Influenza and sarscoronavirus activating proteases. By employing pseudovirusbased entry inhibition assays including h5n1 influenza a virus iav, and vsvg, the mechanism study indicated that the antiviral activity may be associated with the. Influenza a viruses can be broken down into subtypes depending on the genes that make up the surface proteins. Influenza virus genome sequencing and genetic characterization. Influenza, commonly known as the flu, is an infectious disease caused by an influenza virus. Viruses generally have one of two mechanisms for entry and uncoating. Some viruses, such as adenoassociated virus serotype 2 aav2, sfv and influenza can cross the endosomal membranes very rapidly within seconds, and the efficiency of entry can be as much, or. Virus entry is best understood in the case of viruses with a lipid envelope see first section of text, which introduce their genome into the cell by a fusion event between the viral and the cellular membrane. Distinguishing the novel coronavirus from influenza. The section will also welcome the case reports of influenza outbreaks in both. Influenza viruses can persist on nonporous surfaces for 24 hours or more, but quantities of the virus sufficient for human infection are likely to persist for shorter periods. This curriculum explains how influenza viruses infect cells and replicate.
Influenza a viruses attach to sialic acids on host cells. The goal of a virus particle is to transport its genome in a replicationcompetent form from an infected cell to an uninfected cell. Immunology and vaccinepreventable diseases pink book. Antiflu traditional chinese medicine tcm has played a significant role in fighting the virus pandemic. Influenza virus methods and protocols yohei yamauchi. Following binding to cell surface sialic acid, entry of influenza viruses into cells is mediated by endocytosis. The segmentation of the influenza genome makes these.
To enter a new host cell, the majority of viruses take advantage of the endocytic mechanisms of the cell and wait until reaching endocytic vacuoles or other cytoplasmic compartments before penetrating into the cytosol. D virus isolation and passage in embryonated chicken eggs 39. The structures of three conformations of the ectodomain of the 1968 hong kong influenza virus ha have been determined by xray crystallography. Dec 28, 2004 a widely held view of influenza virus infection is that the viral receptor consists of cell surface carbohydrate sialic acid, which can be present as glycoprotein or glycolipid.
Mar 27, 2017 influenza a virus iav membrane proteins hemagglutinin ha and neuraminidase na are determinants of virus infectivity, transmissibility, pathogenicity, host specificity, and major antigenicity. The who estimates that annual epidemics of influenza result in 1 billion infections, 3. This multivalent attachment by multiple copies of trimetric ha triggers endocytosis of influenza virus that is contained in the endosome. Evidence suggests that dandelion is associated with a. For virus to successfully transmit through the air, it must be exhaled from an infected donor in sufficient quantities and retain infectiousness in the air. Structure of ha the human influenza virus aaichi268 is the prototype of the h3 antigenic subtype viruses responsible for the pandemic of. Each of our cells contains antiviral factors that work to inhibit infection. Acquisition of new influenza viruses is more likely when different species are kept in close proximity. Influenza is a different disease, caused by a different virus. Ifitm3 inhibits influenza a virus infection by preventing. It was discovered nearly 70 years ago that upon addition of influenza virus to chicken erythrocytes, the cells would agglutinate at 4c. Release of virus from the endosome and import of the viral ribonucleoproteins into the host cell nucleus are also outlined.
A nanomolar multivalent ligand as entry inhibitor of the. Influenza in birds is often referred to as avian influenza, in pigs as swine influenza, in horses as equine influenza and so on. Attachment first step surface protein on virus attaches to specific receptors on cell surfacemay be specialized proteins with limited tissue distribution or more widely distributedvirus specific receptor is necessary but not sufficient for viruses to infect cells and complete replicative cycle. Antiinfluenza virus effect of aqueous extracts from dandelion. Receptor binding and membrane fusion in virus entry. The function of ha during virus entry has been extensively investigated, however, examination of na has long. Ha binds sa through its receptorbinding sites, while na is a receptordestroying enzyme by removing sas. Cdc responds to approval of new flu antiviral drug cdc. Influenza a virus iav infection is mediated by attachment of the viral hemagglutinin to sialic acid on the host cell surface. Competitive cooperation of hemagglutinin and neuraminidase. Viruses free fulltext microtubules in influenza virus. Subtypes are named by combining the h and n numbers e.
