Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Streptococcus pneumoniae PepO promotes host anti-infection defense via autophagy in a Toll-like receptor 2/4 dependent manner.

ABSTRACT: Macrophage is essential for host anti-bacterial defense by directly eliminating invading microbes and inducing a series of immune reactions. Here we identified a Streptococcus pneumoniae protein, PepO, as a TLR2/TLR4 bi-ligand. We found that PepO enhances macrophage unspecific phagocytosis and bactericidal activity, which is related to the induction of autophagy in macrophage, for the inhibition of autophagy significantly decreased the phagocytosis and bactericidal activity of PepO-treated macrophage. We confirmed that these effects of PepO are dependent on interacting with both TLR2 and TLR4. The tlr2 or tlr4 deficiency partially abolished the effect of PepO while tlr2/tlr4 deficiency abolished it completely. In vivo study demonstrated that PepO reduced the bacteria load in WT mice significantly, while the depletion of macrophage or tlr2/tlr4 deficiency abrogated the effect of PepO. Our findings suggested the therapeutic potential of PepO and provided experimental evidence for immunotherapy against infectious disease.

SUBMITTER: Shu Z

PROVIDER: S-EPMC7161686 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Nrf2 Modulates Host Defense during Streptococcus pneumoniae Pneumonia in Mice.

Project description:Nrf2 regulates the transcriptional response to oxidative stress. These studies tested the role of Nrf2 during Streptococcus pneumoniae pneumonia and identified Nrf2-dependent genes and pathways in lung tissue and in recruited neutrophils. Nrf2 null and wild type (WT) mice were studied at 6 and 24 h after instillation of S. pneumoniae or PBS. At 6 h, fewer neutrophils were recruited and the number of bacteria remaining in the lungs tended to be less (p = 0.06) in the Nrf2 null compared with WT mice. In uninfected lungs, 53 genes were already differentially expressed in Nrf2 null compared with WT mouse lungs, and gene sets involved in phagocytosis, Fc receptor function, complement, and Ig regulation are enhanced in PBS-treated Nrf2 null gene profiles compared with those of WT mice. These results suggest that initial host defense is enhanced in Nrf2 null mice, resulting in less recruitment of neutrophils. At 24 h, neutrophil recruitment was greater. The percentages of early apoptotic and late apoptotic/necrotic neutrophils were similar. At increasing inoculum numbers, mortality rates strikingly increased from 15 to 31 and 100% in Nrf2 null mice, whereas all WT mice survived, and Nrf2 null mice had a defect in clearance, particularly at the intermediate dose. The mortality was due to enhanced lung injury and greater systemic response. Gene profiling identified differentially regulated genes and pathways in neutrophils and lung tissue, including those involved in redox stress response, metabolism, inflammation, immunoregulatory pathways, and tissue repair, providing insight into the mechanisms for the greater tissue damage and increased neutrophil accumulation.

| S-EPMC5026972 | biostudies-literature

Streptococcus pneumoniae endopeptidase O (PepO) induces trained immunity to defend the host against numerous pathogen infections

Project description:Antibiotic resistance and the pandemic of infectious diseases pose major hazards to human health. As a novel anti-infection strategy, trained immunity has a promising future. Recombinant Streptococcus pneumoniae Endopeptidase O (rPepO) is a novel trained immunity inducer that is a highly effective broad-spectrum anti-infective molecule. Here, we demonstrate that rPepO training induces a protective effect by improving the function of several immune cells. rPepO trains macrophages in the periphery to improve their immunological response. In addition, macrophage-derived complement C3 stimulates B lymphocytes to bolster the host's initial line of defense. While trained-macrophage-derived G-CSF changes the host's hematopoiesis and promotes central trained immunity. The "trained" label is found on freshly differentiated mononuclear macrophages, which also possess significantly enhanced anti-infective properties. Consequently, our research reveals that rPepO can induce peripheral and central trained immunity and possesses broad-spectrum and durable antimicrobial characteristics.

2023-12-31 | GSE222201 | GEO

Importance of Toll-like receptor 9 in host defense against M1T1 group A Streptococcus infections.

