Systems Biology Approaches to Understanding the Human Immune System

Systems biology is an approach to interrogate complex biological systems through large-scale quantification of numerous biomolecules. The immune system involves >1,500 genes/proteins in many interconnected pathways and processes, and a systems-level approach is critical in broadening our understanding of the immune response to vaccination. Changes in molecular pathways can be detected using high-throughput omics datasets (e.g., transcriptomics, proteomics, and metabolomics) by using methods such as pathway enrichment, network analysis, machine learning, etc. Importantly, integration of multipleomicdatasets is becoming key to revealing novel biological insights. In this perspective article, we highlight the use of protein-protein interaction (PPI) networks as a multi-omics integration approach to unravel information flow and mechanisms during complex biological events, with a focus on the immune system. This involves a combination of tools, including:InnateDB, a database of curated interactions between genes and protein products involved in the innate immunity;NetworkAnalyst, a visualization and analysis platform for InnateDB interactions; andMetaBridge, a tool to integrate metabolite data into PPI networks. The application of these systems techniques is demonstrated for a variety of biological questions, including: the developmental trajectory of neonates during the first week of life, mechanisms in host-pathogen interaction, disease prognosis, biomarker discovery, and drug discovery and repurposing. Overall, systems biology analyses of omics data have been applied to a variety of immunology-related questions, and here we demonstrate the numerous ways in which PPI network analysis can be a powerful tool in contributing to our understanding of the immune system and the study of vaccines.