Meta-Biol

• Pathways

Antimicrobial compounds kill microorganisms or inhibit their growth, either in the host, outside on the skin (antiseptics), or in the environment (disinfectants). In the host they are named after the target symbiont, for example antibiotics, antifungals, and antiparasitics. It suffices to permanently stop an essential pathway in the symbiont to kill it. Broad spectrum antimicrobials usually target a conserved pathway like protein synthesis or cell wall construction, in order to affect a whole taxonomic group (Arenz & Wilson 2016, Barry et al. 2007, Green 2002).

Resistance of microorganisms (bacteria, viruses, parasites) to antimicrobials is one of the most important public health problems. Many mechanisms exist, and they are either acquired by mutation, by horizontal gene transfer, or are already intrinsic to the organism. The main mechanisms are modification of the antimicrobial, or its removal from the place of action, modification of its binding partner in the affected pathway, or usage of a back-up pathway. Participation of the organism in a consortium (like in biofilms) enables additional resistance mechanisms (Aminov & Mackie 2007, Peterson & Kaur 2018, van Acker et al. 2014, van Acker & Coenye 2016).

The events described here are specific to Mtb infection.

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.