Meta-Biol

• Pathways

This COVID-19 pathway has been created by a combination of computational inference from SARS-CoV-1 data (https://reactome.org/documentation/inferred-events) and manual curation, as described in the summation for the overall SARS-CoV-2 infection pathway. Steps of SARS-CoV-2 genome replication that have been studied directly include binding of the replication transcription complex (RTC) to the RNA template and the polymerase activity of nsp12 (Hillen et al. 2020, Wang et al. 2020, Yin et al. 2020), helicase activity of nsp13 (Chen et al. 2020, Ji et al. 2020, Shu et al. 2020), capping activity of nsp16 (Viswanathan et al. 2020), and polyadenylation of SARS-CoV-2 genomic RNA (Kim et al. 2020). Replication is localized in double-membrane vesicles (DMVs) that are created by distortion of ER membranes (Cortese et al, 2020; Snijder et al, 2020). One host factor needed for formation of these replication organelles is phosphatidic acid (Tabata et al, 2021). Other steps have been inferred from previous studies in SARS-CoV-1 and related coronaviruses.

The plus strand RNA genome of the human SARS coronavirus 1 (SARS-CoV-1) is replicated by the viral replication-transcription complex (RTC) composed of nonstructural proteins nsp3-nsp16, encoded by open reading frames ORF1a and ORF1b. Two RTC proteins, nsp8 and nsp12, possess 5'-3' RNA-dependent RNA polymerase activity. nsp12 is the main RNA polymerase, while nsp8 is thought to act as an RNA primase. nsp14 acts as a 3'-5' exonuclease, increasing the fidelity of the RTC. nsp14 also has the RNA capping activity and, in concert with nsp16, it caps viral plus strand and minus strand genomic and subgenomic RNAs, which confers stability to viral RNAs by enabling them to escape interferon-mediated innate immune responses of the host. nsp13 is an RNA helicase which is thought to melt secondary structures in the genomic RNA during replication and transcription. The plus strand genomic RNA is first used to synthesize the minus strand genomic RNA complement, which is subsequently used as a template for synthesis of plus strand viral RNA genomes that are packaged into mature virions. For review, please refer to Yang and Leibowitz 2015, Snijder et al. 2016, Fung and Liu 2019.

Infectious diseases are ones due to the presence of pathogenic microbial agents in human host cells. Processes annotated in this category include bacterial, viral and parasitic infection pathways.

Bacterial infection pathways currently include some metabolic processes mediated by intracellular Mycobacterium tuberculosis, the actions of clostridial, anthrax, and diphtheria toxins, and the entry of Listeria monocytogenes into human cells.

Viral infection pathways currently include the life cycles of SARS-CoV viruses, influenza virus, HIV (human immunodeficiency virus), and human cytomegalovirus (HCMV).

Parasitic infection pathways currently include Leishmania infection-related pathways.

Fungal infection pathways and prion diseases have not been annotated.

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.