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Meningitic Escherichia Coli Α-Hemolysin Aggravates Blood

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Meningitic Escherichia Coli Α-Hemolysin Aggravates Blood Fu et al. Mol Brain (2021) 14:116 https://doi.org/10.1186/s13041-021-00826-2 RESEARCH Open Access Meningitic Escherichia coli α-hemolysin aggravates blood–brain barrier disruption via targeting TGFβ1-triggered hedgehog signaling Jiyang Fu1,2, Liang Li1,2, Dong Huo1,2, Ruicheng Yang1,2, Bo Yang1,2, Bojie Xu1,2, Xiaopei Yang5, Menghong Dai1,2, Chen Tan1,2,3,4, Huanchun Chen1,2,3,4 and Xiangru Wang1,2,3,4* Abstract Bacterial meningitis is a life-threatening infectious disease with severe neurological sequelae and a high mortality rate, in which Escherichia coli is one of the primary Gram-negative etiological bacteria. Meningitic E. coli infection is often accompanied by an elevated blood–brain barrier (BBB) permeability. BBB is the structural and functional barrier com- posed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, and we have previously shown that astrocytes-derived TGFβ1 physiologically maintained the BBB permeability by triggering a non-canonical hedgehog signaling in brain microvascular endothelial cells (BMECs). Here, we subsequently demonstrated that meningitic E. coli infection could subvert this intercellular communication within BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we identifed E. coli α-hemolysin as the critical determinant responsible for 2 this attenuation through Sp1-dependent TGFBRII reduction and triggering Ca + infux and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG exhibited promising protection against the infection-caused BBB dysfunction. Our work revealed a hedgehog-targeted pathogenic mechanism dur- ing meningitic E. coli-caused BBB disruption and suggested that activating hedgehog signaling within BBB could be a potential protective strategy for future therapy of bacterial meningitis. Keywords: Escherichia coli, α-Hemolysin, Blood–brain barrier, Intercellular communication, TGFβ1, Hedgehog signaling Introduction barrier (BBB), destroy the brain parenchyma and thus Bacterial meningitis is an important life-threatening cause CNS disorders [5]. infection in the central nervous system (CNS), especially BBB is a specialized structure composed of brain in newborn infants, young teenagers, and the elder with microvascular endothelial cells (BMECs), astrocytes, low immunity [1–3]. Escherichia coli is the most common and pericytes. Tis barrier separates the brain from Gram-negative bacillary organism that causes meningi- the bloodstream and maintains the CNS homeostasis tis [4]. Most cases of E. coli meningitis initiate from the [6–8]. Among these component cells, BMECs act as hematogenous spread and develop as circulating patho- the frst and direct barrier unit to determine the BBB genic bacteria penetrate and breakdown the blood–brain function [9, 10]. In decades, multiple efectors have been reported to participate in barrier function regula- tion. For instance, GDNF activated the GFRα1 and led *Correspondence: [email protected] to higher trans-endothelial electrical resistance (TEER) 1 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China and lower permeability of BMECs [11]. Also, Ang1/ Full list of author information is available at the end of the article Tie2 and Flk1 were reported to promote the capillary © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Fu et al. Mol Brain (2021) 14:116 Page 2 of 19 tube-like formation of BMECs [12]. We previously of bacterial-caused CNS dysfunction from perspective demonstrated that astrocytes-derived transforming of intercellular communication within BBB, and shall be growth factor-β1 (TGFβ1) enhanced the endothelial benefcial for future prevention and control of bacterial ZO-1 expression and maintained the BBB integrity meningitis. by triggering a non-canonical hedgehog signaling in BMECs, indicating that the TGFβ1-mediated intercel- Methods lular communication between astrocytes and BMECs is Bacterial strain and cell culture benefcial for BBB integrity maintaining [13], and exog- E. coli strain RS218 (O18:K1:H7) was originally obtained enous TGFβ1 addition would exhibit a protective efect from the cerebrospinal fuid of a neonate