Project description:Timely recognition and elimination of invasive group A Streptococcus (GAS) by innate immunity is crucial to control infection. The intracellular pattern recognition receptor Toll-like receptor 9 (TLR9) promotes macrophage hypoxia-inducible factor-1? levels, oxidative burst and nitric oxide production in response to GAS. TLR9 contributes to GAS clearance in vivo in both localized cutaneous and systemic infection models.

| S-EPMC3388268 | biostudies-literature

Streptococcus pneumoniae highjacks host autophagy by deploying CbpC as a decoy for Atg14 depletion

Project description:Pneumococcal cell surface-exposed choline-binding proteins (CBPs) play pivotal roles in multiple infectious processes with pneumococci. Intracellular pneumococci can be recognized at multiple steps during bactericidal autophagy. However, whether CBPs are involved in pneumococci-induced autophagic processes remains unknown. In this study, we demonstrate that CbpC from S. pneumoniae strain TIGR4 activates autophagy through an interaction with Atg14. However, S. pneumoniae also interferes with autophagy by deploying CbpC as a decoy to cause autophagic degradation of Atg14 through an interaction with p62/SQSTM1. Thus, S. pneumoniae suppresses the autophagic degradation of intracellular pneumococci and survives within cells. Domain analysis reveals that the coiled-coil domain of Atg14 and residue Y83 of the dp3 domain in the N-terminal region of CbpC are crucial for both the CbpC-Atg14 interaction and the subsequent autophagic degradation of Atg14. Although homology modeling indicates that CbpC orthologs have similar structures in the dp3 domain, autophagy induction through Atg14 binding is an intrinsic property of CbpC. Our data provide novel insights into the evolutionary hijacking of host-defense systems by intracellular pneumococci.

| S-SCDT-EMBOR-2019-49232V1 | biostudies-other

Streptococcus pneumoniae hijacks host autophagy by deploying CbpC as a decoy for Atg14 depletion.

| S-EPMC7202210 | biostudies-literature

Wnt5A Signaling Promotes Defense Against Bacterial Pathogens by Activating a Host Autophagy Circuit.

Project description:Bacterial pathogens are associated with severe infections (e.g., sepsis) and exacerbation of debilitating conditions such as chronic obstructive pulmonary disease (COPD). The interactions of bacterial pathogens with macrophages, a key component of innate immunity and host defense, are not clearly understood and continue to be intensively studied. Having previously demonstrated a role of Wnt5A signaling in phagocytosis, we proceeded to decipher the connection of Wnt5A signaling with infection by pathogenic bacteria, namely Pseudomonas aeruginosa (PA) and Streptococcus pneumoniae (SP), which are related with the progression of COPD and sepsis. We found that during the initial hours of infection with PA and SP, there is decrease in the steady state levels of the Wnt5A protein in macrophages. Suppression of Wnt5A signaling, moreover, impairs macrophage clearance of the bacterial infection both in vitro and in vivo. Activation of Wnt5A signaling, on the other hand, enhances clearance of the infection. Macrophage-mediated containment of bacterial infection in our study is dependant on Wnt5A-induced Rac1/Disheveled activation and cytochalasin D inhibitable actin assembly, which is associated with ULK1 kinase activity and LC3BII accumulation. Our experimental findings are consistent with Wnt5A signaling-dependent induction of autophagic killing (xenophagy) of PA and SP, as further substantiated by transmission electron microscopy. Overall, our study unveils the prevalence of a Wnt5A-Rac1-Disheveled-mediated actin-associated autophagy circuit as an important component of innate immunity in host macrophages that may turn out crucial for restricting infection by leading bacterial pathogens.

| S-EPMC5900007 | biostudies-literature

Type 1 interferon gene transfer enhances host defense against pulmonary Streptococcus pneumoniae infection via activating innate leukocytes.

