scholarly journals ADP-heptose is a pathogen-associated molecular pattern of Shigella flexneri infection

2018 ◽  
Author(s):  
Diego García-Weber ◽  
Anne-Sophie Dangeard ◽  
Johan Cornil ◽  
Linda Thai ◽  
Héloise Rytter ◽  
...  
Keyword(s):  
Shigella Flexneri ◽  
Deletion Mutants ◽  
Gram Negative Bacteria ◽  
Biosynthesis Pathway ◽  
Inflammatory Gene Expression ◽  
Molecular Pattern ◽  
Pathogen Recognition Receptors ◽  
Molecular Patterns ◽  
Rule Out

ABSTRACTDuring an infection, the detection of pathogens is mediated through interactions between pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors. β-Heptose 1,7-bisphosphate (βHBP), a metabolite of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a PAMP of gram-negative bacteria. It was reported that βHBP sensing leads within minutes to oligomerization of the protein TIFA, a mechanism controlling NF-κB activation and pro-inflammatory gene expression. Here, we compared the ability of chemically synthesized βHBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. In contrast to lysate, we found that βHBP fails to trigger rapid oligomerization of TIFA. βHBP only induces delayed signaling, suggesting that it has to be processed intracellularly to induce inflammation. By dissecting the LPS biosynthesis pathway with deletion mutants and functional complementation experiments, we show that ADP-D-glycero-β-D-manno-heptose and ADP-L-glycero-β-D-manno-heptose are the bacterial metabolites responsible for rapid TIFA oligomerization, and that they strongly induce interleukin-8 expression during S. flexneri infection. Altogether, our results rule out a major role of βHBP in S. flexneri infection and identify ADP-heptose as a new PAMP.

scholarly journals Clinical Management of Il-6 Driven Cytokine Storm Related to COVID-19 in a Patient with Recent Spinal Cord Stimulator Implants: A Case Report

2020 ◽  
Vol 10 (4) ◽  
Author(s):  
Alfonso Papa ◽  
Maria Teresa Di Dato ◽  
Pietro Buonavolonta ◽  
Elisabetta Saracco ◽  
Anna Maria Salzano ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Local Reaction ◽  
Spinal Cord Stimulator ◽  
Cytokine Storm ◽  
Case Presentation ◽  
Pathogen Recognition Receptors ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Total Remission

Introduction: In the last months of 2019, the advent of a new virus called SARS-CoV-2 caused the spread of a pandemic disease, COVID-19, that has afflicted patients with chronic pain. Case Presentation: We describe a COVID-19 patient recently implanted with a spinal cord stimulator for FBSS, treated with Tocilizumab for cytokine storm complicating SARS-COV-2 infection. This patient developed a delayed hyperimmune reaction, causing an inflammatory reaction in the surgical pocket site, well treated with total remission. The total resolution of this local reaction occurred after the resolution of systemic COVID-19 infection by Tocilizumab. Conclusions: We discuss the balance between damage-associated molecular patterns (DAMPs) and pathogen-recognition receptors (PRRs), and the putative role of polymorphism in the IL-6/174 position of the promoter region.

scholarly journals The Role of Bacteria and Pattern Recognition Receptors in GvHD

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
E. Holler ◽  
K. Landfried ◽  
J. Meier ◽  
M. Hausmann ◽  
G. Rogler
Keyword(s):  
Innate Immunity ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Long Time ◽  
Potential Risk Factors ◽  
Pathogen Recognition Receptors ◽  
Antigen Presenting ◽  
Molecular Patterns ◽  
Gastrointestinal Decontamination

Graft-versus-Host Disease (GvHD) is the most serious complication of allogeneic stem cell transplantation (SCT) and results from an activation of donor lymphocytes by recipient antigen-presenting cells (APCs). For a long time, it has been postulated that the intestinal microflora and endotoxin exert a crucial step in this APC activation, as there is early and severe gastrointestinal damage induced by pretransplant conditioning. With the detailed description of pathogen-associated molecular patterns and pathogen recognition receptors single nucleotide polymorphisms of TLRs and especially NOD2 have been identified as potential risk factors of GvHD and transplant related complications thus further supporting the crucial role of innate immunity in SCT, related complications. Gastrointestinal decontamination and neutralization of endotoxin have been used to interfere with this early axis of activation with some success but more specific approaches of modulation of innate immunity are needed for further improvement of clinical outcome.

