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Event: 2180

Key Event Title

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

Immune mechanisms antagonized by viral proteins

Short name

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immune mechanisms antagonized

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Biological Context

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Level of Biological Organization
Molecular

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
toll-like receptor 7 signaling pathway	influenzavirus NS gene translation product	decreased
toll-like receptor 3 signaling pathway	influenzavirus NS gene translation product	decreased
suppression by virus of host cytokine production		occurrence
virus induced gene silencing		occurrence
modulation by virus of host immune response		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 and other cells in culture	human and other cells in culture	High	NCBI
human	Homo sapiens	High	NCBI

Life Stages

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

Life stage	Evidence
Adult, reproductively mature	High

Sex Applicability

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

Term	Evidence
Unspecific	Moderate

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 infection is detected by multiple host sensors. Within the infected cell, viral RNA in the cytosol (potentially as part of a stress granule) is recognized by RIG-I which signals through MAVS to induce pro-inflammatory cytokines and type 1 IFN (1). Additionally, while toll-like receptor (TLR) expression is usually localized to immune cells, nasal epithelial cells also express a majority of TLR subtypes (2). This allows for recognition of IAV through TLR3 or TLR7(1). Sensing of dsRNA through TLR3 and TRIF intermediate leads to a signaling cascade via NFkB and IRF3 to induce expression of Type I IFNs and ISGs as well as IL-1B and other pro-inflammatory cytokines (1). This is despite the fact that IAV does not produce dsRNA, however due to interactions with UAP56, TLR3 is able to recognize different RNA structures (5). Sensing ssRNA through TLR7 and Myd88 intermediate leads to a signaling cascade involving NFkB and IRF7 to also induce expression of Type I IFNs and ISGs as well as pro-inflammatory cytokines (1).

The IAV NS1 protein binds to CPSF30 blocking the cleavage of pre-mRNAs and recruitment of the poly(A) polymerase and is considered the key antagonizing factor (3,4). This causes accumulation of unprocessed cellular pre-mRNA accumulation in the nucleus leading to the inhibition of general gene expression as well as induction of IFN, ISGs, and other pro-inflammatory gene (3). Additionally, NS1 can bind cellular dsDNA as well as components of mRNA export machinery, again preventing the expression of antiviral genes (3).Additionally, the IAV PA-X protein also blocks cellular antiviral responses by selectively degrading host RNA Pol II transcribed RNAs in the nucleus, sparing Pol I and Pol III products (3). This again inhibits expression of antiviral and proinflammatory genes.

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
OhKuni, T., et. al. Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-a via distinct NF-kB pathways in human nasal epithelial cells. Toxicology and Applied Pharmacology.(2010) https://doi.org/10.1016/j.taap.2010.09.023	RNA (RT-PCR) and protein (Western and immunohistochemistry) expression	Signaling occurs through TLRs in nasal epithelial cells
Mibayashi, M., et. al, Inhbition of Retinoic Acid- Inducible Gene I- Mediated Induction of Beta Interferon by the NS1 Protein of Influenza A virus. Journal of Virology. (2007). https://doi.org/10.1128/JVI.01265-06	Expression of reporter gene construct and co-precipitation, fluorescent microscopy, western blot	NS1 binds RIG-I to inhibit downstream activation of IRF3 to prevent IFN-binduction
Nemeroff, M., et. al., Influenza Virus NS1 Protein Interacts with the Cellular 30 kDa Subunit of CPSF and Inhibits 3’ End Formation of Cellular Pre-mRNAs. Molecular Cell. (1998). https://doi.org/10.1016/S1097-2765(00)80099-4	Co-precipitation and gel shift assay	labeled IAV NS1 protein co-precipitated with CPSF 30kDa protein and incubation with NS1 prevented CPSF binding to pre-mRNA for processing
Khaperskyy DA, Schmaling S, Larkins-Ford J, McCormick C, Gaglia MM (2016) Selective Degradation of Host RNA Polymerase II Transcripts by Influenza A Virus PA-X Host Shutoff Protein. PLOS Pathogens 12(2): e1005427. https://doi.org/10.1371/journal.ppat.1005427	Transfection of reporter genes with different Pol-driven promoters and evaluation of expression by RT-qPCR	Selective degradation of Pol-II transcripts by PA-X

Domain of Applicability

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

Current research (mostly in mouse models and from clinical data anaylsis) suggests that sex differences in response to infection emerge during the adaptive immune response. The innate immune response steps outlined in this KE are expected to be universal, but the magnitude and some mechanisms may differ between sexes and more work is needed to understand (6-8)

References

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

Iwasaki, A., Pillai, P. Innate immunity to influenza virus infection. Nat Rev Immunol 14, 315–328 (2014). https://doi.org/10.1038/nri3665
McClure, R. and Massari, P. TLR-dependent human mucosal epithelial responses to microbial pathogens. Front. Immunol. (2014). doi: 10.3389/fimmu.2014.00386
Nogales, A., et. al., Modulation of Innate Immune Responses by the Influenza A NS1 and PA-X Proteins. MDPI viruses. (2018). doi: 10.3390/v10120708
Zhang, Y., Xu, Z., and Cao, Y., Host-Virus Interaction: How Host Cells defend against Influenza A Virus Infection. MDPI viruses. (2020). doi: 10.3390/v12040376
Schulz, O., Diebold, S., Chen, M. et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887–892 (2005). https://doi.org/10.1038/nature03326
Peretz J, Pekosz A, Lane AP, Klein SL. Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors. Am J Physiol Lung Cell Mol Physiol. 2016 Mar 1;310(5):L415-25. doi: 10.1152/ajplung.00398.2015. Epub 2015 Dec 18. PMID: 26684252; PMCID: PMC4773846.
Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016 Oct;16(10):626-38. doi: 10.1038/nri.2016.90. Epub 2016 Aug 22. PMID: 27546235.
Jacobsen H, Klein SL. Sex Differences in Immunity to Viral Infections. Front Immunol. 2021 Aug 31;12:720952. doi: 10.3389/fimmu.2021.720952. PMID: 34531867; PMCID: PMC8438138.