CIDO ontology updates and secondary analysis of host responses to COVID-19 infection based on ImmPort reports and literature

Abstract

Background: With COVID-19 still in its pandemic stage, extensive research has generated increasing amounts of data and knowledge. As many studies are published within a short span of time, we often lose an integrative and comprehensive picture of host-coronavirus interaction (HCI) mechanisms. As of early April 2021, the ImmPort database has stored 7 studies (with 6 having details) that cover topics including molecular immune signatures, epitopes, and sex differences in terms of mortality in COVID-19 patients. The Coronavirus Infectious Disease Ontology (CIDO) represents basic HCI information. We hypothesize that the CIDO can be used as the platform to represent newly recorded information from ImmPort leading the reinforcement of CIDO.

Methods: The CIDO was used as the semantic platform for logically modeling and representing newly identified knowledge reported in the 6 ImmPort studies. A recursive eXtensible Ontology Development (XOD) strategy was established to support the CIDO representation and enhancement. Secondary data analysis was also performed to analyze different aspects of the HCI from these ImmPort studies and other related literature reports.

Results: The topics covered by the 6 ImmPort papers were identified to overlap with existing CIDO representation. SARS-CoV-2 viral S protein related HCI knowledge was emphasized for CIDO modeling, including its binding with ACE2, mutations causing different variants, and epitope homology by comparison with other coronavirus S proteins. Different types of cytokine signatures were also identified and added to CIDO. Our secondary analysis of two cohort COVID-19 studies with cytokine panel detection found that a total of 11 cytokines were up-regulated in female patients after infection and 8 cytokines in male patients. These sex-specific gene responses were newly modeled and represented in CIDO. A new DL query was generated to demonstrate the benefits of such integrative ontology representation. Furthermore, IL-10 signaling pathway was found to be statistically significant for both male patients and female patients.

Conclusion: Using the recursive XOD strategy, six new ImmPort COVID-19 studies were systematically reviewed, the results were modeled and represented in CIDO, leading to the enhancement of CIDO. The enhanced ontology and further seconary analysis supported more comprehensive understanding of the molecular mechanism of host responses to COVID-19 infection.

Keywords: CIDO; COVID-19; Coronavirus infectious disease ontology; Host-coronavirus interaction; ImmPort; Metadata; OBO foundry; Ontology; SARS-CoV-2; Sex difference.

Fig. 1

Strategy of CIDO updating using recursive XOD strategy. The recursive XOD strategy applies the use of the different principles of XOD design for use of new term generation along with creation of new axioms. Further knowledge either from literature or secondary analysis is used as a basis to generate new terms

Fig. 2

CIDO representation of host-coronavirus interactions and the addition of new knowledge learned from papers of ImmPort studies to CIDO. ImmPort studies are labeled with their study IDs (e.g., SDY1667). The termed highlighted are the terms newly added to incorporate the knowledge learned from the corresponding ImmPort studies. This figure shows how CIDO can be updated through our ontology reinforcement strategy

Fig. 3

Ontological representation of S protein processes and variations. a CIDO ontological representation of viral life cycle in host (cell invasion, genetic replication, and release for cell and invading other cells) of virulent SARS-CoV-2. CIDO ontological representation of coronaviral molecular processes. The right bottom side of the screenshot represents different axioms for the SARS-CoV-2 S binding to human ACE2. b Seven SARS-CoV-2 clades are defined with each has its specific definition. For example, SARS-CoV-2 clade G virus has AA variant S-D614G, which is a variant of S protein of SARS-CoV-2. c CIDO representation of SARS-CoV-2 virus variants such as SARS-CoV-2 Delta variant based on the WHO classification

Fig. 4

Ontological representation of RAS pathway and drug roles. The bold text represents newly added terms from the ImmPort-focused data annotations

Fig. 5

Ontological representation of gene signature and quality-based immune responses. a General pattern of gene expression patterns in human. b CIDO representation of gene expression patterns in SARS-CoV-2 infected patients

Fig. 6

Sex differences in gene ontology and DL query. a CIDO ontological representation of sex-based immune response for SARS-CoV-2. The genes listed are chosen from the results in Table 2. b DL Query infers properties provide a list to identify shared genes between males and females