AOP: 379

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 to ACE2 leading to thrombosis and disseminated intravascular coagulation

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

SARS-CoV2 to thrombosis and DIC

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

Shihori Tanabe¹, Youngjun Kim², Sally Mayasich³, Maria João Amorim⁴, Nikolaos Parissis⁵, Penny Nymark⁶, Marvin Martens⁷, Dan Jacobson⁸, Felicity N. E. Gavins⁹, Luigi Margiotta-Casaluci¹⁰, Sabina Halappanavar¹¹, Natàlia Garcia-Reyero¹², Julija Filipovska¹³, Stephen W. Edwards¹⁴‚ Rebecca Ram¹⁵, Adrienne Layton¹⁶, Brigitte Landesmann⁵, Hasmik Yepiskoposyan¹⁷, Jukka Sund¹⁸, Clemens Wittwehr⁵, Laure-Alix Clerbaux⁵

¹Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan

²KIST Europe Forschungsgesellschaft mbH, Saarbrücken, Germany

³University of Wisconsin-Madison at U.S. Environmental Protection Agency, Duluth, Minnesota, United States

⁴Instituto Gulbenkian de Ciência – Fundação Calouste Gulbenkian, Oeiras, Portugal

⁵European Commission, Joint Research Centre (JRC), Ispra, Italy

⁶Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

⁷Maastricht University, Maastricht, Netherlands

⁸Oak Ridge National Laboratory, Oak Ridge, United States

⁹Brunel University London, London, United Kingdom

¹⁰King’s College London, London, United Kingdom

¹¹Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada

¹²U.S. Army Engineer Research and Development Center (ERDC), Vicksburg, United States

¹³Independent Scientist & Consultant, North Macedonia

¹⁴GenOmics, Bioinformatics, and Translational Research Center, RTI International, Washington DC, United States

¹⁵Safer Medicines Trust, Kingsbridge, United Kingdom

¹⁶U.S. Consumer Product Safety Commission, Bethesda, United States

¹⁷Philip Morris International, Neuchatel, Switzerland

¹⁸Finnish Safety and Chemicals Agency, Finland

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

Shihori Tanabe (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

Shihori Tanabe

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 November 20, 2023 21:16

Revision dates for related pages

Page	Revision Date/Time
Coagulation	August 30, 2023 20:39
Thrombosis and Disseminated Intravascular Coagulation	November 25, 2022 01:38
Increased SARS-CoV-2 production	June 14, 2022 08:49
SARS-CoV-2 cell entry	April 04, 2023 07:39
Diminished protective oxidative stress response	October 30, 2023 03:36
Binding to ACE2	August 30, 2023 20:36
Interferon-I antiviral response, antagonized by SARS-CoV-2	April 03, 2023 15:20
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	April 03, 2023 15:49
IFN-I response, antagonized leads to SARS-CoV-2 production	October 24, 2021 17:11
SARS-CoV-2 production leads to Diminished Protective Response to ROS	September 26, 2023 01:47
Diminished Protective Response to ROS leads to Coagulation	October 16, 2023 03:24
Coagulation leads to Diminished Protective Response to ROS	October 17, 2023 00:34
Coagulation leads to Thrombosis and DIC	February 05, 2023 20:49
Stressor:624 SARS-CoV-2	April 20, 2021 03:40

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

Coronavirus disease-19 (COVID-19) is circulating all over the world. To understand and find a way of the COVID-19 treatment, the signaling pathway and therapeutic mechanism of COVID-19 should be investigated. The pathogenesis of COVID-19 includes molecular networks such as the binding of the membrane proteins, signaling pathways, and RNA replication. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a new type of coronavirus causing COVID-19, infects the cells via the binding of the membrane proteins of human cells and is internalized by the cells. The viral genome is replicated by RNA-dependent RNA polymerase (RdRp), followed by the packaging and releasing of the viral particles. These steps can be the main targets for the therapeutics of COVID-19. The AOP379 "Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation" consists of the molecular initiating event (MIE) as “Binding to ACE2” (KE1739), key events (KEs) as “SARS-CoV-2 cell entry” (KE1738), “Interferon-I antiviral response, antagonized by SARS-CoV-2” (KE1901), "Increased SARS-CoV-2 production" (KE1847), “Diminished protective oxidative stress response" (KE1869) and "Coagulation" (KE1845), and adverse outcome (AO) as "Thrombosis and Disseminated Intravascular Coagulation" (KE1846).

