A comprehensive map of the SARS-CoV-2 replication cycle

The coronavirus disease 2019 (COVID-19) pandemic has so far resulted in the infection of more than 42 million people worldwide with more than one million deaths (https://covid19.who.int). Caused by the SARS-CoV-2 virus, COVID-19 is complex and involves multiple biological pathways. To understand how COVID-19 develops, it is crucial to decipher the underlying molecular mechanisms of the SARS-CoV-2 replication cycle since all signalling cascades that culminate in the emergence of clinical symptoms derive essentially from the events encompassing the replication cycle. Aiming to provide a comprehensive resource for assisting the COVID-19 research community in this quest, we built, in collaboration with the Reactome database and University of Edinburgh teams under the COVID-19 Disease Map project, a comprehensive map of the SARS-CoV-2 replication cycle containing all sequential events making up the replication cycle: virus attachment, entry, transcription, replication, assembly and release to extracellular space. Encoded in a CellDesigner’s SBML format, our SARS-CoV-2 replication cycle map currently contains 104 reactions and 105 bioentities manually collected from 18 publications. Additionally, all entities and reactions are annotated according to the standards provided by the Minimal Information Requested In the Annotation of Models (MIRIAM). While virus attachment and entry events are based solely on the biomedical literature concerning SARS-CoV-2, the other events are based mostly on the coronaviruses SARS-CoV and MHV-A49 for which more studies are available. This map shows important features of the SARS-CoV-2 infectivity. First, cell susceptibility to SARS-CoV-2 infection depends on multiple host entry factors, namely, angiotensin-converting enzyme 2 (ACE2), cholesterol, heparan sulfate, the proteases cathepsin B (CTSB), cathepsin L (CTSL) and TMPRSS2, the proprotein convertase furin, and the transmembrane receptor neuropilin 1 (NRP1). Second, SARS-CoV-2 can enter cells either by direct fusion of the virion and cell membranes in the presence of proteases TMPRSS2 and furin or by endocytosis in their absence. Third, SARS-CoV-2 replication and transcription take place within double-membrane vesicles (DMVs) that protect intermediate double-stranded RNAs from the cell innate immunity sensors. We expect that this map, along with the other maps under the COVID-19 Disease Map project, can be both a standardised knowledge repository for the COVID-19 and coronaviruses research communities as well as a hypothesis-generating resource for new discoveries concerning the crosstalk between SARS-CoV-2 replication cycle and host cell signalling pathways.