Ontology-based systematic classification and analysis of coronaviruses, hosts, and host-coronavirus interactions towards deep understanding of COVID-19

Yu, Hong; Li, Li; Huang, Hsin-hui; Wang, Yang; Liu, Yingtong; Ong, Edison; Huffman, Anthony; Zeng, Tao; Zhang, Jingsong; Li, Pengpai; Liu, Zhiping; Zhang, Xiangyan; Ye, Xianwei; Handelman, Samuel K.; Higgins, Gerry; Omenn, Gilbert S.; Athey, Brian; Hur, Junguk; Chen, Luonan; He, Yongqun

Given the existing COVID-19 pandemic worldwide, it is critical to systematically study the interactions between hosts and coronaviruses including SARS-Cov, MERS-Cov, and SARS-CoV-2 (cause of COVID-19). We first created four host-pathogen interaction (HPI)-Outcome postulates, and generated a HPI-Outcome model as the basis for understanding host-coronavirus interactions (HCI) and their relations with the disease outcomes. We hypothesized that ontology can be used as an integrative platform to classify and analyze HCI and disease outcomes. Accordingly, we annotated and categorized different coronaviruses, hosts, and phenotypes using ontologies and identified their relations. Various COVID-19 phenotypes are hypothesized to be caused by the backend HCI mechanisms. To further identify the causal HCI-outcome relations, we collected 35 experimentally-verified HCI protein-protein interactions (PPIs), and applied literature mining to identify additional host PPIs in response to coronavirus infections. The results were formulated in a logical ontology representation for integrative HCI-outcome understanding. Using known PPIs as baits, we also developed and applied a domain-inferred prediction method to predict new PPIs and identified their pathological targets on multiple organs. Overall, our proposed ontology-based integrative framework combined with computational predictions can be used to support fundamental understanding of the intricate interactions between human patients and coronaviruses (including SARS-CoV-2) and their association with various disease outcomes.