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

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

This AOP379 has been developed in the collaboration of Modelling the Pathogenesis of COVID-19 using the AOP framework (CIAO) international consortium (Clerbaux et al., 2022). Extensive efforts in discussion and literature search of the group crystalized into many AOPs related to coronavirus pathogenesis and coronavirus infectious disease 2019 (COVID-19), where the AOP379 focuses on the thrombosis and disseminated intravascular coagulation as adverse outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through reactive oxygen species-induced oxidative stress response (Tanabe et al., 2022).

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

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
KE	1869	Diminished protective oxidative stress response	Diminished Protective Response to ROS
KE	1845	Coagulation	Coagulation

1846

Thrombosis and Disseminated Intravascular Coagulation

Thrombosis and DIC

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

Binding to ACE2 leads to SARS-CoV-2 cell entry	adjacent	High	Moderate
SARS-CoV-2 cell entry leads to IFN-I response, antagonized	adjacent	Moderate	Moderate
IFN-I response, antagonized leads to SARS-CoV-2 production	adjacent	Moderate	Moderate
SARS-CoV-2 production leads to Diminished Protective Response to ROS	adjacent	Moderate	Not Specified
Diminished Protective Response to ROS leads to Coagulation	adjacent	Moderate	Not Specified
Coagulation leads to Diminished Protective Response to ROS	adjacent	Moderate	Not Specified
Coagulation leads to Thrombosis and DIC	adjacent	High

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

Name
Stressor:624 SARS-CoV-2

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
All life stages	Moderate

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
Homo sapiens	Homo sapiens	High	NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Unspecific	High

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

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

This AOP is applicable to all sexes in Homo sapiens.

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

Essentiality of the KEs
Event	ID and Title	Direct Evidence	Indirect Evidence	No experimental evidence
KE1	KE1738: SARS-CoV-2 cell entry	**	***	***
KE2	KE1901: Interferon-I antiviral response, antagonized by SARS-CoV-2		***	***
KE3	KE1847: Increased SARS-CoV-2 production	**	***	***
KE4	KE1869: Diminished protective oxidative stress response		***	***
KE5	KE1845: Coagulation		***	***

