The authors have designated this AOP as all rights reserved. Re-use in any form requires advanced permission from the authors.

AOP: 430

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Binding of SARS-CoV-2 to ACE2 leads to viral infection proliferation

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
SARS-CoV-2 leads to infection proliferation

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Sally Mayasich, University of Wisconsin-Madison Aquatic Sciences Center at US Environmental Protection Agency, Duluth, MN, USA

Maria João Amorim, Instituto Gulbenkian de Ciência, Oeiras, and Universidade Católica Portuguesa, Católica Medical School, Católica Biomedical Research Centre, Portugal

Laure-Alix Clerbaux, European Commission-Joint Research Centre (EC-JRC), Ispra, Italy

Alicia Paini, EC-JRC/EsqLab

Nikolaos Parissis, EC-JRC

Young Jun Kim, KIST Europe, Germany

Penny Nymark, Institute of Environmental Medicine, Karolinska Institute, Sweden

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Sally Mayasich   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Sally Mayasich
  • Laure-Alix Clerbaux
  • Maria Joao Amorim

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help
  • Cinzia La Rocca

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Handbook Version OECD status OECD project
v2.0 Under Development 1.96
This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page Revision Date/Time
Binding to ACE2 August 30, 2023 20:36
SARS-CoV-2 cell entry April 04, 2023 07:39
Interferon-I antiviral response, antagonized by SARS-CoV-2 December 15, 2023 14:27
Increased SARS-CoV-2 production June 14, 2022 08:49
Viral infection and host-to-host transmission, proliferated December 12, 2023 14:48
Binding to ACE2 leads to SARS-CoV-2 cell entry February 07, 2023 23:24
SARS-CoV-2 cell entry leads to IFN-I response, antagonized December 12, 2023 15:15
IFN-I response, antagonized leads to SARS-CoV-2 production December 14, 2023 15:23
SARS-CoV-2 production leads to Viral infection, proliferated March 31, 2023 17:06
SARS-CoV March 01, 2020 10:42
Sars-CoV-2 September 09, 2022 05:09
HCoV-NL63 February 07, 2021 07:01

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Severe accute respiratory syndrome (SARS) and SARS-CoV-2 coronoviruses enter the cell through interaction with the ACE2 receptor. The first event upon cell entry after uncoating is the primary translation of the ORF1a and ORF1b genomic RNA to produce non-structural proteins (nsps). The nsps structural proteins, and accessory proteins, are encoded by 10 ORFs in the SARS-CoV-2 RNA genome. They may have multiple functions during viral replication as well as in evasion of the host innate immune response, thus augmenting viral replication and spread. The early innate immune system evasion proteins produced in the sub-genomic translation after viral genome replication and transcription within the infected cell suppress the Interferon-I antiviral response to increase viral load. Beyond potentially contributing to the severity of clinical symptoms and adverse disease outcome in individuals, increase in viral load can lead to proliferation from person-to-person and across species, also increasing the likelihood of mutations that result in more infective or virulant strains.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

This AOP was developed in the context of other COVID-19 AOPs through the work of a larger international effort to model the pathogenesis of COVID-19 using the AOP framework (the CIAO project, https://www.ciao-covid.net/about-us), initiated by the European Commission-Joint Research Centre (EC-JRC), and supported by the Society for the Advancement of Adverse Outcome Pathways (SAAOP). More than 80 scientists from 50 institutions contributed to the fifteen AOPs connected to the molecular initiating event (1739) SARS-CoV-2 binding to ACE2, and other COVID-19-related AOPs. AOP 430 serves as a hub of early key events leading to viral transmission (AO 1939) and the severe disease outcomes described in the networked COVID-19 AOPs.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