with meningitis on BBB. However, whether such TGFβ1-mediated and gifted from Prof. Kwang Sik Kim in Johns Hopkins intercellular cross-talking within BBB could be hijacked University School of Medicine. E. coli strain was grown during meningitic E. coli infection is entirely unknown. aerobically at 37 °C in Luria-Bertani medium overnight. E. coli α-hemolysin (HlyA), a kind of Repeats-in- Te hBMECs were kindly gifted from Prof. Kwang Sik toxin (RTX) exoprotein, of which synthesis, activation Kim in Johns Hopkins University School of Medicine, and secretion are regulated by the hlyCABD operon and routinely cultured in RPMI 1640 supplemented with [14]. Te HlyB and HlyD act as the transporters which 10 % fetal bovine serum (FBS), 2 mM L-glutamine, 1 mM belong to ATP binding cassette (ABC) superfamily and sodium pyruvate, essential amino acids, nonessential the membrane fusion protein (MFP) family, respec- amino acids, vitamins, and penicillin and streptomycin tively. Te precursor pro-HlyA is acylated by HlyC, a (100 U/mL). Te HEK-293 T cells (ATCC® CRL-3216™) fatty acid acyltransferase, and transferred outside the were cultured in Dulbecco’s Modifed Eagle’s Medium cells by HlyB and HlyD. Te posttranslational acyla- (DMEM) with 10 % FBS and penicillin and streptomycin tion of HlyA by HlyC is determinative for the cytotoxic (100 U/mL). All cells were cultured in a 37 °C incubator activity [15, 16]. HlyA is largely identifed in 40-50 % under 5 % CO2 until reaching monolayer confuence. In uropathogenic E. coli (UPEC) strains, such as the some experiments, confuent hBMECs were starved in CFT073, J96, and UTI89 [17]. It has been demonstrated serum-free medium (1:1 mixture of Ham’s F-12 and 199 that the HlyA in UPEC was involved in infammation medium) for 12–16 h before further treatment. activation and cell death in macrophages [18], and the HlyA was shown to induce bladder epithelial cell exfo- Reagents and antibodies liation and urinary tract infection [17]. Meanwhile, a Te hedgehog pathway agonist SAG and protein kinase A variety of hemolysin toxins also played essential roles (PKA)inhibitor H89 were purchased from MedchemEx- in other bacterial pathogens. In Staphylococcus aureus, press (Princeton, NJ, USA). Te immunofuorescence (IF) the hemolysin induced the disseminated intravascular staining kits containing Cy3-labeled goat anti-rabbit IgG coagulation and liver injury [19]. In Listeria monocy- and FITC-labeled goat anti-rabbit IgG, 4’,6-diamidino- togenes, the hemolysin LLO containing PEST-sequence 2-phenylindole (DAPI) reagent, EGTA, and Fluo-3-AM co-opted the host endocytosis machinery, protecting probe were obtained from Beyotime (Shanghai, China). the integrity of the host plasma membrane and ena- Anti-Gli1, anti-Gli2, and anti-ZO-1 antibodies were from bling the growth of bacteria in host cell cytosol [20]. Proteintech (Chicago, IL, USA). Te anti-Sp1 antibody, Unfortunately, except for UPEC, the HlyA function in HRP-conjugated anti-rabbit IgG antibody, HRP-conju- meningitic E. coli infection was poorly investigated so gated anti-mouse IgG antibody, and SimpleChIP® Plus far. Enzymatic Chromatin IP Kit (Magnetic Beads) were pur- In this study, we demonstrated the meningitic E. coli chased from Cell Signaling Technology (Danvers, MA, interference of TGFβ1-mediated intercellular communi- USA). Anti-ZO-1 antibody for IF was from Abcam (Cam- cation between astrocytes and BMECs. Te α-hemolysin bridge, MA, USA). Anti-β-actin antibody was obtained HlyA in meningitic E. coli was shown to decrease the from HuaAn Biotechnology Co., Ltd. (Hangzhou, TGFβ1 receptor TGFBRII and the key transcription China). Te lipofectamine 3000 transfection reagent was factor Gli2 of hedgehog signaling, which fnally led to obtained from Invitrogen (Carlsbad, CA, USA). Mouse BBB disruption. Together with our recent conclusion recombinant TGFβ1 was obtained from R&D system that astrocytes-derived TGFβ1 facilitates BBB func- (Minneapolis, MN, USA). Evan’s blue dye was purchased tion via activating non-canonical hedgehog signaling in from Santa Cruz Biotechnology (Santa Cruz, CA, USA). BMECs [13], we here revealed a novel strategy for men- ingitic E. coli induction of BBB dysfunction by disturb- Mice infection assays ing the regular
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