Dataset Information

A Study on the Inflammatory Response of the Brain in Neurosyphilis

ABSTRACT: Neurosyphilis (NS) is a clinical condition caused by infection of the central nervous system (CNS) by Treponema pallidum (Tp) that can lead to asymptomatic meningitis and more serious neurological diseases, such as dementia and blindness. However, current studies on the pathogenesis of NS are limited. Here, through the integration analysis of proteomics and single-cell transcriptomics, we identified Toll-like/NF-κB signaling as the key pathway involved in CNS damage caused by Tp. Moreover, monocyte-derived macrophages are key cells involved in the inflammatory response to Tp in the CNS of NS patients. In addition, we found that inflammatory cells in peripheral blood may cause neurological damage through disruption of the blood‒brain barrier (BBB) in individuals with NS. Notably, activation of the Toll-like/NF-κB signaling pathway, as well as dysregulation of neural function, was likewise validated in an in vitro NS brain organoid model. In conclusion, our results revealed the mechanisms of inflammation-mediated brain injury in Tp-induced NS and provided new ideas for the clinical treatment of Tp infection.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ling Leng

PROVIDER: PXD053294 | iProX | Sat Jun 22 00:00:00 BST 2024

REPOSITORIES: iProX

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A Study on the Inflammatory Response of the Brain in Neurosyphilis.

Zhang Qiyu Q Ma Jie J Zhou Jia J Zhang Hanlin H Li Mansheng M Gong Huizi H Wang Yujie Y Zheng Heyi H Li Jun J Leng Ling L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20241122 5

Neurosyphilis (NS) is a clinical condition caused by infection of the central nervous system (CNS) by Treponema pallidum (Tp) that can lead to asymptomatic meningitis and more serious neurological diseases, such as dementia and blindness. However, current studies on the pathogenesis of NS are limited. Here, through the integration analysis of proteomics and single-cell transcriptomics, Toll-like/NF-κB signaling is identified as the key pathway involved in CNS damage caused by Tp. Moreover, monoc ...[more]

PMID: 39574316

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Project description:The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires’ Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis. Three-condition experiment: macrophages left uninfected (negative control), or infected with wildtype Legionella pneumophila, or the mutant Δ5, which lacks five bacterial effectors involved in inhibition of host protein synthesis (lgt1, lgt2, lgt3, sidI, sidL) (two experimental conditions). Biological replicates: two, independently infected, harvested, and hybridized to arrays. One technical replicate per array.

Project description:The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires’ Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis. Four-condition experiment: macrophages left uninfected (negative control), or infected with wildtype Legionella pneumophila, the flagellin-deficient mutant ΔflaA, or the secretion-deficient mutant ΔdotA (three experimental conditions). Biological replicates: two, independently infected, harvested, and hybridized to arrays. One to two technical replicates per array, as indicated in file titles.

Dataset Information

A Study on the Inflammatory Response of the Brain in Neurosyphilis

Publications

A Study on the Inflammatory Response of the Brain in Neurosyphilis.

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