scholarly journals Site-specific adaptation mechanisms of an oral pathobiont in the oral and gut mucosae

2022 ◽  
Author(s):  
Yijie Guo ◽  
Sho Kitamoto ◽  
Gustavo Caballero-Flores ◽  
Daisuke Watanabe ◽  
Kohei Sugihara ◽  
...  
Keyword(s):  
Oral Mucosa ◽  
Iron Acquisition ◽  
Klebsiella Aerogenes ◽  
Pathogenic Role ◽  
Genomic Locus ◽  
Periodontal Inflammation ◽  
Adaptation Mechanisms ◽  
Gut Mucosa

Periodontal inflammation leads to oral dysbiosis with the expansion of oral pathobionts. Besides the pathogenic role of oral pathobionts during periodontal inflammation, studies have revealed that oral pathobionts contribute to diseases in distant organs beyond the oral mucosa. For example, the oral pathobiont Klebsiella aerogenes, which accumulates in the oral mucosa during periodontitis in mice, can exacerbate colitis when it ectopically colonizes the gastrointestinal tract. However, the precise mechanisms by which oral pathobionts establish their colonization in extra-oral mucosal sites remains incompletely understood. We performed high-throughput in vivo genetic screening to identify fitness genes required for the adaptation of the oral pathobiont K. aerogenes to different mucosal sites – the oral and gut mucosae – in the steady state and during inflammation. In addition, the global transcriptome of K. aerogenes in different environments was analyzed. We determined that K. aerogenes employs genes related to iron acquisition and chaperone usher pili, which are encoded on a newly identified genomic locus named “locus of colonization in the inflamed gut” (LIG), for adaptation in the gut mucosa, particularly during inflammation. In contrast, the LIG virulence factors are not required for K. aerogenes to adapt to the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche as compared to their original niche.

scholarly journals Role of Cathepsin S in Periodontal Inflammation and Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
S. Memmert ◽  
A. Damanaki ◽  
A. V. B. Nogueira ◽  
S. Eick ◽  
M. Nokhbehsaim ◽  
...  
Keyword(s):  
Periodontal Diseases ◽  
Interleukin 1 ◽  
Critical Role ◽  
Gingival Tissue ◽  
Cathepsin S ◽  
Protein Levels ◽  
Periodontal Inflammation

Cathepsin S is a cysteine protease and regulator of autophagy with possible involvement in periodontitis. The objective of this study was to investigate whether cathepsin S is involved in the pathogenesis of periodontal diseases. Human periodontal fibroblasts were cultured under inflammatory and infectious conditions elicited by interleukin-1β and Fusobacterium nucleatum, respectively. An array-based approach was used to analyze differential expression of autophagy-associated genes. Cathepsin S was upregulated most strongly and thus further studied in vitro at gene and protein levels. In vivo, gingival tissue biopsies from rats with ligature-induced periodontitis and from periodontitis patients were also analyzed at transcriptional and protein levels. Multiple gene expression changes due to interleukin-1β and F. nucleatum were observed in vitro. Both stimulants caused a significant cathepsin S upregulation. A significantly elevated cathepsin S expression in gingival biopsies from rats with experimental periodontitis was found in vivo, as compared to that from control. Gingival biopsies from periodontitis patients showed a significantly higher cathepsin S expression than those from healthy gingiva. Our findings provide original evidence that cathepsin S is increased in periodontal cells and tissues under inflammatory and infectious conditions, suggesting a critical role of this autophagy-associated molecule in the pathogenesis of periodontitis.

scholarly journals Study of Staphylococcus aureusPathogenic Genes by Transfer and Expression in the Less Virulent Organism Streptococcus gordonii

2001 ◽  
Vol 69 (2) ◽  
pp. 657-664 ◽  
Author(s):  
P. Stutzmann Meier ◽  
J. M. Entenza ◽  
P. Vaudaux ◽  
P. Francioli ◽  
M. P. Glauser ◽  
...  
Keyword(s):  
Single Gene ◽  
Individual Factors ◽  
Gene Products ◽  
Streptococcus Gordonii ◽  
Pathogenic Role ◽  
Gain Of Function ◽  
Function Strategy

