Whole patient knowledge modeling of COVID-19 symptomatology reveals common molecular mechanisms

Abstract

Infection with SARS-CoV-2 coronavirus causes systemic, multi-faceted COVID-19 disease. However, knowledge connecting its intricate clinical manifestations with molecular mechanisms remains fragmented. Deciphering the molecular basis of COVID-19 at the whole-patient level is paramount to the development of effective therapeutic approaches. With this goal in mind, we followed an iterative, expert-driven process to compile data published prior to and during the early stages of the pandemic into a comprehensive COVID-19 knowledge model. Recent updates to this model have also validated multiple earlier predictions, suggesting the importance of such knowledge frameworks in hypothesis generation and testing. Overall, our findings suggest that SARS-CoV-2 perturbs several specific mechanisms, unleashing a pathogenesis spectrum, ranging from “a perfect storm” triggered by acute hyper-inflammation, to accelerated aging in protracted “long COVID-19” syndromes. In this work, we shortly report on these findings that we share with the community via 1) a synopsis of key evidence associating COVID-19 symptoms and plausible mechanisms, with details presented within 2) the accompanying “COVID-19 Explorer” webserver, developed specifically for this purpose (found at https://covid19.molecularhealth.com). We anticipate that our model will continue to facilitate clinico-molecular insights across organ systems together with hypothesis generation for the testing of potential repurposing drug candidates, new pharmacological targets and clinically relevant biomarkers. Our work suggests that whole patient knowledge models of human disease can potentially expedite the development of new therapeutic strategies and support evidence-driven clinical hypothesis generation and decision making.

The COVID-19 explorer—An integrated, whole patient knowledge model of COVID-19 disease

“…A full analytical overview of the generated model is summarized in Supplementary Table S1 and made available via our COVID-19 Explorer. In addition, extended information about specific mechanisms, pathways, clinical phenotypes and insights into the clinico-molecular hypotheses derived from our model are reported in the associated back-to-back publication ( Brock et al, 2022 ).…”

“…Here, we report on our findings and the functionality of the COVID-19 Explorer web resource. Our results are provided at the level of a whole-patient knowledge model, including the possible causative pathogenic mechanisms underlying COVID-19 phenotypes ( Brock et al, 2022 ). To accommodate usability for a variety of use-case scenarios, results are summarized in different formats: the ‘COVID-19 Explorer’ provides a detailed, comprehensive and fully interactive view of the relationships and accompanying evidence, while ‘The COVID-19 Cockpit’ (see Supplementary Table S1 ) is intended to support clinical researchers in diagnostic and hypothesis generation for new therapeutic strategies (see Figure 1 ).…”

“…Treatment modalities indicated by the model include drugs associated with modulation of ACE2 induction, B1R agonists, as well as Kallikrein inhibitors, SerpinG1 enzyme replacement and SIRT-1 or PPARγ activators. Several of these are currently investigated in late phase COVID-19 clinical trial studies (see also ( Brock et al, 2022 )).…”

“…For instance, first reports of silent hypoxemia emerged in April 2020. The symptoms of silent hypoxemia were mapped against the symptomatology of heritable diseases, identifying Congenital Central Hereditary Hypoventilation Syndrome (CCHS) as a phenotypically related disease (see Figure 3 ) ( Brock et al, 2022 ). CCHS is caused by dysfunction of the exocytosis machinery in oxygen sensing cells, providing a direct link to our model ( Supplementary Material S1 , Figure 3 ) (see also Figure 4 ).…”

Rewiring Drug Research and Development through Human Data-Driven Discovery (HD3)

“…The resultant whole-patient model (available at http://covid19.molecularhealth.com, accessed on 8 January 2023) revealed that SARS-CoV-2 perturbs eight core pathogenic processes: inflammatory signaling, coagulation, barrier permeability, senescence, autoimmunity, fibrogenic signaling, nociception and exocytosis [95]. Together, these mechanisms were proposed to be responsible for unleashing a pathogenesis spectrum, ranging from 'a perfect storm' triggered by acute hyper-inflammation to chronic fatigue in protracted COVID-19 syndromes.…”