In silico unravelling pathogen-host signaling cross-talks via pathogen mimicry and human protein-protein interaction networks

摘要

Pathogen-host protein interactions are fundamental for pathogens to manipulate host signaling pathways and subvert host immune defense. For most pathogens, very few or no experimental studies have been conducted to investigate their signaling cross-talks with host. In this study, we propose a computational framework to validate the biological assumption that human protein–protein interaction (PPI) networks alone are sufficient to infer pathogen-host PPIs via pathogen functional mimicry. Pathogen functional mimicry assumes that a pathogen functionally mimics and substitutes host counterpart proteins in order for the pathogen to get involved in or hijack the host cellular processes. Through pathogen functional mimicry defined via gene ontology (GO) semantic similarity, we first use the known human PPIs as templates to infer pathogen-host PPIs, and the PPIs are further used as training data to build an lsub2/sub-regularized logistic regression model for novel pathogen-host PPI prediction. Independent tests on the experimental data from human immunodeficiency virus and Francisella tularensis validate the effectiveness of the proposed pathogen functional mimicry technique. Performance comparisons also show that the proposed technique y excels the existing pathogen sequence mimicry approaches and transfer learning methods. The proposed framework provides a new avenue to study the experimentally less-studied pathogens in the worst scenarios that very few or no experimental pathogen-host PPIs are available. As two case studies, we apply the proposed framework to Salmonella typhimurium and Human respiratory syncytial virus to reconstruct the pathogen-host PPI networks and further investigate the interference of these two pathogens with human immune signaling and transcription regulatory system.