ABSTRACT Because Staphylococcus aureus strains contain multiple virulence factors, studying their pathogenic role by single-gene inactivation generated equivocal results. To circumvent this problem, we have expressed specific S. aureus genes in the less virulent organism Streptococcus gordonii and tested the recombinants for a gain of function both in vitro and in vivo. Clumping factor A (ClfA) and coagulase were investigated. Both gene products were expressed functionally and with similar kinetics during growth by streptococci and staphylococci. ClfA-positive S. gordoniiwas more adherent to platelet-fibrin clots mimicking cardiac vegetations in vitro and more infective in rats with experimental endocarditis (P < 0.05). Moreover, deletingclfA from clfA-positive streptococcal transformants restored both the low in vitro adherence and the low in vivo infectivity of the parent. Coagulase-positive transformants, on the other hand, were neither more adherent nor more infective than the parent. Furthermore, coagulase did not increase the pathogenicity ofclfA-positive streptococci when both clfA andcoa genes were simultaneously expressed in an artificial minioperon in streptococci. These results definitively attribute a role for ClfA, but not coagulase, in S. aureus endovascular infections. This gain-of-function strategy might help solve the role of individual factors in the complex the S. aureus-host relationship.

scholarly journals Siderophore-Mediated Iron Acquisition Plays a Critical Role in Biofilm Formation and Survival of Staphylococcus epidermidis Within the Host

2021 ◽  
Vol 8 ◽  
Author(s):  
Fernando Oliveira ◽  
Tânia Lima ◽  
Alexandra Correia ◽  
Ana Margarida Silva ◽  
Cristina Soares ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Iron Acquisition ◽  
Critical Role ◽  
Siderophore Production ◽  
Restricted Environment ◽  
Underlying Mechanisms ◽  
First Time ◽  
Comprehensive Study

Iron acquisition through siderophores, a class of small, potent iron-chelating organic molecules, is a widely spread strategy among pathogens to survive in the iron-restricted environment found in the host. Although these molecules have been implicated in the pathogenesis of several species, there is currently no comprehensive study addressing siderophore production in Staphylococcus epidermidis. Staphylococcus epidermidis is an innocuous skin commensal bacterium. The species, though, has emerged as a leading cause of implant-associated infections, significantly supported by an inherent ability to form biofilms. The process of adaptation from skin niche environments to the hostile conditions during invasion is yet not fully understood. Herein, we addressed the possible role of siderophore production in S. epidermidis virulence. We first identified and deleted a siderophore homolog locus, sfaABCD, and provided evidence for its involvement in iron acquisition. Our findings further suggested the involvement of siderophores in the protection against oxidative stress-induced damage and demonstrated the in vivo relevance of a siderophore-mediated iron acquisition during S. epidermidis infections. Conclusively, this study addressed, for the first time in this species, the underlying mechanisms of siderophore production, highlighting the importance of a siderophore-mediated iron acquisition under host relevant conditions and, most importantly, its contribution to survival within the host.

scholarly journals Live-cell micromanipulation of a genomic locus reveals interphase chromatin mechanics

2021 ◽  
Author(s):  
Veer I. P. Keizer ◽  
Simon Grosse-Holz ◽  
Maxime Woringer ◽  
Laura Zambon ◽  
Koceila Aizel ◽  
...  
Keyword(s):  
New Technology ◽  
Future Research ◽  
Minor Role ◽  
Polymer Model ◽  
Interphase Chromatin ◽  
Genomic Locus ◽  
Novel Approach ◽  
Physical Principles

AbstractOur understanding of the physical principles organizing the genome in the nucleus is limited by the lack of tools to directly exert and measure forces on interphase chromosomes in vivo and probe their material nature. Here, we present a novel approach to actively manipulate a genomic locus using controlled magnetic forces inside the nucleus of a living human cell. We observe viscoelastic displacements over microns within minutes in response to near-picoNewton forces, which are well captured by a Rouse polymer model. Our results highlight the fluidity of chromatin, with a moderate contribution of the surrounding material, revealing the minor role of crosslinks and topological effects and challenging the view that interphase chromatin is a gel-like material. Our new technology opens avenues for future research, from chromosome mechanics to genome functions.

scholarly journals Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Hiroshi Mitoma ◽  
Mario Manto ◽  
Christiane S. Hampe
Keyword(s):  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
In Vitro Studies ◽  
Acid Decarboxylase ◽  
Pathogenic Role ◽  
Cerebellar Ataxias ◽  
Glutamic Acid Decarboxylase 65

Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum.

scholarly journals Direct Proof of the In Vivo Pathogenic Role of the AChR Autoantibodies from Myasthenia Gravis Patients

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e108327 ◽  
Author(s):  
Gregory Kordas ◽  
George Lagoumintzis ◽  
Sotirios Sideris ◽  
Konstantinos Poulas ◽  
Socrates J. Tzartos
Keyword(s):  
Myasthenia Gravis ◽  
Direct Proof ◽  
Pathogenic Role

scholarly journals Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy

2021 ◽  
Vol 118 (4) ◽  
pp. e2012685118
Author(s):  
Maria Elena Pero ◽  
Cristina Meregalli ◽  
Xiaoyi Qu ◽  
Grace Ji-eun Shin ◽  
Atul Kumar ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Pathogenic Role ◽  
Unmyelinated Fibers ◽  
Microtubule Stability ◽  
Altered Regulation

