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Event: 2159

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Influenza A virus (IAV) cell entry

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

IAV cell entry

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
respiratory epithelial cell

Organ term

Organ term
respiratory tract

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
protein localization to endosome	clathrin-coated vesicle membrane	occurrence
receptor-mediated endocytosis	influenzavirus hemagglutinin	occurrence
membrane fusion	vesicle membrane	occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
IAV infection proliferation	KeyEvent	Jessica Resnick (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
dog	Canis lupus familiaris	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

IAV has two major surface proteins: hemagglutinin (HA) and neuraminidase (NA). HA binds to sialic acid glycans on the host cell surface to facilitate viral entry (1,2). Following this, the virion enters the cell through receptor—mediated endocytosis (usually involving clathrin) or micropinocytosis (1,3,4). The virus is then trafficked to the endosome, where the change in pH activates the M2 ion channel protein of the virus, leading to a conformational change in the HA exposing the fusion peptide and causing subsequent fusion of the viral envelope with the membrane of the vesicle (1). Following fusion, the vRNPs are released into the cytoplasm in a process known as “uncoating” and trafficked to the nucleus (1). This entire process takes about 10 minutes (5)

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Reference	Technique	Finding
Matlin, K.S., Reggio, H., Helenius, A. & Simons, K. Infectious entry pathway of influenza-virus in a canine kidney-cell line. J. Cell Biol. 91, 601–613 (1981)	Electron microscopy	Virus was seen bound to microvilli, in coated pits, coated vesicles, and large smooth-surfaced vacuoles, low pH was required for fusion, suggesting entry by endocytosis
Rust, M., Lakadamyali, M., Zhang, F. et al. Assembly of endocytic machinery around individual influenza viruses during viral entry. Nat Struct Mol Biol 11, 567–573 (2004). https://doi.org/10.1038/nsmb769	Real- time fluorescent microscopy	Clathrin-mediated and clathrin- and caveolin-independent endocytic pathways used in parallel with similar efficiency
De Vries, E. et. al., Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway. Plos Pathogens (2011). https://doi.org/10.1371/journal.ppat.1001329	Luciferase reporter assay	Macropinocytosis is an alternative entry pathway
Chen, C. and Zhuang, X. Epsin 1 is a cargo- specific adaptor for the clathrin-mediated endocytosis of the influenza virus	Colocalization of immunofluorescence	influenza entry via clathrin- mediated pathway
Sieczkarski, S. and Whittaker, G. Influenza Virus Can Enter and Infect Cells in the Absence of Clathrin-Mediated Endocytosis	Flow cytommetry	IAV cell entry via non-clathrin dependent route

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

References

List of the literature that was cited for this KE description. More help

Dou, D., et. al. Influenza A Virus Cell Entry, Replication, Virion Assembly, and Movement. Front. Immunol. (2018) https://doi.org/10.3389/fimmu.2018.01581
Sempere Borau, M. and Stertz, S. Entry of influenza A virus into host cells- recent progress and remaining challenges. Current Opinion in Virology (2021) https://doi.org/10.1016/j.coviro.2021.03.001
Matlin, K.S., Reggio, H., Helenius, A. & Simons, K. Infectious entry pathway of influenza-virus in a canine kidney-cell line. J. Cell Biol. 91, 601–613 (1981) https://doi.org/10.1083/jcb.91.3.601
De Vries, E. et. al., Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway. Plos Pathogens (2011). https://doi.org/10.1371/journal.ppat.1001329
Dou D, Hernandez-Neuta I, Wang H, Ostbye H, Qian X, Thiele S, et al. Analysis of IAV replication and co-infection dynamics by a versatile RNA viral genome labeling method. Cell Rep (2017) 20:251–63. doi:10.1016/j.celrep.2017.06.021