scholarly journals Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Gloria Lopez-Castejon ◽  
Mariola J. Edelmann
Keyword(s):  
Small Molecules ◽  
Tissue Injury ◽  
Immune Surveillance ◽  
Therapeutic Targets ◽  
Inflammasome Activation ◽  
Ubiquitin System ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Potential Use

Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies.

scholarly journals Role of Damage-Associated Molecular Pattern/Cell Death Pathways in Vaccine-Induced Immunity

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2340
Author(s):  
Sun Min Lee ◽  
Paul Kim ◽  
Jinsuh You ◽  
Eui Ho Kim
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Natural Infection ◽  
Cell Death Pathways ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Induced Immunity ◽  
Pathogenic Infection

Immune responses induced by natural infection and vaccination are known to be initiated by the recognition of microbial patterns by cognate receptors, since microbes and most vaccine components contain pathogen-associated molecular patterns. Recent discoveries on the roles of damage-associated molecular patterns (DAMPs) and cell death in immunogenicity have improved our understanding of the mechanism underlying vaccine-induced immunity. DAMPs are usually immunologically inert, but can transform into alarming signals to activate the resting immune system in response to pathogenic infection, cellular stress and death, or tissue damage. The activation of DAMPs and cell death pathways can trigger local inflammation, occasionally mediating adaptive immunity, including antibody- and cell-mediated immune responses. Emerging evidence indicates that the components of vaccines and adjuvants induce immunogenicity via the stimulation of DAMP/cell death pathways. Furthermore, strategies for targeting this pathway to enhance immunogenicity are being investigated actively. In this review, we describe various DAMPs and focus on the roles of DAMP/cell death pathways in the context of vaccines for infectious diseases and cancer.

scholarly journals The Controversies Surrounding Tocilizumab Administration Following Pathogen-Associated Molecular Pattern (PAMP) Induced by COVID-19

2020 ◽  
Author(s):  
Shayesteh Gheibi ◽  
Farhad Najmeddin ◽  
Bita Shahrami ◽  
Kourosh Sadeghi ◽  
Mojtaba Mojtahedzadeh
Keyword(s):  
Viral Infections ◽  
Virus Disease ◽  
Organ Damage ◽  
Immune Dysregulation ◽  
Global Pandemic ◽  
Molecular Pattern ◽  
Life Threatening ◽  
Molecular Patterns ◽  
Valuable Role

A new corona virus disease (COVID-19) has affected more than 17 million people worldwide so far, and has become a global pandemic. Since there is no definitive cure for this life threatening disease, many clinical studies are in progress in this regard. Pathogen-associated molecular patterns (PAMP) prompting by coronavirus seems to generate cellular, structural, and functional derangements induced by immune dysregulation as well as many biological abnormalities including cytokine storm. The role of IL-6 in viral pneumonia and also its inhibition impact on the prevention of organ damage are still unknown.IL-6 seems to behave as a double blade evil cytokine, by playing a valuable role in cell to cell natural physiological communication. Tocilizumab, as an inhibitor of interleukin (IL)-6, may interrupt the paracrine system while causing dissemination of bacterial, fungal, and other viral infections, especially COVID-19, who are at a high-risk for development of sepsis and life-threatening superinfection.

scholarly journals Advances in Understanding Activation and Function of the NLRC4 Inflammasome

2021 ◽  
Vol 22 (3) ◽  
pp. 1048
Author(s):  
Balamurugan Sundaram ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Innate Immune ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Immune Receptors ◽  
Caspase 1 ◽  
Cell Death Pathway ◽  
Molecular Patterns

Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1–mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro–IL-1β and pro–IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Salmonella Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease.

scholarly journals The 33 carboxyl-terminal residues of Spa40 orchestrate the multi-step assembly process of the type III secretion needle complex in Shigella flexneri

