Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Salmonella and S. aureus Escape From the Clearance of Macrophages via Controlling TFEB.

ABSTRACT: Phagosome- and xenophagosome-lysosome systems play a critical role in the defense of pathogenic bacteria, such as Salmonella and S. aureus, in macrophages. A great part of the bacteria escapes from the digestion and can survive through some mechanisms that are still poorly understood and which require further exploration. Here we identified that Salmonella inhibited the expression and activation of TFEB to blunt the functions of lysosomes and defense of clearance by activating caspase-1. The expression and activation of TFEB were enhanced early under the infection of S. aureus, which was followed by shrinkage to weaken lysosomal functions due to the delayed activation of ERK, mTOR, and STAT3. Thus, we have identified novel escape mechanisms for Salmonella and S. aureus to deepen and strengthen our strategies fighting with pathogens.

SUBMITTER: Rao S

PROVIDER: S-EPMC7726115 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Salmonella and S. aureus Escape From the Clearance of Macrophages via Controlling TFEB.

Rao Shanshan S Xu Tao T Xia Yu Y Zhang Hongfeng H

Frontiers in microbiology 20201126

Phagosome- and xenophagosome-lysosome systems play a critical role in the defense of pathogenic bacteria, such as Salmonella and S. aureus, in macrophages. A great part of the bacteria escapes from the digestion and can survive through some mechanisms that are still poorly understood and which require further exploration. Here we identified that Salmonella inhibited the expression and activation of TFEB to blunt the functions of lysosomes and defense of clearance by activati ...[more]

PMID: 33324360

Similar Datasets

Flagella facilitate escape of Salmonella from oncotic macrophages.

Project description:The intracellular parasite Salmonella enterica serovar Typhimurium causes a typhoid-like systemic disease in mice. Whereas the survival of Salmonella in phagocytes is well understood, little has been documented about the exit of intracellular Salmonella from host cells. Here we report that in a population of infected macrophages Salmonella induces "oncosis," an irreversible progression to eukaryotic cell death characterized by swelling of the entire cell body. Oncotic macrophages (OnMphis) are terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling negative and lack actin filaments (F-actin). The plasma membrane of OnMphis filled with bacilli remains impermeable, and intracellular Salmonella bacilli move vigorously using flagella. Eventually, intracellular Salmonella bacilli intermittently exit host cells in a flagellum-dependent manner. These results suggest that induction of macrophage oncosis and intracellular accumulation of flagellated bacilli constitute a strategy whereby Salmonella escapes from host macrophages.

| S-EPMC2168665 | biostudies-literature

Selenium Treatment Enhanced Clearance of Salmonella in Chicken Macrophages (HD11).

Project description:As an important micronutrient, selenium (Se) plays many essential roles in immune response and protection against pathogens in humans and animals, but underlying mechanisms of Se-based control of salmonella growth within macrophages remain poorly elucidated. In this study, using RNA-seq analyses, we demonstrate that Se treatment (at an appropriate concentration) can modulate the global transcriptome of chicken macrophages HD11. The bioinformatic analyses (KEGG pathway analysis) revealed that the differentially expressed genes (DEGs) were mainly enriched in retinol and glutathione metabolism, revealing that Se may be associated with retinol and glutathione metabolism. Meanwhile, Se treatment increased the number of salmonella invading the HD11 cells, but reduced the number of salmonella within HD11 cells, suggesting that enhanced clearance of salmonella within HD11 cells was potentially modulated by Se treatment. Furthermore, RNA-seq analyses also revealed that nine genes including SIVA1, FAS, and HMOX1 were differentially expressed in HD11 cells infected with salmonella following Se treatment, and GO enrichment analysis showed that these DEGs were mainly enriched in an extrinsic apoptotic signaling pathway. In summary, these results indicate that Se treatment may not only affect retinol and glutathione metabolism in macrophages, but could also inhibit salmonella-induced macrophage apoptosis via an extrinsic apoptotic signaling pathway involving SIVA1.

| S-EPMC6912687 | biostudies-literature

COMMD10-Guided Phagolysosomal Maturation Promotes Clearance of Staphylococcus aureus in Macrophages.

Project description:Staphylococcus aureus is a major cause of infectious disease. Liver Kupffer cells (KCs) are responsible for sequestering and destroying S. aureus through the phagolysosomal pathway. Proteins belonging to the COMMD family emerge as key intracellular regulators of protein trafficking, but the role of COMMD10 in macrophage-mediated S. aureus eradication is unknown. Here we report that COMMD10 in macrophages was necessary for its timely elimination, as demonstrated with two different S. aureus subspecies. In vivo, COMMD10-deficient liver KCs exhibited impaired clearance of systemic S. aureus infection. S. aureus-infected COMMD10-deficient macrophages exhibited impaired activation of the transcription factor EB, resulting in reduced lysosomal biogenesis. Moreover, S. aureus-initiated phagolysosomal maturation and function were significantly attenuated in COMMD10-deficient macrophages. Finally, expression of COMMD/CCDC22/CCDC93 complex, linked to phagolysosomal maturation, was reduced by COMMD10 deficiency. Collectively, these results support an important role for COMMD10 in instructing macrophage phagolysosomal biogenesis and maturation during S. aureus infection.

| S-EPMC6453835 | biostudies-literature

mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases.