The evolution and epidemiology of influenza a virus iav infections in swine have been integrally tied to the segmented nature of the genome of the virus, which facilitates gene reassortment, and to the adaptability of these genes through mutation, which sometimes facilitates replication in a new host. Since the screen was performed using three pseudo viruses in a comparative way, we were able to identify putative influenza virus specific entry inhibitors which show inhibition against the entry of iav but not marburg virus or lassa virus. Sa has long been believed to be the sole receptor for the influenza virus. These genes contain instructions for making new viruses, and its these instructions that an influenza virus uses once it infects a human cell to trick the cell into producing more influenza viruses, thereby spreading infection. Although a focus has been on viral protein function during entry, recent studies have revealed exciting information on cellular factors required for influenza virus entry. The hemagglutinin ha and neuraminidase na of influenza a virus possess antagonistic activities on interaction with sialic acid sa, which is the receptor for virus attachment.
Influenza viruses, together with thogotolike viruses, form the family orthomyxoviridae. Therefore, influenza virus has a substantial impact on health and the global economy. It is necessary to understand the detailed and complex interactions between influenza virus and its host cells in order to identify successful strategies for therapeutic intervention. Utilizing this method with total rna extracted from the allantoic fluid of influenza rapuerto rico81934 h1n1 virus infected chicken eggs eid50 6. Influenza pneumonia incidence was high in 2005, a year when influenza ah3n2 subtype virus strains predominated, low in 2006 when ah1n1 viruses were more common, moderate in 2007 when h3n2 and. Exposure to influenza virus aerosols during routine patient. Manual for the laboratory diagnosis and virological. To initiate infection, the virus first binds to cellularreceptors comprising either 2,3 or 2,6 linked sialic acid. Mechanisms of cell entry by influenza virus volume 3 issue 21 karen j. The endosometrapped virus traffics via a unidirectional pathway to near the nucleus.
Influenza a virus causes influenza in birds and some mammals, and is the only species of the genus alphainfluenzavirus of the virus family orthomyxoviridae. However, it is at present largely unclear to what extent these proteases are expressed in viral target cells in human tissues. The efficacy of barrier precautions to prevent influenza transmission is unknown. Strains of all subtypes of influenza a virus have been isolated from wild birds, although disease is uncommon. Despite the variation among viruses, there are several shared generalities concerning viral entry.
Author summary influenza epidemics exact a great toll on world health. In 1936, burnet discovered that influenza virus could. Emerging antiviral strategies to interfere with influenza. Pdf new influenza a virus entry inhibitors derived from. Interim guidance for cleaning international port of entry. Target membrane cholesterol modulates single influenza.
Pdf competition between influenza a virus genome segments. Hemagglutinin ha is the receptorbinding and membrane fusion glycoprotein of influenza virus and the target for infectivityneutralizing antibodies. Pa to constitute the biological active replicationtranscription units of influenza virus. Compans, georg herrler, in mucosal immunology third edition, 2005. A the cells were infected with influenza apuerto rico834, and the virus infected cells were then treated with quercetin in 02 h, 25 h, 58 h, 810 h and 010 h time intervals respectively. Influenza virus entry and infection require host cell n. Since viruses are simple in structurecomposition and lack any locomotive capacity, viruses depend on cellular trafficking mechanisms. Influenza pneumonia incidence was high in 2005, a year when influenza ah3n2 subtype virus strains predominated, low in 2006 when ah1n1 viruses were more common, moderate in. There are 18 different ha subtypes and 11 different na subtypes. Satoh 1 prabha nepal 1 sayaka kashiwagi 1 jing wang. Quercetin performed the inhibitory activity in the initial stage of influenza virus infection. Gal inhibited the infection of cells by influenza virus.
In tcm, dandelion is a commonly used ingredient in many therapeutic remedies, either alone or in conjunction with other natural substances. It also has students explore where influenza viruses come from, how viruses change, and why some become deadly. Defining dispersal of influenza virus via aerosol is essential for the development of prevention measures. Viral hemagglutinin is a homotrimeric receptor, and thus, tri or. Based on receptorbinding analysis and structural studies, song et al. Mechanisms of cell entry by influenza virus cambridge core.
