scholarly journals Peptidoglycan Recognition Protein 4 Suppresses Early Inflammatory Responses toBordetella pertussisand Contributes to Sphingosine-1-Phosphate Receptor Agonist-Mediated Disease Attenuation

2018 ◽  
Vol 87 (2) ◽  
Author(s):  
Ciaran Skerry ◽  
William E. Goldman ◽  
Nicholas H. Carbonetti
Keyword(s):  
Bordetella Pertussis ◽  
Inflammatory Responses ◽  
Whooping Cough ◽  
Pulmonary Inflammation ◽  
Breakdown Product ◽  
Transcriptional Responses ◽  
Content Type ◽  
Peptidoglycan Recognition Protein ◽  
Sphingosine 1 Phosphate ◽  
Recognition Protein

ABSTRACTIncidence of whooping cough (pertussis), a bacterial infection of the respiratory tract caused by the bacteriumBordetella pertussis, has reached levels not seen since the 1950s. Antibiotics fail to improve the course of disease unless administered early in infection. Therefore, there is an urgent need for the development of antipertussis therapeutics. Sphingosine-1-phosphate receptor (S1PR) agonists have been shown to reduce pulmonary inflammation duringBordetella pertussisinfection in mouse models. However, the mechanisms by which S1PR agonists attenuate pertussis disease are unknown. We report the results of a transcriptome sequencing study examining pulmonary transcriptional responses inB. pertussis-infected mice treated with S1PR agonist AAL-R or vehicle control. This study identified peptidoglycan recognition protein 4 (PGLYRP4) as one of the most highly upregulated genes in the lungs of infected mice following S1PR agonism. PGLYRP4, a secreted, innate mediator of host defenses, was found to limit early inflammatory pathology in knockout mouse studies. Further, S1PR agonist AAL-R failed to attenuate pertussis disease in PGLYRP4 knockout (KO) mice.B. pertussisvirulence factor tracheal cytotoxin (TCT), a secreted peptidoglycan breakdown product, induces host tissue damage. TCT-oversecreting strains were found to drive an early inflammatory response similar to that observed in PGLYRP4 KO mice. Further, TCT-oversecreting strains induced significantly greater pathology in PGLYRP4-deficient animals than their wild-type counterparts. Together, these data indicate that S1PR agonist-mediated protection against pertussis disease is PGLYRP4 dependent. Our data suggest PGLYRP4 functions, in part, by preventing TCT-induced airway damage.

Triggering receptor expressed on myeloid cells-1 (TREM-1) contributes to Bordetella pertussis inflammatory pathology

2021 ◽  
Author(s):  
Danisha Gallop ◽  
Karen Scanlon ◽  
Jeremy Ardanuy ◽  
Alexander B. Sigalov ◽  
Nicholas H. Carbonetti ◽  
...  
Keyword(s):  
Bordetella Pertussis ◽  
Inflammatory Responses ◽  
Whooping Cough ◽  
Pulmonary Inflammation ◽  
Myeloid Cells ◽  
Cell Surface Receptor ◽  
Bacterial Burden ◽  
Emerging Pathogens ◽  
Pertussis Infection ◽  
Bacterial Control

Whooping cough (pertussis) is a severe pulmonary infectious disease caused by the bacteria Bordetella pertussis . Pertussis infects an estimated 24 million people annually, resulting in >150,000 deaths. The NIH placed pertussis on the list of emerging pathogens in 2015. Antibiotics are ineffective unless administered before the onset of the disease characteristic cough. Therefore, there is an urgent need for novel pertussis therapeutics. We have shown that sphingosine-1-phosphate receptor (S1PR) agonists reduce pertussis inflammation, without increasing bacterial burden. Transcriptomic studies were performed to identify this mechanism and allow for the development of pertussis therapeutics which specifically target problematic inflammation without sacrificing bacterial control. These data suggested a role for triggering receptor expressed on myeloid cells-1 (TREM-1). TREM-1 cell surface receptor functions as an amplifier of inflammatory responses. Expression of TREM-1 is increased in response to bacterial infection of mucosal surfaces. In mice, B. pertussis infection results in TLR9-dependent increased expression of TREM-1 and its associated cytokines. Interestingly, S1PR agonists dampen pulmonary inflammation and TREM-1 expression. Mice challenged intranasally with B. pertussis and treated with ligand-dependent (LP17) and ligand-independent (GF9) TREM-1 inhibitors showed no differences in bacterial burden and significantly reduced TNF-α and CCL-2 expression compared to controls. Mice receiving TREM-1 inhibitors showed reduced pulmonary inflammation compared to controls indicating that TREM-1 promotes inflammatory pathology, but not bacterial control, during pertussis infection. This implicates TREM-1 as a potential therapeutic target for the treatment of pertussis.

