Bacteria reduce flagellin synthesis to evade microglia-astrocyte-driven immunity in the brain

Sun, Hao; Wan, Xuehua; Yu, Fan; Liu, Peng; Song, Yajun; Zhu, Ning; Duan, Zhifeng; Wang, Qian; Chen, Fang; Zhou, Chunxia; Zheng, Yangyang; Ding, Peng; Liu, Fenxia; Feng, Lu; Kim, Kwang Sik; Wang, Lei

doi:10.1016/j.celrep.2022.111033

Cited by 14 publications

(7 citation statements)

References 69 publications

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“…In S. enterica , a leader RNA originating from the mgtCBR virulence operon was shown to affect the synthesis of one of the two flagellin genes that exist in this bacterium, impacting virulence and motility ( Choi et al, 2017 ). In neonatal meningitis-causing E. coli , a sRNA missing from the E. coli MG1655 strain used in our study, was shown to reduce fliC mRNA levels ( Sun et al, 2022 ). Additionally, a very recent study of the Campylobacter jejuni FlmE and FlmR sRNAs showed that these two sRNAs have opposite effects on flagellar gene expression ( König et al, 2023 ), resembling the opposing effects of MotR and FliX in E. coli .…”

Section: Discussionmentioning

confidence: 89%

σ28-dependent small RNA regulation of flagella biosynthesis

Melamed

Zhang

Jarník

et al. 2023

eLife

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Flagella are important for bacterial motility as well as for pathogenesis. Synthesis of these structures is energy intensive and, while extensive transcriptional regulation has been described, little is known about the posttranscriptional regulation. Small RNAs (sRNAs) are widespread posttranscriptional regulators, most base pairing with mRNAs to affect their stability and/or translation. Here we describe four UTR-derived sRNAs (UhpU, MotR, FliX and FlgO) whose expression is controlled by the flagella sigma factor σ28 (fliA) in Escherichia coli. Interestingly, the four sRNAs have varied effects on flagellin protein levels, flagella number and cell motility. UhpU, corresponding to the 3’ UTR of a metabolic gene, likely has hundreds of targets including a transcriptional regulator at the top flagella regulatory cascade connecting metabolism and flagella synthesis. Unlike most sRNAs, MotR and FliX base pair within the coding sequences of target mRNAs and uniquely act on ribosomal protein mRNAs connecting ribosome production and flagella synthesis. The study shows how sRNA-mediated regulation can overlay a complex network enabling nuanced control of flagella synthesis.

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Section: Discussionmentioning

confidence: 89%

σ28-dependent small RNA regulation of flagella biosynthesis

Melamed

Zhang

Jarník

et al. 2023

eLife

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“…S9 ) ( 38 ). Although some bacterial pathogens have gained the ability to counteract host immunity in the brain and immune responses against these bacteria in the brain can be substantial ( 39 , 40 ), it is not surprising that only a small number of bacteria invading the brain can lead to meningitis ( Figs. 4 O , 5 G , and 6 D and E ).…”

Section: Discussionmentioning

confidence: 99%

Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood–brain barrier

Cheng,

Zheng,

Yang

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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The human blood–brain barrier (BBB) comprises a single layer of brain microvascular endothelial cells (HBMECs) protecting the brain from bloodborne pathogens. Meningitis is among the most serious diseases, but the mechanisms by which major meningitis-causing bacterial pathogens cross the BBB to reach the brain remain poorly understood. We found that Streptococcus pneumoniae , group B Streptococcus , and neonatal meningitis Escherichia coli commonly exploit a unique vesicle fusion mechanism to hitchhike on transferrin receptor (TfR) transcytosis to cross the BBB and illustrated the details of this process in human BBB model in vitro and mouse model. Toll-like receptor signals emanating from bacteria-containing vesicles (BCVs) trigger K33-linked polyubiquitination at Lys168 and Lys181 of the innate immune regulator TRAF3 and then activate the formation of a protein complex containing the guanine nucleotide exchange factor RCC2, the small GTPase RalA and exocyst subcomplex I (SC I) on BCVs. The distinct function of SEC6 in SC I, interacting directly with RalA on BCVs and the SNARE protein SNAP23 on TfR vesicles, tethers these two vesicles and initiates the fusion. Our results reveal that innate immunity triggers a unique modification of TRAF3 and the formation of the HBMEC-specific protein complex on BCVs to authenticate the precise recognition and selection of TfR vesicles to fuse with and facilitate bacterial penetration of the BBB.

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“…9m). These findings suggest that C3 may be expressed by astrocytes to exert natural antimicrobial functions 49,50 around sites of tissue damage and that C3 expression is not necessarily an absolute indicator of a neurotoxic reactive astrocyte phenotype.…”

Section: Phenotypic Features Of Mature Lesion Border Astrocytesmentioning

confidence: 97%

“…5e). Microbiocidal 49,50 C3 and C4b were initially downregulated at 2 and 5 days but were then persistently upregulated through 70 days (Fig. 5e), and immunoreactive C3 protein was prominently detected in lesion border astrocytes that interfaced with non-neural lesion core cells in SCI and stroke (Fig.…”

Section: Immune Regulation Antigen Presentation Antimicrobial Defensementioning

confidence: 98%

Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice

O’Shea,

Ao,

Wang

et al. 2024

Nat Neurosci

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Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes; however, fundamental features of these cells are poorly understood. Here we show that following spinal cord injury or stroke, 90% and 10% of border-forming astrocytes derive, respectively, from proliferating local astrocytes and oligodendrocyte progenitor cells in adult mice of both sexes. Temporal transcriptome analysis, single-nucleus RNA sequencing and immunohistochemistry show that after focal CNS injury, local mature astrocytes dedifferentiate, proliferate and become transcriptionally reprogrammed to permanently altered new states, with persisting downregulation of molecules associated with astrocyte–neuron interactions and upregulation of molecules associated with wound healing, microbial defense and interactions with stromal and immune cells. These wound repair astrocytes share morphologic and transcriptional features with perimeningeal limitans astrocytes and are the predominant source of neuroprotective borders that re-establish CNS integrity around lesions by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.

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Bacteria reduce flagellin synthesis to evade microglia-astrocyte-driven immunity in the brain

Cited by 14 publications

References 69 publications

σ28-dependent small RNA regulation of flagella biosynthesis

σ28-dependent small RNA regulation of flagella biosynthesis

Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood–brain barrier

Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice

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