Dec 14, 2011 human influenza is a seasonal disease associated with significant morbidity and mortality. This broad tropism makes highly pathogenic influenza a strains, such as h5n1, potentially dangerous to humans if they gain the ability to jump from an animal reservoir to humans. We here focus on emerging options to interfere with the influenza virus entry process, which consists of the following steps. For all influenza viruses, after virus entry into the host cell, incoming vrnps are transported toward the nucleus, where they are transcribed into viral mrnas and replicated into new vrnas by the viral polymerase with the support of the host rna polymerase ii and transcriptosome machinery 5 7. As with all viruses, influenza virus needs to penetrate target cells to cause infection. Entry of influenza viruses into cells is inhibited by a. Many viruses infect their host cells through endocytosis. During the 20102011 influenza season, subjects with influenzalike illness were enrolled in an emergency department and throughout a tertiary care hospital, nasopharyngeal swab specimens were obtained, and symptom severity, treatment, and medical history. Here, we seek to better understand how one of these antiviral.
This uncommon rna virus trait provides influenza with the advantage of access to. Influenza virus is a major human pathogen that causes annual epidemics and occasional pandemics. Influenza a virus hemagglutinin and neuraminidase act as. In the united states, the virus is responsible for 20,000 deaths annually, with the frequent emergence of new and potentially deadly strains of the virus. Virus entry is the process during which viruses gain access to viral replication sites within uninfected cells, a multistep course of events that starts with binding to target cells. A widely held view of influenza virus infection is that the viral receptor consists of cell surface carbohydrate sialic acid, which can be present as glycoprotein or glycolipid. A large component of this antiviral program is regulated by the interferon family of signaling molecules. Influenza a viruses are classified by subtypes based on the properties of their hemagglutinin h and neuraminidase n surface proteins. Influenza a virus strains adopt different host specificities mainly depending on their hemagglutinin ha protein.
Receptor binding and ph stability how influenza a virus. For virus entry, hemagglutinin, the major glycoprotein on the surface of influenza virion, plays multiple roles in each step of the virus entry pathway. As a major pathogen of human and certain animal species, influenza virus causes wide spread and potentially devastating disease. Influenza a virus is an rna virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle 1. Host lipid composition influences many stages of the influenza a virus iav entry process, including initial binding of iav to sialylated glycans, fusion between the viral envelope and the host membrane, and the formation of a fusion pore through which the viral genome is transferred into a target cell. The laboratory diagnosis and virological surveillance of influenza 27 2. Influenza a and b viruses the primary influenza viruses that infect people are rna viruses that have eight gene segments. Pdf entry properties and entry inhibitors of a human. Some viruses, such as adenoassociated virus serotype 2 aav2, sfv and influenza can cross the endosomal membranes very rapidly within seconds, and the efficiency of entry. Chapters detail a broad range of methods from diagnosis, virus propagation, proteomics, haploid screening, lentiviral screening, virus entry, single molecule rna imaging, correlative light and electron microscopy clem, em, lightsheet microscopy, biochemistry, viral transcription, physiological infection models, animal models, in vivo imaging.
These aspects of transmission are poorly understood due to a paucity of methods for quantifying infectious virus from airborne particles. Influenza a viruses have broad host tropism, being able to infect a range of hosts from wild fowl to swine to humans. Influenza viruses replicate within the nucleus of the host cell. Here we report certain pentacyclic triterpenes exhibiting conserved structure features and with in vitro anti influenza virus activity comparable to and even higher than that of oseltamivir. Transocular entry of seasonal influenzaattenuated virus. The endocytic pathways used by some viruses have been determined, but the entry mechanisms for most. Mechanistic studies indicated that these lead triterpenoids bind tightly to the. Influenza is an acute respiratory illness, caused by influenza a, b, and c viruses, that occurs in local outbreaks or seasonal epidemics. Influenza is an infection caused by a member of the ribonucleic acid rna orthomyxovirus family.
Here, we examined influenza virus entry and infection in lec1 cells, a mutant cho cell line deficient in terminal nlinked glycosylation caused by a mutation in the n acetylglucosaminyltransferase i gnt1 gene. The first step of influenza virus entry is the recognition of the host cell receptor molecule, terminal. Influenza virus attaches to the sa on the host cells, where avian and equine influenza viruses bind to the sa. The type ii transmembrane serine proteases tmprss2 and hat activate influenza viruses and the sarscoronavirus tmprss2 in cell culture and may play an important role in viral spread and pathogenesis in the infected host. However, it also increases the complexity of the intracellular trafficking that is required for the viral components to establish a productive infection. Baseline susceptibility to baloxavir was established by testing more than 100 seasonal human influenza viruses representing each influenza subtype and b virus lineage e. Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. Although the relative importance of virus transfer from inanimate objects to humans in spreading influenza is not known, hand transfer of the virus to the mucous. Influenza virus attaches itself to sialic acids on the surface of epithelial cells of the upper respiratory tract of the host using its own protein hemagglutinin. Influenza a viruses use the voltagedependent calcium channel ca v 1.
