Meta-Biol

• Pathways

The precise timing and location of uncoating (early vs. late endosomes) depends on the pH-mediated transition of the specific viral hemagglutinin (HA) molecule involved. The uncoating of influenza viruses in endosomes is blocked by changes in pH caused by weak bases (e.g. ammonium chloride and chloroquine) or ionophores (e.g. monensin). Effective uncoating is also dependent on the presence of the viral M2 ion channel protein. Early on it was recognized that amantadine and rimantadine inhibit replication immediately following virus infection. Later it was found that the virus-associated M2 protein allows the influx of H+ ions into the virion, which disrupts protein-protein interactions, resulting in the release of viral RNP free of the viral matrix (M1) protein. Amantadine and rimantadine have been shown to block the ion channel activity of the M2 protein and thus uncoating. The HA mediated fusion of the viral membrane with the endosomal membrane and the M2-mediated release of the RNP results in the appearance of free RNP complexes in the cytosol. This completes the uncoating process. The time frame for the uncoating process has been examined by inhibiting virus penetration with ammonium chloride. Typically, virus particles show a penetration half time of about 25 minutes after viral adsorption. Ten minutes later (half time of 34 minutes after adsorption) RNP complexes are found in the nucleus. Uptake of RNP molecules through nuclear pores is an active process, involving the nucleo-cytoplasmic trafficking machinery of the host cell.

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.