Microbiology ◽  
2010 ◽  
Vol 156 (9) ◽  
pp. 2807-2817 ◽  
Author(s):  
Anne Botteaux ◽  
Christian A. Kayath ◽  
Anne-Laure Page ◽  
Nouredine Jouihri ◽  
Musa Sani ◽  
...  
Keyword(s):  
Type Iii Secretion ◽  
Shigella Flexneri ◽  
Gram Negative Bacteria ◽  
Assembly Process ◽  
Gram Negative ◽  
Type Iii ◽  
Carboxyl Terminal ◽  
Functional Analyses ◽  
Two Hybrid

The type III secretion apparatus (T3SA) is a central virulence factor of many Gram-negative bacteria. Its overall morphology consists of a cytoplasmic region, inner- and outer-membrane sections and an extracellular needle. In Shigella, the length of the needle is regulated by Spa32. To understand better the role of Spa32 we searched for its interacting partners using a two-hybrid screen in yeast. We found that Spa32 interacts with the 33 C-terminal residues (CC*) of Spa40, a member of the conserved FlhB/YscU family. Using a GST pull-down assay we confirmed this interaction and identified additional interactions between Spa40 and the type III secretion components Spa33, Spa47, MxiK, MxiN and MxiA. Inactivation of spa40 abolished protein secretion and led to needleless structures. Genetic and functional analyses were used to investigate the roles of residues L310 and V320, located within the CC* domain of Spa40, in the assembly of the T3SA. Spa40 cleavage, at the conserved NPTH motif, is required for assembly of the T3SA and for its interaction with Spa32, Spa33 and Spa47. In contrast, unprocessed forms of Spa40 interacted only with MxiA, MxiK and MxiN. Our data suggest that the conformation of the cytoplasmic domain of Spa40 defines the multi-step assembly process of the T3SA.

Ultrastructure of periplasmic bodies in gram-negative bacteria

1990 ◽  
Vol 48 (3) ◽  
pp. 640-641
Author(s):  
Xie Nianming ◽  
Ding Shaoqing ◽  
Wang Luping ◽  
Yuan Zenglin ◽  
Zhan Guolai ◽  
...  
Keyword(s):  
Electron Microscope ◽  
Campylobacter Jejuni ◽  
Proteus Mirabilis ◽  
Shigella Flexneri ◽  
Morphological Description ◽  
Gram Negative Bacteria ◽  
Periplasmic Space ◽  
Clostridium Tetani ◽  
Gram Negative ◽  
Brucella Canis

Perhaps the data about periplasmic enzymes are obtained through biochemical methods but lack of morphological description. We have proved the existence of periplasmic bodies by electron microscope and described their ultrastructures. We hope this report may draw the attention of biochemists and mrophologists to collaborate on researches in periplasmic enzymes or periplasmic bodies with each other.One or more independent bodies may be seen in the periplasmic space between outer and inner membranes of Gram-negative bacteria, which we called periplasmic bodies. The periplasmic bodies have been found in seven species of bacteria at least, including the Pseudomonas aeroginosa. Shigella flexneri, Echerichia coli. Yersinia pestis, Campylobacter jejuni, Proteus mirabilis, Clostridium tetani. Vibrio cholerae and Brucella canis.

scholarly journals Flavonoids Ameliorate Stress-Induced Depression by Preventing NLRP3 Inflammasome Priming

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1231-1231
Author(s):  
Giulio Pasinetti
Keyword(s):  
Mrna Expression ◽  
Chronic Stress ◽  
Nlrp3 Inflammasome ◽  
Signaling Cascades ◽  
Dietary Polyphenols ◽  
Funding Sources ◽  
Glycation End Products ◽  
Molecular Patterns

Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), stimulating the NLRP3 inflammasome. NLRP3 activation triggers the release of pro-inflammatory cytokine IL-1β. The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. Our previous studies show that polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the relevant mechanism has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US – induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration significantly improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary flavonoids prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of dietary polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH/ODS.

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