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Key Event Title
Viral infection and host-to-host transmission, proliferated
|Level of Biological Organization|
Key Event Components
|viral release from host cell||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Sars-CoV-2 IFN-I antiviral antagonism leading to infection proliferation||AdverseOutcome||Arthur Author (send email)||Under development: Not open for comment. Do not cite||Under Development|
|All life stages||High|
Key Event Description
Much is now understood in terms of human-to-human COVID-19 transmission. Coronaviruses, as with many other respiratory viruses, are transmitted primarily through respiratory droplets, but can also spread through aerosols, fecal-oral transmission, or contact with contaminated surfaces (Harrison et al. 2020). Respiratory droplets and aerosols containing the virus are generated through an infected person coughing, sneezing or talking, and enter the secondary host system through upper and lower respiratory tissues, with the lung being the primary tropism. Barriers to transmission in place worldwide include social distancing, face shields, cloth masks, frequent hand washing, and surface disinfection (Harrison et al. 2020).
Vaccination is the standard strategy for reducing or eliminating viral disease transmission, symptoms, and mortality in humans, and in some cases domesticated animals. However, the weight of evidence indicates that the reservoir species (bats in the case of betacoronaviruses) and potential intermediate hosts are wildlife, and different control measures will be required to prevent future spillover. Indeed, the intermediate host of the SARS-CoV-2 virus has yet to be identified (Delahay et al. 2021). This key event is therefore focused primarily on the species of potential concern, exposure and transmission routes across species, and the conditions indicative of or conducive toward cross-species spillover of zoonoses or infectious viral diseases of animal origin.
Species of Potential Concern
The reservoir host for SARS-CoV-2-like viruses is believed to be the bat.
Exposure and Transmission Routes
SARS-CoV-2-infected media (respiratory droplets, bodily fluids, tissues, feces): Exposure routes are the pathway into the body of the virus shed from an infected reservoir host animal to the intermediate host, or either type of host animal to humans. These routes may include inhalation, oral, or through broken skin or mucosal membranes (e.g., eyes, nostrils) after touching contaminated media or surfaces and then touching the face (Harrison et al. 2020). Animals may transfer saliva or nasal discharge directly through facial contact, licking or biting. Transmission occurs through these routes when the virus reaches a tissue with cells that allow entry and replication.
Conditions that allow for exposure and transmission across species:
- Close proximity of animal communities (bats to potential intermediate hosts; wildlife to domestic animal farms).
- Direct human contact with wildlife (Johnson et al. 2015), including:
- Zoos, wildlife farms, domesticated animal farms, feeding and animal care;
- Hunting and dressing wild game;
- Cleaning of storage buildings, barns, or other structures that may be used by wildlife for shelter, breeding, or feeding, with potential for feces or other contamination (CDC, 2021);
- Wet markets where live animals or bush meat are traded;
- Research facilities that express viruses from wild samples in cell culture, that house potential host species, or that collect and store bodily fluid or tissue samples.
- Virus isolated from animal species shows genomic similarity to the human virus, but also high host plasticity to be capable of cross-species viral immune evasion and replication (Johnson et al. 2015).
Similar host genetics. Spillover species and new host species share genetic similarity in the components of the cell entry, immune system and replication machinery (Warren et al. 2019). That is, the virus can enter the cell and evade the virus detection and immediate systemic type I interferon (IFN) response to allow replication and generation of viral load in both species. The viral proteins must be capable of interacting with the appropriate cellular proteins in either species. The most studied and considered indicative of infectability is the ACE2 and other cell entry proteins.
How It Is Measured or Detected
Either the virus or antibodies can be detected with available tests. Active infection can be detected through PCR tests from nasal swab, oropharyngeal swab, rectal swab or saliva samples that indicate the quantity and/or presence of the virus. Antibodies can be detected in blood using various assays including immunofluorescence.
ELISA, Indirect immunofluorescence assay (IIFA) for antibodies (Schlottau et al. 2020; Freuling et al. 2020)
Virus neutralization test (VNT) for antibodies (Schlottau et al. 2020; Freuling et al. 2020)
Quantitative reverse transcription PCR (qRT-PCR) for viral load (log10 genome copies) (Freuling et al. 2020)
Titration (Tissue culture infectious dose where 50% of infected cells display cytopathic effect [TCID50 assay]: levels of infectious virus, or viral titre) (Freuling et al. 2020)
Virus-specific immunoglobulin characterization (Freuling et al. 2020)
SARS-CoV-2 spike protein neutralizing antibodies in saliva from animals that developed serum antibodies (Freuling et al. 2020)
Serum sample, autopsy, histopathology for tissue lesions (Schlottau et al. 2020; Freuling et al. 2020)
Domain of Applicability
Broad mammalian host range based on spike protein tropism for and binding to ACE2 (Conceicao et al. 2020; Wu et al. 2020) and cross-species ACE2 structural analysis (Damas et al. 2020). Some literature found on non-human hosts indicates that NSPs and accessory proteins can interact in a similar manner with bird (chicken) and other mammal proteins in the IFN-I pathway (Moustaqil et al. 2021; Rui et al. 2021).
Evidence for Perturbation by Stressor
Regulatory Significance of the Adverse Outcome
Freuling CM, Breithaupt A, Müller T, et al. 2020. Susceptibility of Raccoon Dogs for Experimental SARS-CoV-2 Infection. Emerging Infectious Diseases. 26(12):2982-2985. doi:10.3201/eid2612.203733.
Conceicao et al. 2020. The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins. PLoS Biol 18(12): e3001016. https://doi.org/10.1371/journal.pbio.3001016
Damas et al. 2020. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates. PNAS vol. 117 no. 36:22311–22322 www.pnas.org/cgi/doi/10.1073/pnas.2010146117
Moustaqil et al. 2021. SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species, Emerging Microbes & Infections, 10:1, 178-195. https://doi.org/10.1080/22221751.2020.1870414
Rui et al. 2021. Unique and complementary suppression of cGAS-STING and RNA sensing-triggered innate immune responses by SARS-CoV-2 proteins. Sig Transduct Target Ther 6, 123. https://doi.org/10.1038/s41392-021-00515-5
Wu et al. 2020. Broad host range of SARS-CoV-2 and the molecular basis for SARS-CoV-2 binding to cat ACE2. Cell Discovery 6:68. https://doi.org/10.1038/s41421-020-00210-9