Background <p>Neuroinvasive pathogens are capable of breaching the blood–brain barrier (BBB), and causing central nervous system infections. Although the response of human brain microvascular endothelial cells (hBMECs), the forefront cells of BBB has been extensively studied, the roles of astrocytes and pericytes in modulating BBB integrity during infection remain less defined.</p> Aims <p>The study aims for a meta-analysis of RNA-seq data to compare the transcriptional response of hBMECs alone and in co-culture with astrocytes and pericytes (BBB-spheroids) following infection with <i>Neisseria meningitidis</i> and <i>Borrelia bavariensis</i>. Subsequently, identifying the pathogen-specific gene signatures that regulates the signalling pathways associated with infection and BBB disruption. </p> Methods <p>Unique and shared differentially expressed genes (DEGs) of hBMECs and BBB-spheroids were identified and analysed for functional enrichment using DAVID. Protein–protein interaction networks were constructed and analysed in Cytoscape using MCODE and cytoHubba to identify infection-related hub genes.</p> Results <p>A large proportion of DEGs were unique to each BBB model during infection, 49% in <i>Neisseria</i> and 66% in <i>Borrelia</i> infection, whereas only 4.9% were shared. hBMECs predominantly expressed defence-related genes, whereas BBB-spheroids expressed genes linked to barrier function. Notably, IFIH1, IFIT1, IFIT3, ISG15, MX1, OAS1, and RSAD2 were identified as regulators of the BBB’s transcriptomic response to infection.</p> Conclusions <p>The meta-analysis highlights distinct yet complementary roles of endothelial cells and the supporting pericytes and astrocytes in BBB regulation to bacterial invasion. The identified hub genes may serve as key regulators of infection-driven inflammation and form potential diagnostic or prognostic targets.</p> Graphical Abstract <p></p>