Gene network inference from single-cell omics data and domain knowledge for constructing COVID-19-specific ICAM1-associated pathways

Abstract

Introduction: Intercellular adhesion molecule 1 (ICAM-1) is a critical molecule responsible for interactions between cells. Previous studies have suggested that ICAM-1 triggers cell-to-cell transmission of HIV-1 or HTLV-1, that SARS-CoV-2 shares several features with these viruses via interactions between cells, and that SARS-CoV-2 cell-to-cell transmission is associated with COVID-19 severity. From these previous arguments, it is assumed that ICAM-1 can be related to SARS-CoV-2 cell-to-cell transmission in COVID-19 patients. Indeed, the time-dependent change of the ICAM-1 expression level has been detected in COVID-19 patients. However, signaling pathways that consist of ICAM-1 and other molecules interacting with ICAM-1 are not identified in COVID-19. For example, the current COVID-19 Disease Map has no entry for those pathways. Therefore, discovering unknown ICAM1-associated pathways will be indispensable for clarifying the mechanism of COVID-19. Materials and methods: This study builds ICAM1-associated pathways by gene network inference from single-cell omics data and multiple knowledge bases. First, single-cell omics data analysis extracts coexpressed genes with significant differences in expression levels with spurious correlations removed. Second, knowledge bases validate the models. Finally, mapping the models onto existing pathways identifies new ICAM1-associated pathways. Results: Comparison of the obtained pathways between different cell types and time points reproduces the known pathways and indicates the following two unknown pathways: (1) upstream pathway that includes proteins in the non-canonical NF-κB pathway and (2) downstream pathway that contains integrins and cytoskeleton or motor proteins for cell transformation. Discussion: In this way, data-driven and knowledge-based approaches are integrated into gene network inference for ICAM1-associated pathway construction. The results can contribute to repairing and completing the COVID-19 Disease Map, thereby improving our understanding of the mechanism of COVID-19.

Keywords: COVID-19; ICAM-1; cell-to-cell transmission; data-driven and knowledge-based approach; model validation; pathway enrichment analysis; single-cell omics data analysis.

FIGURE 1

Schematic representation of the framework. Step 1: single-cell omics data analysis. Step 2: undirected graphical model construction. Step 3: model corroboration and validation. Step 4: gene-to-protein conversion. Step 5: pathway mapping and unification. The circuits are subpathways transmitting a signal from input receptor nodes to output effector nodes, where the nodes mostly represent proteins such as metabolic enzymes. QC: quality control; DR: dimensionality reduction; CL: clustering; WX: Wilcoxon rank-sum test; DEGs: differentially expressed genes; DCGs: differentially coexpressed genes. See also DOI: 10.6084/m9.figshare.18095717.

FIGURE 2

The cell types for which data were collected. Pulmonary tissue illustrations: created with BioRender.com. See also DOI: 10.6084/m9.figshare.18095714.

FIGURE 3

ICAM1-associated pathways at different locations (cell types). (A): No pathway available (infected alveolar type 1 and 2 cells); (B): NF-κB/non-canonical NF-κB/integrin pathway putative (migratory dendritic cells); (C): NF-κB/integrin pathway putative (tissue-resident alveolar macrophages); (D): NF-κB/integrin pathway putative (monocyte-derived alveolar macrophages); (E): TNF/NF-κB/non-canonical NF-κB/integrin pathway putative (summation). The rectangular nodes colored blue, yellow, and lime green reflect the proteins only on the dependency graphs, the proteins common to both the dependency graphs and the KEGG pathways, and the proteins only on the KEGG pathways, respectively. Gray lines are the directed or undirected edges only on the dependency graphs. Orange lines represent the directed or undirected edges between yellow nodes on the dependency graphs. Green lines are the directed edges only on the KEGG pathways. Orange edges do not have direction if the KEGG pathways indirectly connect its yellow node pair. See also DOI: 10.6084/m9.figshare.17261540.

FIGURE 4

ICAM1-associated pathways at different time points. (A) NF-κB/MAPK pathway putative (day 1). (B) NF-κB/MAPK pathway putative (day 5). (C) NF-κB/MAPK pathway putative (day 10). The light yellow, green, and orange nodes represent data-driven DCGs, the genes listed only in the KEGG pathways, and the genes derived from both data and the KEGG pathways, respectively. The directed edges are the edges whose directions are given in the KEGG pathways. See this figure for a larger view in figshare: 10.6084/m9.figshare.23576226.