scholarly journals G Proteins Gαi1/3Are Critical Targets for Bordetella pertussis Toxin-Induced Vasoactive Amine Sensitization

2013 ◽  
Vol 82 (2) ◽  
pp. 773-782 ◽  
Author(s):  
Sean A. Diehl ◽  
Benjamin McElvany ◽  
Rajkumar Noubade ◽  
Nathan Seeberger ◽  
Brock Harding ◽  
...  
Keyword(s):  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Inflammatory Responses ◽  
Whooping Cough ◽  
Differential Susceptibility ◽  
Inbred Strains ◽  
Content Type ◽  
Multiple Loci ◽  
Inbred Strains Of Mice

ABSTRACTPertussis toxin (PTX) is an AB5-type exotoxin produced by the bacteriumBordetella pertussis, the causative agent of whooping cough.In vivointoxication with PTX elicits a variety of immunologic and inflammatory responses, including vasoactive amine sensitization (VAAS) to histamine (HA), serotonin (5-HT), and bradykinin (BDK). Previously, by using a forward genetic approach, we identified the HA H1receptor (Hrh1/H1R) as the gene in mice that controls differential susceptibility toB. pertussisPTX-induced HA sensitization (Bphs). Here we show, by using inbred strains of mice, F1hybrids, and segregating populations, that, unlike Bphs, PTX-induced 5-HT sensitivity (Bpss) and BDK sensitivity (Bpbs) are recessive traits and are separately controlled by multiple loci unlinked to 5-HT and BDK receptors, respectively. Furthermore, we found that PTX sensitizes mice to HA independently of Toll-like receptor 4, a purported receptor for PTX, and that the VAAS properties of PTX are not dependent upon endothelial caveolae or endothelial nitric oxide synthase. Finally, by using mice deficient in individual Gαi/oG-protein subunits, we demonstrate that Gαi1and Gαi3are the criticalin vivotargets of ADP-ribosylation underlying VAAS elicited by PTX exposure.

scholarly journals Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection

2014 ◽  
Vol 82 (10) ◽  
pp. 4212-4221 ◽  
Author(s):  
Karen M. Scanlon ◽  
Yael Gau ◽  
Jingsong Zhu ◽  
Ciaran Skerry ◽  
Susan M. Wall ◽  
...  
Keyword(s):  
Mouse Models ◽  
Bordetella Pertussis ◽  
Pulmonary Inflammation ◽  
Dependent Manner ◽  
Lung Pathology ◽  
Transcriptional Responses ◽  
Pertussis Infection ◽  
Content Type ◽  
Young Infants ◽  
Anion Transporter

ABSTRACTPertussis disease, characterized by severe and prolonged coughing episodes, can progress to a critical stage with pulmonary inflammation and death in young infants. However, there are currently no effective treatments for pertussis. We previously studied the role of pertussis toxin (PT), an importantBordetella pertussisvirulence factor, in lung transcriptional responses toB. pertussisinfection in mouse models. One of the genes most highly upregulated in a PT-dependent manner encodes an epithelial transporter of bicarbonate, chloride, and thiocyanate, named pendrin, that contributes to asthma pathology. In this study, we found that pendrin expression is upregulated at both gene and protein levels in the lungs ofB. pertussis-infected mice. Pendrin upregulation is associated with PT production by the bacteria and with interleukin-17A (IL-17A) production by the host.B. pertussis-infected pendrin knockout (KO) mice had higher lung bacterial loads than infected pendrin-expressing mice but had significantly reduced levels of lung inflammatory pathology. However, reduced pathology did not correlate with reduced inflammatory cytokine expression. Infected pendrin KO mice had higher levels of inflammatory cytokines and chemokines than infected pendrin-expressing mice, suggesting that these inflammatory mediators are less active in the airways in the absence of pendrin. In addition, treatment ofB. pertussis-infected mice with the carbonic anhydrase inhibitor acetazolamide reduced lung inflammatory pathology without affecting pendrin synthesis or bacterial loads. Together these data suggest that PT contributes to pertussis pathology through the upregulation of pendrin, which promotes conditions favoring inflammatory pathology. Therefore, pendrin may represent a novel therapeutic target for treatment of pertussis disease.