Evidence Assessment

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

[Evidence Assessment]
1. Support for Biological Plausibility of KERs
MIE => KE1: KER2056: Binding to ACE2 leads to SARS-CoV-2 cell entry	Biological Plausibility of the MIE => KE1 is high. Rationale: Binding of SARS-CoV-2 to ACE2 cell-surface receptor initiates infection of SARS-CoV-2 where SARS-CoV-2 cell entry is essential (Zhou P et al., 2020, Benton DJ et al., 2020).
KE1 => KE2: KER2496: SARS-CoV-2 cell entry leads to IFN-I response, antagonized	Biological Plausibility of the KE1 => KE2 is moderate. Rationale: The expression of type I interferons (IFN-I) is antagonized by SARS-CoV-2 (Benton DJ et al., 2020). Individual viral proteins interact with and block host proteins in the IFN-I pathway or IFN-I stimulated genes.
KE2 => KE3: KER2497: IFN-I response, antagonized leads to SARS-CoV-2 production	Biological Plausibility of the KE2 => KE3 is moderate. Rationale: Inhibition of IFN-I response induces SARS-CoV-2 production.
KE3 => KE4: KER2358: SARS-CoV-2 production leads to Diminished Protective Response to ROS	Biological Plausibility of the KE3 => KE4 is moderate. Rationale: The fixation of SARS-CoV-2 in ACE2 receptor results in excessive production of pro-inflammatory and pro-oxidant agents (Ramdani and Bachari, 2020).
KE4 => KE5: KER2359: Diminished Protective Response to ROS leads to Coagulation	Biological Plausibility of the KE4 => KE5 is moderate. Rationale: The ROS results in lung injury and coagulopathy (Barrett CD et al., 2018).
KE5 => KE4: KER2360: Coagulation leads to Diminished Protective Response to ROS	Biological Plausibility of the KE5 => KE4 is moderate. Rationale: Coagulation imbalance induces oxidative stress (Robea MA et al., 2023).
KE5 => AO: KER2290: Coagulation leads to Thrombosis and DIC	Biological Plausibility of the KE5 => AO is high. Rationale: Extreme aggravation of blood coagulation induces multiple thrombi in the microvasculature, which leads to consumption coagulopathy followed by disseminated intravascular disease.
2. Support for Essentiality of KEs
AOP379	Rationale for Essentiality of KEs in the AOP is Moderate.
3. Empirical Support for KERs
MIE => KE1: KER2056: Binding to ACE2 leads to SARS-CoV-2 cell entry	Empirical Support of the MIE => KE1 is moderate. Rationale: The SARS-CoV-2 binding to ACE2 induce fusion of the virus and cell membranes to release the virus genome into the cell. (Zhou P et al., 2020, Benton DJ et al., 2020).
KE1 => KE2: KER2496: SARS-CoV-2 cell entry leads to IFN-I response, antagonized	Empirical Support of the KE1 => KE2 is moderate. Rationale: SARS-CoV-2-infection induces IFN-I pathway reduction (Sui C et al., 2022, Blanco-Melo, 2020).
KE2 => KE3: KER2497: IFN-I response, antagonized leads to SARS-CoV-2 production	Empirical Support of the KE2 => KE3 is moderate. Rationale: Reduced IFN-I response induces SARS-CoV-2 production.
KE3 => KE4: KER2358: SARS-CoV-2 production leads to Diminished Protective Response to ROS	Empirical Support of the KE3 => KE4 is moderate. Rationale: As SARS-CoV-2 is attached to ACE2, ACE2 is not available within the renin-angiotensin system to convert Ang II to angiotensin-(1,7) resulting in Ang II to accumulate. Ang II stimulates membrane-bound NADPH oxidase, which in turn generate ROS and oxidative stress (Janardhan et al., 2020).
KE4 => KE5: KER2359: Diminished Protective Response to ROS leads to Coagulation	Empirical Support of the KE4 => KE5 is moderate. Rationale: The presence of ROS assists in the transformation of a circulating, non-oxidized, circular-shaped beta2-glycoprotein 1 into an oxidized J-shape, which binds to antiphospholipid antibodies such as anticardiolipin, lupus anticoagulant, and anti-beta2-GP1 antibodies (Janardhan et al., 2020). Domain V of beta2gP1 binds with the phospholipid layer of platelets or endothelial cells via Annexin (Janardhan et al., 2020).
KE5 => KE4: KER2360: Coagulation leads to Diminished Protective Response to ROS	Empirical Support of the KE5 => KE4 is moderate. Rationale: Excessive coagulation induces oxidative stress.
KE5 => AO: KER2290: Coagulation leads to Thrombosis and DIC	Empirical Support of the KE5 => AO is high. Rationale: Extreme aggravation of blood coagulation induces multiple thrombi in the microvasculature, which leads to consumption coagulopathy followed by disseminated intravascular disease.

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

The AOP379 focuses on the coronavirus-induced thrombosis and disseminated intravascular coagulation, which may contribute to the development of therapeutics of COVID-19 and long COVID syndrome. The understanding of the mechanism of the coronavirus-induced vascular adverse outcome may predict adverse responses of COVID-19 vaccines.

References

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

Banerjee AK, Blanco MR, Bruce EA, Honson DD, Chen LM, Chow A, et al. SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses. Cell. 2020;183(5):1325-39.e21.

Barrett CD, Hsu AT, Ellson CD, B YM, Kong YW, Greenwood JD, et al. Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy. Clin Exp Immunol. 2018;194(1):103-17.

Benton DJ, Wrobel AG, Xu P, Roustan C, Martin SR, Rosenthal PB, et al. Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion. Nature. 2020;588(7837):327-30.

Blanco Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 181;(5):1036-1045.

Chen B, Tian EK, He B, Tian L, Han R, Wang S, et al. Overview of lethal human Coronaviruses. Signal Transduction and Targeted Therapy, 2020;5(1):89.

