effectiveness of influenza vaccines.
Topics: COVID-19; Evolution, Molecular; Extinction, Biological; Global Health; Humans; Influenza, Human; Alphainfluenzavirus; Betainfluenzavirus; SARS-CoV-2
PubMed: 34584246
DOI: 10.1038/s41579-021-00642-4 -
BMC Psychiatry Feb 2021Prior to the COVID-19 pandemic, physicians experienced unprecedented levels of burnout. The uncertainty of the ongoing COVID-19 pandemic along with increased workload... (Review)
Review
BACKGROUND
Prior to the COVID-19 pandemic, physicians experienced unprecedented levels of burnout. The uncertainty of the ongoing COVID-19 pandemic along with increased workload and difficult medical triage decisions may lead to a further decline in physician psychological health.
METHODS
We searched Medline, EMBASE, and PsycINFO for primary research from database inception (Medline [1946], EMBASE [1974], PsycINFO [1806]) to November 17, 2020. Titles and abstracts were screened by one of three reviewers and full-text article screening and data abstraction were conducted independently, and in duplicate, by three reviewers.
RESULTS
From 6223 unique citations, 480 articles were reviewed in full-text, with 193 studies (of 90,499 physicians) included in the final review. Studies reported on physician psychological symptoms and management during seven infectious disease outbreaks (severe acute respiratory syndrome [SARS], three strains of Influenza A virus [H1N1, H5N1, H7N9], Ebola, Middle East respiratory syndrome [MERS], and COVID-19) in 57 countries. Psychological symptoms of anxiety (14.3-92.3%), stress (11.9-93.7%), depression (17-80.5%), post-traumatic stress disorder (13.2-75.2%) and burnout (14.7-76%) were commonly reported among physicians, regardless of infectious disease outbreak or country. Younger, female (vs. male), single (vs. married), early career physicians, and those providing direct care to infected patients were associated with worse psychological symptoms.
INTERPRETATION
Physicians should be aware that psychological symptoms of anxiety, depression, fear and distress are common, manifest differently and self-management strategies to improve psychological well-being exist. Health systems should implement short and long-term psychological supports for physicians caring for patients with COVID-19.
Topics: COVID-19; Depression; Disease Outbreaks; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Male; Pandemics; Physicians; SARS-CoV-2; Stress, Psychological
PubMed: 33568141
DOI: 10.1186/s12888-021-03090-9 -
Cold Spring Harbor Perspectives in... Nov 2020Generally comprised of less than a dozen components, RNA viruses can be viewed as well-designed genetic circuits optimized to replicate and spread within a given host.... (Review)
Review
Generally comprised of less than a dozen components, RNA viruses can be viewed as well-designed genetic circuits optimized to replicate and spread within a given host. Understanding the molecular design that enables this activity not only allows one to disrupt these circuits to study their biology, but it provides a reprogramming framework to achieve novel outputs. Recent advances have enabled a "learning by building" approach to better understand virus biology and create valuable tools. Below is a summary of how modifying the preexisting genetic framework of influenza A virus has been used to track viral movement, understand virus replication, and identify host factors that engage this viral circuitry.
Topics: Humans; Influenza A virus; Synthetic Biology; Virology; Virus Replication
PubMed: 31871242
DOI: 10.1101/cshperspect.a038703