The landscape of abnormal pathway activation confers COVID-19 patients' molecular sequelae earlier than clinical phenotype

Rationale: The 2019 coronavirus disease (COVID-19) pandemic poses a significant threat to human health. After SARS-CoV-2 infection, major clinical concerns are organ damage and possible sequelae. Methods: In this study, we analyzed serum multi-omics data based on population-level, including healthy cohort, non-COVID-19 and COVID-19 covered different severity cohorts. We applied the pseudo-SpatioTemporal Consistency Alignment (pST-CA) strategy to correct for individualized disease course differences, and developed pseudo-deterioration timeline model and pseudo-recovery timeline model based on the "severe index" and "course index". Further, we comprehensively analyzed and discussed the dynamic damage signaling in COVID-19 deterioration and/or recovery, as well as the potential risk of sequelae. Results: The deterioration and course models based on the pST-CA strategy can effectively map the activation of blood molecular signals on cellular, pathway, functional and disease phenotypes in COVID-19 deterioration and throughout the disease course. The models revealed the neurological, cardiovascular, and hepatic toxicity present in SARS-CoV-2. The abundance of differentially expressed proteins and the activity of upstream regulators were comprehensively analyzed and evaluated to predict possible target drugs for SARS-CoV-2. On molecular docking simulation analysis, it was further demonstrated that blocking CEACAM1 is a potential therapeutic target for SARS-CoV-2. Conclusions: Clinically, the risk of organ failure and death in COVID-19 patients rises with increasing number of infections. Individualized sequelae prediction for patients and assessment of individualized intervenable targets and available drugs in combination with the upstream regulator analysis results are of great clinical value.