Background: Cardiovascular Disease (CVD) is one of the most common causes of mortality in humans. Presently, the role of pathogens in the initiation and progression of the CVDs is not clearly understood. Hence, it is essential to understand the molecular-level interactions between the human proteins and the microbial proteins to deduce their functional roles in the CVDs. Method: The host-pathogen interactions (HPI) related to CVDs in the case of E. coli str. O157:H7 colonization were curated, and also the protein-protein interactions (PPI) between humans and E. coli were collected. Gene interaction network (GIN) and functional enrichment analyses (FEA) were utilized for this. Results: The GIN revealed dense interactions between the functional partners. The FEA indicated that the essential pathways played a significant role in humans as well as in E. coli. The primary responses against most of the bacterial pathogens in humans are different from that of E. coli; Terpenoid biosynthesis and production of secondary metabolite pathways aid the survival of the E. coli inside the host. Interestingly, network analysis divulged that the E. coli genes ksgA, rpsT, ispE, rpsI, ispH, and the human genes TP53, CASP3, CYCS, EP300, RHOA communicated by significant numbers in direct interactions. Conclusions: The results obtained from the present study will help researchers understand the molecular-level interactions in the CVDs between the human and the E. coli genes. The important genes with vital interactions can be considered as hub molecules and can be exploited for new drug discovery. © 2021 Elsevier Ltd