scholarly journals Bordetella pertussis Lipid A Glucosamine Modification Confers Resistance to Cationic Antimicrobial Peptides and Increases Resistance to Outer Membrane Perturbation

2014 ◽  
Vol 58 (8) ◽  
pp. 4931-4934 ◽  
Author(s):  
Nita R. Shah ◽  
Robert E. W. Hancock ◽  
Rachel C. Fernandez
Keyword(s):  
Immune System ◽  
Antimicrobial Peptides ◽  
Outer Membrane ◽  
Bordetella Pertussis ◽  
Lipid A ◽  
Whooping Cough ◽  
Human Immune System ◽  
Cationic Antimicrobial Peptides ◽  
Content Type ◽  
Membrane Perturbation

ABSTRACTBordetella pertussis, the causative agent of whooping cough, has many strategies for evading the human immune system. Lipopolysaccharide (LPS) is an important Gram-negative bacterial surface structure that activates the immune system via Toll-like receptor 4 and enables susceptibility to cationic antimicrobial peptides (CAMPs). We show modification of the lipid A region of LPS with glucosamine increased resistance to numerous CAMPs, including LL-37. Furthermore, we demonstrate that this glucosamine modification increased resistance to outer membrane perturbation.

Defect in neutrophil killing and increased susceptibility to infection with nonpathogenic gram-positive bacteria in peptidoglycan recognition protein-S (PGRP-S)–deficient mice

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 689-697 ◽  
Author(s):  
Roman Dziarski ◽  
Kenneth A. Platt ◽  
Eva Gelius ◽  
Håkan Steiner ◽  
Dipika Gupta
Keyword(s):  
Inflammatory Responses ◽  
Protein S ◽  
Intracellular Killing ◽  
Gram Positive ◽  
Peptidoglycan Recognition Protein ◽  
Susceptibility To Infection ◽  
Gram Positive Bacteria ◽  
Recognition Protein ◽  
Factor Α ◽  
Increased Susceptibility

AbstractInsect peptidoglycan recognition protein-S (PGRP-S), a member of a family of innate immunity pattern recognition molecules conserved from insects to mammals, recognizes bacterial cell wall peptidoglycan and activates 2 antimicrobial defense systems, prophenoloxidase cascade and antimicrobial peptides through Toll receptor. We show that mouse PGRP-S is present in neutrophil tertiary granules and that PGRP-S–deficient (PGRP-S-/-) mice have increased susceptibility to intraperitoneal infection with gram-positive bacteria of low pathogenicity but not with more pathogenic gram-positive or gram-negative bacteria. PGRP-S-/- mice have normal inflammatory responses and production of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Neutrophils from PGRP-S-/- mice have normal phagocytic uptake of bacteria but are defective in intracellular killing and digestion of relatively nonpathogenic gram-positive bacteria. Therefore, mammalian PGRP-S functions in intracellular killing of bacteria. Thus, only bacterial recognition by PGRP-S, but not its effector function, is conserved from insects to mammals.

scholarly journals The RNA Chaperone Hfq Is Required for Virulence of Bordetella pertussis

2013 ◽  
Vol 81 (11) ◽  
pp. 4081-4090 ◽  
Author(s):  
Ilona Bibova ◽  
Karolina Skopova ◽  
Jiri Masin ◽  
Ondrej Cerny ◽  
David Hot ◽  
...  
Keyword(s):  
Bordetella Pertussis ◽  
Posttranscriptional Regulation ◽  
Noncoding Rna ◽  
Whooping Cough ◽  
Lethal Dose ◽  
Rna Chaperone ◽  
Content Type ◽  
Small Noncoding Rna ◽  
Mrna Targets