Clerbaux, L.-A., Amigó, N., Amorim, M. J., Bal-Price, A., Batista Leite, S., Beronius, A., Bezemer, G. F. G., Bostroem, A.-C., Carusi, A., Coecke, S., Concha, R., Daskalopoulos, E. P., De Bernardi, F., Edrosa, E., Edwards, S. W., Filipovska, J., Garcia-Reyero, N., Gavins, F. N. E., Halappanavar, S., Hargreaves, A. J., Hogberg, H. T., Huynh, M. T., Jacobson, D., Josephs-Spaulding, J., Kim, Y. J., Kong, H. J., Krebs, C. E., Lam, A., Landesmann, B., Layton, A., Lee, Y. O., Macmillan, D. S., Mantovani, A., Margiotta-Casaluci, L., Martens, M., Masereeuw, R., Mayasich, S. A., Mei, L. M., Mortensen, H., Munoz Pineiro, A., Nymark, P., Ohayon, E., Ojasi, J., Paini, A., Parissis, N., Parvatam, S., Pistollato, F., Sachana, M., Sørli, J. B., Sullivan, K. M., Sund, J., Tanabe, S., Tsaioun, K., Vinken, M., Viviani, L., Waspe, J., Willett, C. and Wittwehr, C. (2022) “COVID-19 through adverse outcome pathways: Building networks to better understand the disease – 3rd CIAO AOP Design Workshop”, ALTEX - Alternatives to animal experimentation, 39(2), pp. 322–335. doi: 10.14573/altex.2112161.

Cui J, Li F, Shi ZL. Origin and evolution of pathogenic Coronaviruses. Nature Reviews Microbiology. 2019;17(3):181-192.

Florindo HF, Kleiner R, Vaskovich-Koubi D, Acúrcio RC, Carreira B, Yeini,E, et al. Immune-mediated approaches against COVID-19. Nature Nanotechnology. 2020:15(8):630-45.

Janardhan V, Janardhan V, Kalousek V. COVID-19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy. Journal of Neuroimaging. 2020;30(5):555-61.

Kowalewski J, Ray A. Predicting novel drugs for SARS-CoV-2 using machine learning from a & g 10 million chemical space. Heliyon. 2020;6(8).

Pizzorno A, Padey B, Julien T, Trouillet-Assant S, Traversier A, Errazuriz-Cerda E, et al. Characterization and Treatment of SARS-CoV-2 in Nasal and Bronchial Human Airway Epithelia. Cell Reports Medicine. 2020:1(4).

Ramdani LH and Bachari K. Potential therapeutic effects of resveratrol against SARS-CoV-2. Acta virologica 2020;64, 276-280

Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature. 2020.

Robea MA, Balmus I-M, Girleanu I, Huiban L, Muzica C, Ciobica A, et al. Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease—Oxidative Stress and Inflammation Relevance. Medicina. 2023;59(9):1614.

Sui C, Xiao T, Zhang S, Zeng H, Zheng Y, Liu B, et al. SARS-CoV-2 NSP13 Inhibits Type I IFN Production by Degradation of TBK1 via p62-Dependent Selective Autophagy. The Journal of Immunology. 2022;208(3):753-61.

Tanabe S (2020a). Cellular Internalization and RNA Regulation of RNA virus. Adv Clin Med Res. 2020;1(1):1-3. https://www.genesispub.org/cellular-internalization-and-rna-regulation-of-rna-virus

Tanabe S (2020b). The Therapeutic Mechanism of COVID-19. J Clin Med Res. 2020;2(5):1-3. DOI: https://doi.org/10.37191/Mapsci-2582-4333-2(5)-048

Tanabe, S., Beaton, D., Chauhan, V., Choi, I., Danielsen, P. H., Delrue, N., Esterhuizen, M., Filipovska, J., FitzGerald, R., Fritsche, E., Gant, T., Garcia-Reyero, N., Helm, J., Huliganga, E., Jacobsen, N., Kay, J. E., Kim, Y.-J., Klose, J., La Rocca, C., Luettich, K., Mally, A., O’Brien, J., Poulsen, S. S., Rudel, R. A., Sovadinova, I., Tollefsen, K. E., Vogel, U., Yepiskoposyan, H. and Yauk, C. (2022) “Report of the 1st and 2nd Mystery of Reactive Oxygen Species Conferences”, ALTEX - Alternatives to animal experimentation, 39(2), pp. 336–338. doi: 10.14573/altex.2203011.

Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3.