Pathogens invade and infect humans. Understanding the infection mechanism is essential for determining targets for new therapeutics. Existing methods provide too many false positive results. A method and system for predicting protein-protein interaction between a host and a pathogen has been provided. The disclosure provides a pipeline for predicting HPIs, which is a combination of biological knowledge-based filters, domain-based filter and sequence-based predictions. Biologically feasible interactions are only possible when both the proteins share common localization and overlapping expression profiles. This observation was used as the first filter to remove biologically irrelevant HPIs. Proteins interact with each other through domains. Both interacting and non-interacting protein pairs provide valuable information about the probability of protein-protein interactions and hence both were used to derive statistical inferences to remove improbable HPIs. Finally, sequence composition of known interacting pairs of HPIs were used to train an XGBoost model and filter the most probable HPIs.