Project description:Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases.

| S-EPMC5303831 | biostudies-literature

Caspase-11 counteracts mitochondrial ROS-mediated clearance of Staphylococcus aureus in macrophages.

Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a growing health concern due to increasing resistance to antibiotics. As a facultative intracellular pathogen, MRSA is capable of persisting within professional phagocytes including macrophages. Here, we identify a role for CASP11 in facilitating MRSA survival within murine macrophages. We show that MRSA actively prevents the recruitment of mitochondria to the vicinity of the vacuoles they reside in to avoid intracellular demise. This process requires CASP11 since its deficiency allows increased association of MRSA-containing vacuoles with mitochondria. The induction of mitochondrial superoxide by antimycin A (Ant A) improves MRSA eradication in casp11-/- cells, where mitochondria remain in the vicinity of the bacterium. In WT macrophages, Ant A does not affect MRSA persistence. When mitochondrial dissociation is prevented by the actin depolymerizing agent cytochalasin D, Ant A effectively reduces MRSA numbers. Moreover, the absence of CASP11 leads to reduced cleavage of CASP1, IL-1β, and CASP7, as well as to reduced production of CXCL1/KC. Our study provides a new role for CASP11 in promoting the persistence of Gram-positive bacteria.

| S-EPMC6893291 | biostudies-literature

Corrigendum: mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases.

Project description:This corrects the article DOI: 10.1038/ncomms14338.

| S-EPMC5474731 | biostudies-literature

Controlling escape from angiogenesis inhibitors.

Project description:Selective inhibition of vascular endothelial growth factor (VEGF) increases the efficacy of chemotherapy and has beneficial effects on multiple advanced cancers, but response is often limited and the disease eventually progresses. Changes in the tumour microenvironment--hypoxia among them--that result from vascular pruning, suppressed angiogenesis and other consequences of VEGF inhibition can promote escape and tumour progression. New therapeutic approaches that target pathways that are involved in the escape mechanisms add the benefits of blocking tumour progression to those of slowing tumour growth by inhibiting angiogenesis.

| S-EPMC3969886 | biostudies-literature

YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization.

Project description:As a master regulator of the macroautophagy/autophagy-lysosomal pathway, TFEB (transcription factor EB) plays a prominent role in regulating neurodegenerative diseases and cancer. The transcription activity of TFEB is tightly controlled by phosphorylation and dephosphorylation. Phosphorylated S211 (p-S211) of TFEB can be recognized by YWHA/14-3-3 proteins for TFEB cytoplasmic localization. Here, we characterized the interactions between phosphorylated TFEB and YWHA/14-3-3 proteins and determined the structures of YWHA/14-3-3 proteins in complex with a TFEB p-S211-peptide. Although the critical arginine for YWHA/14-3-3 recognition is missing in the N terminus of the TFEB p-S211-peptide, the C-terminal additional hydrophobic residues of the peptide unexpectedly occupy nearly half of the target-binding groove of YWHA/14-3-3 proteins, which compensates for the N-terminal defect and is distinct from the canonical YWHA/14-3-3-binding mode. Mutations of essential residues in the interaction interface between TFEB and YWHA/14-3-3 proteins disrupted their interactions and severely impaired the cytoplasmic localization of TFEB, which altered the expression of TFEB target genes and affected autophagy. Thus, YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization and its activity. Abbreviation: ACTB: actin beta; ALP: autophagy-lysosomal pathway; ATP6V1H: ATPase H+ transporting V1 subunit H; bHLH: basic helix-loop-helix; CLEAR: coordinated lysosomal expression and regulation; Co-IP: co-immunoprecipitation; CTSB: cathepsin B; CTSD: cathepsin D; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MITF: melanocyte inducing transcription factor; NLS: nuclear localization signal; TFEB: transcription factor EB; YWHA/14-3-3: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein.

| S-EPMC6526839 | biostudies-literature

Salmonella Virulence and Immune Escape.

Project description:Salmonella genus represents the most common foodborne pathogens causing morbidity, mortality, and burden of disease in all regions of the world. The introduction of antimicrobial agents and Salmonella-specific phages has been considered as an effective intervention strategy to reduce Salmonella contamination. However, data from the United States, European countries, and low- and middle-income countries indicate that Salmonella cases are still a commonly encountered cause of bacterial foodborne diseases globally. The control programs have not been successful and even led to the emergence of some multidrug-resistant Salmonella strains. It is known that the host immune system is able to effectively prevent microbial invasion and eliminate microorganisms. However, Salmonella has evolved mechanisms of resisting host physical barriers and inhibiting subsequent activation of immune response through their virulence factors. There has been a high interest in understanding how Salmonella interacts with the host. Therefore, in the present review, we characterize the functions of Salmonella virulence genes and particularly focus on the mechanisms of immune escape in light of evidence from the emerging mainstream literature.

| S-EPMC7143636 | biostudies-literature

Genetic and chemical activation of TFEB mediates clearance of aggregated ?-synuclein.

Project description:Aggregation of ?-synuclein (?-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of ?-syn aggregates results from aberrant accumulation of misfolded ?-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in preventing the accumulation of ?-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated ?-syn by inducing autophagic clearance of ?-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-?-cyclodextrin promotes autophagic clearance of aggregated ?-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of ?-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of ?-syn aggregates.

| S-EPMC4366176 | biostudies-literature