ABSTRACTBordetella pertussisis a Gram-negative pathogen causing the human respiratory disease called pertussis or whooping cough. Here we examined the role of the RNA chaperone Hfq inB. pertussisvirulence. Hfq mediates interactions between small regulatory RNAs and their mRNA targets and thus plays an important role in posttranscriptional regulation of many cellular processes in bacteria, including production of virulence factors. We characterized anhfqdeletion mutant (Δhfq) ofB. pertussis18323 and show that the Δhfqstrain produces decreased amounts of the adenylate cyclase toxin that plays a central role inB. pertussisvirulence. Production of pertussis toxin and filamentous hemagglutinin was affected to a lesser extent.In vitro, the ability of the Δhfqstrain to survive within macrophages was significantly reduced compared to that of the wild-type (wt) strain. The virulence of the Δhfqstrain in the mouse respiratory model of infection was attenuated, with its capacity to colonize mouse lungs being strongly reduced and its 50% lethal dose value being increased by one order of magnitude over that of the wt strain. In mixed-infection experiments, the Δhfqstrain was then clearly outcompeted by the wt strain. This requirement for Hfq suggests involvement of small noncoding RNA regulation inB. pertussisvirulence.

scholarly journals BspR/BtrA, an Anti-σ Factor, Regulates the Ability ofBordetella bronchisepticaTo Cause Cough in Rats

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Keiji Nakamura ◽  
Noriko Shinoda ◽  
Yukihiro Hiramatsu ◽  
Shinya Ohnishi ◽  
Shigeki Kamitani ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Bordetella Pertussis ◽  
Rat Model ◽  
Whooping Cough ◽  
Respiratory Infections ◽  
Wild Type ◽  
Content Type ◽  
Infection Models ◽  
Natural Hosts ◽  
Σ Factor

ABSTRACTBordetella pertussis,B. parapertussis, andB. bronchisepticacause respiratory infections, many of which are characterized by coughing of the infected hosts. The pathogenesis of the coughing remains to be analyzed, mainly because there were no convenient infection models of small animals that replicate coughing afterBordetellainfection. Here, we present a coughing model of rats infected withB. bronchiseptica. Rats, which are one of natural hosts ofB. bronchiseptica, were readily infected with the organisms and showed frequent coughing.B. pertussisalso caused coughing in rats, which is consistent with previous reports, but the cough response was less apparent than theB. bronchiseptica-induced cough. By using the rat model, we demonstrated that adenylate cyclase toxin, dermonecrotic toxin, and the type III secretion system are not involved in cough production, but BspR/BtrA (different names for the same protein), an anti-σ factor, regulates the production of unknown factor(s) to cause coughing. Rat coughing was observed by inoculation of not only the living bacteria but also the bacterial lysates. Infection withbspR(btrA)-deficient strains caused significantly less frequent coughing than the wild type; however, intranasal inoculation of the lysates from abspR(btrA)-deficient strain caused coughing similarly to the wild type, suggesting that BspR/BtrA regulates the production of the cough factor(s) only when the bacteria colonize host bodies. Moreover, the cough factor(s) was found to be heat labile and produced byB. bronchisepticain the Bvg+phase. We consider that our rat model provides insight into the pathogenesis of cough induced by theBordetellainfection.IMPORTANCEWhooping cough is a contagious respiratory disease caused byBordetella pertussis. This disease is characterized by severe paroxysmal coughing, which becomes a heavy burden for patients and occasionally results in death; however, its pathogenesis remains largely unknown. The major obstacle to analyzingBordetella-induced coughing is the lack of conventional animal models that replicate coughing. AsBordetella pertussisis highly adapted to humans, infection models in experimental animals are not considered to be well established. In the present study, we examined coughing in rats infected withB. bronchiseptica, which shares many virulence factors withB. pertussis. Using this rat model, we demonstrated that some of the major virulence factors ofBordetellaare not involved in cough production, but an anti-σ factor, BspR/BtrA, ofB. bronchisepticaregulates the production of unknown cough-causing bacterial factor(s). Our results provide important clues to understand the mechanism by whichBordetellainduces cough.