Project description:Pneumococcal infections are the leading cause of community-acquired pneumonia. Although the type 1 interferon-α (IFN-α) is a well-known antiviral cytokine, the role of IFN-α in antipneumococcal host defense and its therapeutic potential remain poorly understood. We have investigated these issues by using a murine transgene expression model. We found that in control animals, Streptococcus pneumoniae infection caused severe weight loss and excessive lung inflammation, associated with rapid bacterial outgrowth. In contrast, the animals that received a single dose of an adenoviral vector expressing IFN-α prior to pneumococcal infection demonstrated rapid and effective control of bacterial replication and lung inflammation and improved clinical outcome. Enhanced protection by IFN-α was due to increased activation of neutrophils and macrophages with increased release of reactive oxygen and nitrogen species and bacterial killing. Furthermore, we found that raised levels of IFN-α in the lung remained immune protective even when the gene transfer vector was given at a time postpneumococcal infection. Our study thus shows that the classically antiviral type 1 IFN can be exploited for enhancing immunity against pneumococcal infection via its activating effects on innate immune cells. Our findings hold implications for the therapeutic use of IFN-α gene transfer strategies to combat pneumococcal infections.

| S-EPMC4378291 | biostudies-literature

Streptococcus pneumoniae endopeptidase O (PepO) is a multifunctional plasminogen- and fibronectin-binding protein, facilitating evasion of innate immunity and invasion of host cells.

Project description:Streptococcus pneumoniae infections remain a major cause of morbidity and mortality worldwide. Therefore a detailed understanding and characterization of the mechanism of host cell colonization and dissemination is critical to gain control over this versatile pathogen. Here we identified a novel 72-kDa pneumococcal protein endopeptidase O (PepO), as a plasminogen- and fibronectin-binding protein. Using a collection of clinical isolates, representing different serotypes, we found PepO to be ubiquitously present both at the gene and protein level. In addition, PepO protein was secreted in a growth phase-dependent manner to the culture supernatants of the pneumococcal isolates. Recombinant PepO bound human plasminogen and fibronectin in a dose-dependent manner and plasminogen did not compete with fibronectin for binding PepO. PepO bound plasminogen via lysine residues and the interaction was influenced by ionic strength. Moreover, upon activation of PepO-bound plasminogen by urokinase-type plasminogen activator, generated plasmin cleaved complement protein C3b thus assisting in complement control. Furthermore, direct binding assays demonstrated the interaction of PepO with epithelial and endothelial cells that in turn blocked pneumococcal adherence. Moreover, a pepO-mutant strain showed impaired adherence to and invasion of host cells compared with their isogenic wild-type strains. Taken together, the results demonstrated that PepO is a ubiquitously expressed plasminogen- and fibronectin-binding protein, which plays role in pneumococcal invasion of host cells and aids in immune evasion.

| S-EPMC3591595 | biostudies-literature

Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells.

Project description:Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. The infection process involves bacterial cell surface receptors, which interact with host extracellular matrix components to facilitate colonization and dissemination of bacteria. Here, we investigated the role of host-derived extracellular RNA (eRNA) in the process of pneumococcal alveolar epithelial cell infection. Our study demonstrates that eRNA dose-dependently increased S. pneumoniae invasion of alveolar epithelial cells. Extracellular enolase (Eno), a plasminogen (Plg) receptor, was identified as a novel eRNA-binding protein on S. pneumoniae surface, and six Eno eRNA-binding sites including a C-terminal 15 amino acid motif containing lysine residue 434 were characterized. Although the substitution of lysine 434 for glycine (K434G) markedly diminished the binding of eRNA to Eno, the adherence to and internalization into alveolar epithelial cells of S. pneumoniae strain carrying the C-terminal lysine deletion and the mutation of internal Plg-binding motif were only marginally impaired. Accordingly, using a mass spectrometric approach, we identified seven novel eRNA-binding proteins in pneumococcal cell wall. Given the high number of eRNA-interacting proteins on pneumococci, treatment with RNase1 completely inhibited eRNA-mediated pneumococcal alveolar epithelial cell infection. Our data support further efforts to employ RNAse1 as an antimicrobial agent to combat pneumococcal infectious diseases.

| S-EPMC5125276 | biostudies-literature

Macrophage LC3-associated phagocytosis is an immune defense against <i>Streptococcus pneumoniae</i> that diminishes with host aging.

Project description:Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

| S-EPMC7776987 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data