{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T22:32:57Z","timestamp":1776205977758,"version":"3.50.1"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The blood-brain barrier (BBB), a highly regulated interface between the blood and the brain, prevents blood-borne substances and pathogens from entering the CNS. Nevertheless, pathogens like <jats:italic>Neisseria meningitidis<\/jats:italic> and <jats:italic>Borrelia bavariensis<\/jats:italic> can breach the BBB and infect the brain parenchyma. The self-assembling BBB-spheroids can simulate the cross talk occurring between the cells of the barrier and neuroinvasive pathogens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>BBB spheroids were generated by co-culturing human brain microvascular endothelial cells (hBMECs), pericytes and astrocytes. The BBB attributes of spheroids were confirmed by mapping the localization of cells, observing permeability of angiopep2 and non-permeability of dextran. Fluorescent <jats:italic>Neisseria<\/jats:italic>, <jats:italic>Borrelia<\/jats:italic> or <jats:italic>E. coli<\/jats:italic> (non-neuroinvasive) were incubated with spheroids to observe the adherence, invasion and spheroid integrity. Transcriptome analysis with NGS was employed to investigate the response of BBB cells to infections.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>hBMECs were localized throughout the spheroids, whereas pericytes and astrocytes were concentrated around the core. Within 1 hr of exposure, <jats:italic>Neisseria<\/jats:italic> and <jats:italic>Borrelia<\/jats:italic> adhered to spheroids, and their microcolonization increased from 5 to 24 hrs. Integrity of spheroids was compromised by both <jats:italic>Neisseria<\/jats:italic> and <jats:italic>Borrelia<\/jats:italic>, but not by <jats:italic>E. coli<\/jats:italic> infection. Transcriptome analysis revealed a significant change in the expression of 781 genes (467 up and 314 down regulated) in spheroids infected with <jats:italic>Neisseria<\/jats:italic>, while <jats:italic>Borrelia<\/jats:italic> altered the expression of 621 genes (225 up and 396 down regulated). The differentially expressed genes could be clustered into various biological pathways like cell adhesion, extracellular matrix related, metallothionines, members of TGF beta, WNT signaling, and immune response. Among the differentially expressed genes, 455 (48%) genes were inversely expressed during <jats:italic>Neisseria<\/jats:italic> and <jats:italic>Borrelia<\/jats:italic> infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The self-assembling spheroids were used to perceive the BBB response to neuroinvasive pathogens - <jats:italic>Neisseria<\/jats:italic> and <jats:italic>Borrelia<\/jats:italic>. Compromised integrity of spheroids during <jats:italic>Neisseria<\/jats:italic> and <jats:italic>Borrelia<\/jats:italic> infection as opposed to its intactness and non-adherence of <jats:italic>E. coli<\/jats:italic> (non-neuroinvasive) denotes the pathogen dependent fate of BBB. Genes categorized into various biological functions indicated weakened barrier properties of BBB and heightened innate immune response. Inverse expression of 48% genes commonly identified during <jats:italic>Neisseria<\/jats:italic> and <jats:italic>Borrelia<\/jats:italic> infection exemplifies unique response of BBB to varying neuropathogens.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2023.1326578","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T08:47:37Z","timestamp":1702975657000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Differential transcriptome response of blood brain barrier spheroids to neuroinvasive Neisseria and Borrelia"],"prefix":"10.3389","volume":"13","author":[{"given":"Amod","family":"Kulkarni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Jozefiakov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katar\u00edna","family":"Bhide","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evel\u00edna","family":"Mochna\u0107ov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mangesh","family":"Bhide","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood\u2013brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. 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