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Relationship: 2498


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

SARS-CoV-2 production leads to Viral infection, proliferated

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Binding of SARS-CoV-2 to ACE2 leads to viral infection proliferation adjacent High Not Specified Arthur Author (send email) Under development: Not open for comment. Do not cite Under Development

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mammals mammals High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

In the process of SARS-CoV-2 production, the genome is replicated, packaged, and assembled with the structural proteins into virions that are then released from the host cell. The virions can infect nearby cells or be transported to distal organs, or be expelled from the host through coughing, sneezing, or vocalization, or in saliva and bodily waste. The amount of virus expelled from the host is dependent on the viral load produced. The viral load quantity produced in the upstream KE 1847 through the viral hijacking and modifications of host cell resources has been measured or modelled in several studies to determine the downstream terminal KE (1939) response: actual or potential transmission and successful infection of the exposed cell, organ, or new individual host. Transmission at the population level has also been monitored based on contact tracing, or experimental infection and transmission studies, or modelling community spread. Transmission at the ecosystem level has been demonstrated with human-to-animal-to-human transmission.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Empirical evidence supporting this relationship is described below.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

In pathogen evolution it is the nature of the virus to replicate in a host (upstream KE 1847) and take advantage of internal and external transport mechanisms to reach another suitable habitat (downstream KE/AO 1939) to replicate again and result in infection. For this AOP and specifically for this KER, it is helpful to be aware of historical development of disease theory, i.e., the germ theory of disease and Koch’s postulates from the 19th century. Importantly, the first postulate that the microbe must be found in diseased individuals but not those without symptoms, had to be revised when it was realized that some bacteria like those causing cholera and typhoid could be carried by hosts who were asymptomatic (Fredricks and Relman, 1996). Viruses were discovered and were found to only replicate in cells and cannot be grown in pure culture, confounding the second postulate. Therefore, modifications of these disease principles have been applied to viruses (Rivers, 1937), and are basically an attempt at proving causation. Fredricks and Relman (1996) present a review citing several of these important revisions and their application with current technology like sequence-based identification of pathogens to prove the biological plausibility of the causal agent moving from host to host. Interestingly, Fouchier et al. (2003) carry out a proof that Koch’s postulates, as modified by Rivers (1937), are fulfilled for the (first) SARS virus. Numerous studies on SARS-CoV-2 demonstrate both the presence of the viral sequence by PCR (viral load), and the presence of neutralizing antibodies to the virus in upstream cases as considered by Evans’ (1976) proposed ‘‘Elements of Immunological Proof of Causation.’’ These principles go on to cover the downstream event, transmission to a healthy contact, where the antibody to the agent (SARS-CoV-2) is absent prior to the disease and exposure to the agent, the antibody appears during illness, and a downstream contact with no antibodies to the agent is susceptible to infection and disease produced by the agent (Evans, 1976; Fredricks and Relman, 1996). Literature providing empirical evidence of these principles specific to SARS-CoV-2 is provided below.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


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