At the time the CIAO project was initiated in mid- to late 2020, the molecular initiating event of the SARS-CoV-2 spike protein binding to the host ACE2 receptor was known, and many of the severe disease outcomes required binding, cell entry and viral replication to spread to other tissues and organs from the point of infection. With the strategy of reuse of key events in the AOP-Wiki, AOP 430 was developed as a hub containing the MIE and early KEs of viral entry and replication. Through early literature and understanding of the virus, it was determined that evasion of the innate immune interferon-I (IFN-I) antiviral response is a key event to allow the virus to replicate and produce new virions to spread from cell to cell, and to generate a viral load for host-to-host transmission, including transmission across species (zoonotic spillover) and was included in the hub. The contributors are experts in their fields, including Dr. Young Jun Kim, who has conducted ACE2 binding research; Dr. Maria João Amorim, virologist; Dr. Laure-Alix Clerbaux, EU-JRC researcher and CIAO coordinator with other EU-JRC researchers Dr. Nikolaos Parissis and Dr. Alicia Paini; Dr. Penny Nymark, researcher with a background in genetics, cancer, toxicology and AOP development, and member of the CIAO coordination team; and Dr. Sally Mayasich, researcher with a background in molecular biology of endocrine and immune interactions, bioinformatics, toxicology and risk assessment. These researchers developed the AOP through focused literature searches with peer-reviewed literature preferred, but in some cases pre-prints are referenced due to the short timeframe for emerging information during the rapidly evolving COVID-19 pandemic. The COVID-19 AOPs were developed within a collaborative exchange of information through online platforms and frequent virtual meetings and workshops which also enlisted the guidance of CIAO members experienced as AOP developers and coaches. Dr. Carlie LaLone, bioinformatician, toxicologist and AOP developer and coach, US Environmental Protection Agency, contributed to later stages of development of the AOP.

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1739 Binding to ACE2 Binding to ACE2
KE 1738 SARS-CoV-2 cell entry SARS-CoV-2 cell entry
KE 1901 Interferon-I antiviral response, antagonized by SARS-CoV-2 IFN-I response, antagonized
KE 1847 Increased SARS-CoV-2 production SARS-CoV-2 production
AO 1939 Viral infection and host-to-host transmission, proliferated Viral infection, proliferated

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help
Term Scientific Term Evidence Link
mink Mustela lutreola High NCBI
ferret Mustela putorius furo High NCBI
cat Felis catus High NCBI
dog Canis lupus familiaris High NCBI
Syrian golden hamster Mesocricetus auratus High NCBI
rhesus macaque Macaca mulatta High NCBI
lowland gorilla Gorilla gorilla gorilla High NCBI
crab eating macaque Macaca fascicularis High NCBI
African green monkeys Chlorocebus aethiops High NCBI
humans Homo sapiens High NCBI
Hippopotamus amphibius Hippopotamus amphibius High NCBI
bank vole Myodes glareolus High NCBI
Lynx canadensis Lynx canadensis High NCBI
Puma concolor Puma concolor High NCBI
Panthera tigris jacksoni Panthera tigris jacksoni High NCBI
Panthera uncia Uncia uncia High NCBI
Prionailurus viverrinus Prionailurus viverrinus High NCBI
Crocuta crocuta Crocuta crocuta High NCBI
Arctictis binturong Arctictis binturong High NCBI
Odocoileus virginianus Odocoileus virginianus High NCBI
American mink Neovison vison High NCBI
Nasua nasua Nasua nasua High NCBI
Panthera leo Panthera leo High NCBI
Sus scrofa Sus scrofa High NCBI
European rabbit Oryctolagus cuniculus High NCBI
Castor fiber Castor fiber High NCBI
Aonyx cinereus Aonyx cinerea High NCBI
Vulpes vulpes Vulpes vulpes High NCBI
Nyctereutes procyonoides Nyctereutes procyonoides High NCBI
Tupaia belangeri Tupaia belangeri High NCBI
Bos taurus Bos taurus High NCBI
Odocoileus hemionus Odocoileus hemionus High NCBI
Peromyscus maniculatus bairdii Peromyscus maniculatus bairdii High NCBI
Cynopterus brachyotis Cynopterus brachyotis High NCBI
common marmoset Callithrix jacchus High NCBI
baboon Papio anubis High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific Not Specified

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

See details below.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life stage and sex

Although COVID-19 has shown to be a more severe illness in older than in young people, there is evidence that viral load was not influenced by age or sex (Challenger et al., 2022), and infection rate and viral load did not differ by sex (Arnold et al., 2022; Qi et al., 2021; Cheemarla et al., 2021). Therefore, this AOP is applicable to all life stages and both sexes.

Taxonomic domain

No non-mammals have been found to be infected by SARS-CoV-2. Mammals listed in the Taxonomic Applicability table were either experimentally or naturally infected, as confirmed by polymerase chain reaction (PCR) or antibody assays, hence evidence is high for these species. Other mammalian species are likely also susceptible, but some mammals experimentally exposed to the virus did not become infected (Bosco-Lauth et al., 2021). The AOP is therefore applicable to humans and other mammals. Infections in non-human mammals is important in the potential for zoonotic spillover and is discussed in more detail in the adverse outcome (AO 1939), with species-specific references.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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