A collection, storage and transport of specimens 29 2. The potential of a new flu pandemic is a frightening idea. Influenza virus is an enveloped negativesense rna virus that is a major public health problem worldwide. The influenza virus entry process begins with attachment of the viral hemagglutinin ha protein to sialic acid residues on cell surface glycoproteins, 8, 9 followed by internalization of. The major steps involved in viral entry are shown below. At 10 h postinfection, the viral ha protein was detected by western blotting. Discovery of pentacyclic triterpenoids as potential entry. This uncommon rna virus trait provides influenza with the advantage of access to the nuclear machinery during replication. Jun 28, 2018 each influenza virus isolate receives a unique name according to a set of rules. Entry inhibitors are of particular importance in current efforts to develop a new generation of anti influenza virus drugs. The shift in the receptorbinding specificity of avian influenza virus is critical for the jump from avian to human hosts. Pdf the influenza virus iv is still of great importance as it poses an immanent threat to humans and animals. Characterising viable virus from air exhaled by h1n1.
They can enter the cell either by endocytosis or by direct fusion at the plasma membrane. The influenza viruses section of virology journal will publish articles on all aspects of influenza virus research, including molecular genetics, molecular biology, biochemistry, biophysics, structural biology, cell biology, immunology, morphology, and pathogenesis. The viruses procure their membranes during this process and mature particles pinch off from the cellular membranes. Identification of entry inhibitors with 4aminopiperidine. How influenza a viruses are able to jump the species barrier is incompletely understood due to the. Smith, andrewes, and laidlaw isolated influenza a virus in ferrets in 1933, and francis isolated influenza b virus in 1936. Author summary influenza viruses can transmit through the air between two hosts. It affects mainly the nose, throat, bronchi and, occasionally, lungs carter and saunders, 2007. Under most circumstances, initiation of another round of infection is dependent on two critical functions supplied by the envelope. Influenza virus hemagglutinin recognizes sialyloligosaccharides of glycoproteins and glycolipids as cell surface receptors in the initial stage of the infection process.
The dr isotype of the human leukocyte antigen of the mhc class iior its homologues in bats, pigs, mice and chickensis an essential cell entry determinant for bat influenza a viruses. Helge ewers, mario schelhaas, in methods in enzymology, 2012. The reconstruction of a bat chimera influenza virus harbouring the entry machinery of an influenza a virus allowed us to prove that all genomic segments of. Influenza in humans is often referred to as the seasonal flu. Aviantohuman receptorbinding adaptation by influenza a.
Influenza a virus cell entry, replication, virion assembly. The pentadecapeptides were identified through affinity selection from a phage. Quercetin as an antiviral agent inhibits influenza a virus. Clinical illness follows a short incubation period and presentation ranges from asymptomatic to fulminant, depending on the characteristics of both the virus and the individual host. Species specificity of influenza virus is determined by the linkages of the sialic acids. The first pandemic of the 21st century occurred in 20092010. Influenza viruses are respiratory pathogens that represent a significant threat to public health, despite the largescale implementation of vaccination programs. Early stages of influenza virus entry into mv1 lung cells core. Thus research to identify new anti influenza virus strategies would be useful. B processing of clinical specimens for virus isolation 33 2. We demonstrate that pentadecapeptides that bind to a sialylgalactose structure neu5ac.
First, the name denotes the type of influenza virus a, b, c or d, followed by the host species from which the. Moreover, the virus causes outbreaks in poultry and other animals, such as pigs, requiring costly and laborious countermeasures. Influenza a virus cell entry, replication, virion assembly and. However, the entry properties and tropism of this h7n9 virus were poorly understood. Productive entry of influenza virus requires the lowph environment of the late endosome for fusion and release of the virus into the cytoplasm and transport of the virus genome into the nucleus. Influenza a viruses can also cause sporadic infections or spread worldwide. Spanish influenza in 19181919 caused an estimated 21 million deaths worldwide. Influenza entry tropism is mainly determined by the binding preference of ha 1 to its receptor, sa. Numerous animal or zoonotic influenza viruses that have pandemic potential were tested as well to.
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