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.

scholarly journals Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy

2019 ◽  
Author(s):  
Maria Elena Pero ◽  
Cristina Meregalli ◽  
Xiaoyi Qu ◽  
Atul Kumar ◽  
Matthew Shorey ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Pathogenic Role ◽  
Pathogenic Mechanisms ◽  
Mitochondria Dynamics

ABSTRACTThe pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bort-induced peripheral neuropathy in humans. Furthermore, while induction of D2 was sufficient to cause axonopathy and inhibit mitochondria motility, reducing D2 alleviated both axonal degeneration and loss of mitochondria motility promoted by Bort. Altogether, our data demonstrate that Bort, structurally unrelated to tubulin poisons, can affect the tubulin cytoskeleton in sensory neurons in vitro, in vivo and in humans, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. They further reveal a previously unrecognized pathogenic role for D2 in bortezomib-causing CIPN through its regulation of mitochondria dynamics.

scholarly journals Host-Nonspecific Iron Acquisition Systems and Virulence in the Zoonotic Serovar of Vibrio vulnificus

2013 ◽  
Vol 82 (2) ◽  
pp. 731-744 ◽  
Author(s):  
David Pajuelo ◽  
Chung-Te Lee ◽  
Francisco J. Roig ◽  
Manuel L. Lemos ◽  
Lien-I Hor ◽  
...  
Keyword(s):  
Virulence Genes ◽  
Vibrio Vulnificus ◽  
Iron Acquisition ◽  
Membrane Receptors ◽  
Internal Organs ◽  
Content Type ◽  
Core Genes

ABSTRACTThe zoonotic serovar ofVibrio vulnificus(known as biotype 2 serovar E) is the etiological agent of human and fish vibriosis. The aim of the present work was to discover the role of the vulnibactin- and hemin-dependent iron acquisition systems in the pathogenicity of this zoonotic serovar under the hypothesis that both are host-nonspecific virulence factors. To this end, we selected three genes for three outer membrane receptors (vuuA, a receptor for ferric vulnibactin, andhupAandhutR, two hemin receptors), obtained single and multiple mutants as well as complemented strains, and tested them in a series ofin vitroandin vivoassays, using eels and mice as animal models. The overall results confirm thathupAandvuuA, but nothutR, are host-nonspecific virulence genes and suggest that a third undescribed host-specific plasmid-encoded system could also be used by the zoonotic serovar in fish.hupAandvuuAwere expressed in the internal organs of the animals in the first 24 h of infection, suggesting that they may be needed to achieve the population size required to trigger fatal septicemia.vuuAandhupAwere sequenced in strains representative of the genetic diversity of this species, and their phylogenies were reconstructed by multilocus sequence analysis of selected housekeeping and virulence genes as a reference. Given the overall results, we suggest that both genes might form part of the core genes essential not only for disease development but also for the survival of this species in its natural reservoir, the aquatic environment.

scholarly journals Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders

2018 ◽  
Vol 115 (38) ◽  
pp. 9574-9579 ◽  
Author(s):  
He Li ◽  
Lu Lu ◽  
Xuejin Li ◽  
Pierre A. Buffet ◽  
Ming Dao ◽  
...  
Keyword(s):  
Hereditary Spherocytosis ◽  
Severe Disease ◽  
Blood Disorders ◽  
Pathogenic Role ◽  
Human Spleen ◽  
Two Component ◽  
Hereditary Blood Disorders ◽  
Unique Ability

In red blood cell (RBC) diseases, the spleen contributes to anemia by clearing the damaged RBCs, but its unique ability to mechanically challenge RBCs also poses the risk of inducing other pathogenic effects. We have analyzed RBCs in hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), two typical examples of blood disorders that result in membrane protein defects in RBCs. We use a two-component protein-scale RBC model to simulate the traversal of the interendothelial slit (IES) in the human spleen, a stringent biomechanical challenge on healthy and diseased RBCs that cannot be directly observed in vivo. In HS, our results confirm that the RBC loses surface due to weakened cohesion between the lipid bilayer and the cytoskeleton and reveal that surface loss may result from vesiculation of the RBC as it crosses IES. In HE, traversing IES induces sustained elongation of the RBC with impaired elasticity and fragmentation in severe disease. Our simulations thus suggest that in inherited RBC disorders, the spleen not only filters out pathological RBCs but also directly contributes to RBC alterations. These results provide a mechanistic rationale for different clinical outcomes documented following splenectomy in HS patients with spectrin-deficient and ankyrin-deficient RBCs and offer insights into the pathogenic role of human spleen in RBC diseases.

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