scholarly journals Complete Genome Sequence of Bordetella pertussis Pelita III, the Production Strain for an Indonesian Whole-Cell Pertussis Vaccine

2017 ◽  
Vol 5 (17) ◽  
Author(s):  
Yusuf Sofyan Efendi ◽  
Dwi Susanti ◽  
Erman Tritama ◽  
Michelle Lueders Pasier ◽  
Gilang Nadia Niwan Putri ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Bordetella Pertussis ◽  
Whooping Cough ◽  
World Health ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Whole Cell ◽  
Content Type ◽  
Health Organization ◽  
Production Strain

ABSTRACT PT Bio Farma, the sole World Health Organization-approved Indonesian vaccine producer, manufactures a whole-cell whooping cough vaccine (wP) that, as part of a pentavalent diphtheria-tetanus-pertussis/hepatitis B/Haemophilus influenzae b (DTP/HB/Hib) vaccine, is used in Indonesia and many other countries. We report here the whole-genome sequence for Bordetella pertussis Pelita III, PT Bio Farma’s wP production strain.

scholarly journals Bordetella pertussis Naturally Occurring Isolates with Altered Lipooligosaccharide Structure Fail To Fully Mature Human Dendritic Cells

2014 ◽  
Vol 83 (1) ◽  
pp. 227-238 ◽  
Author(s):  
Jolanda Brummelman ◽  
Rosanne E. Veerman ◽  
Hendrik Jan Hamstra ◽  
Anna J. M. Deuss ◽  
Tim J. Schuijt ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Bordetella Pertussis ◽  
Lipid A ◽  
Whooping Cough ◽  
Human Monocyte ◽  
Innate Immune ◽  
Clinical Isolates ◽  
Immune Recognition ◽  
Content Type

Bordetella pertussisis a Gram-negative bacterium and the causative agent of whooping cough. Despite high vaccination coverage, outbreaks are being increasingly reported worldwide. Possible explanations include adaptation of this pathogen, which may interfere with recognition by the innate immune system. Here, we describe innate immune recognition and responses to differentB. pertussisclinical isolates. By using HEK-Blue cells transfected with different pattern recognition receptors, we found that 3 out of 19 clinical isolates failed to activate Toll-like receptor 4 (TLR4). These findings were confirmed by using the monocytic MM6 cell line. Although incubation with high concentrations of these 3 strains resulted in significant activation of the MM6 cells, it was found to occur mainly through interaction with TLR2 and not through TLR4. When using live bacteria, these 3 strains also failed to activate TLR4 on HEK-Blue cells, and activation of MM6 cells or human monocyte-derived dendritic cells was significantly lower than activation induced by the other 16 strains. Mass spectrum analysis of the lipid A moieties from these 3 strains indicated an altered structure of this molecule. Gene sequence analysis revealed mutations in genes involved in lipid A synthesis. Findings from this study indicate thatB. pertussisisolates that do not activate TLR4 occur naturally and that this phenotype may give this bacterium an advantage in tempering the innate immune response and establishing infection. Knowledge on the strategies used by this pathogen in evading the host immune response is essential for the improvement of current vaccines or for the development of new ones.

scholarly journals Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis

2017 ◽  
Vol 85 (6) ◽  
Author(s):  
Karolina Skopova ◽  
Barbora Tomalova ◽  
Ivan Kanchev ◽  
Pavel Rossmann ◽  
Martina Svedova ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Bordetella Pertussis ◽  
Whooping Cough ◽  
Lung Parenchyma ◽  
Lung Pathology ◽  
Phagocytic Cells ◽  
Content Type ◽  
Adenylate Cyclase Toxin

ABSTRACT The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of Bordetella pertussis targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, αMβ2 integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first B. pertussis mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b+) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b− cells. The nonhemolytic AC+ Hly− bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells in vitro and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC+ Hly− mutant also infected mouse lungs as efficiently as the parental AC+ Hly+ strain. Hence, elevation of cAMP in CD11b− cells and/or the pore-forming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of B. pertussis infections at higher inoculation doses (>107 CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent.

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