The IL6-amplifier is a proposed model for the induction of cytokine storm by SARS-CoV-2 as described in https://pubmed.ncbi.nlm.nih.gov/32325025/
Retrospective studies have indicated that high levels of a particular pro-inflammatory cytokine called Interleukin 6 is strongly associated with severely infected COVID-19 patients. One proposed mechanism for the observed IL-6 induction is a positive feedback loop known as IL-6 Amplifier, originally discovered in autoimmune disorders, which can result from the simultaneous activation of IL6, STAT3 and NF-𝜅B Ogura 2008, which induces a cytokine storm leading to Acute Respiratory Distress Syndrome (ARDS).
Briefly, SARS-CoV-2, the novel coronavirus that is responsible for the recent COVID-19 pandemic, enters the cell by binding to ACE-2, which normally degrades Angiotensin II, a vasoconstrictor and pro-inflammatory cytokine. Without ACE-2 to degrade it, the increase in abundance of Angiotensin II activates angiotensin receptor type I (AGTR1), which directly activates disintegrin and metalloprotease 17 (ADAM17). ADAM17 is directly responsible for activating Epidermal Growth Factor (EGF) and Tumor Necrosis Factor alpha (TNF𝛼), which both go on to stimulate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-𝜅B) signaling pathway Eguchi 2019. ADAM17 also leads to conversion of the interleukin 6 receptor (IL6R) to its soluble form (sIL6R), which binds to IL6 and the interleukin 6-Signal transducer (IL6ST) which activates signal transducer and activator of transcription 3 (STAT3).Murakami 2019 At the same time, the endocytosis of SARS-CoV-2 is detected by intracellular pathogen pattern recognition receptors (PRR), which also stimulates the NF-𝜅B signaling pathway. Murakami 2019
The newt file is the stable version of the model. Using NewtEditor, we have exported the newt file to SBGN and SBML, with varying levels of fidelity. To do: expand the PRR branch of the pathway based on PAMP model. Add compartment information.