scholarly journals Pertussis Toxin Exacerbates and Prolongs Airway Inflammatory Responses during Bordetella pertussis Infection

2012 ◽  
Vol 80 (12) ◽  
pp. 4317-4332 ◽  
Author(s):  
Carey E. Connelly ◽  
Yezhou Sun ◽  
Nicholas H. Carbonetti
Keyword(s):  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Systemic Disease ◽  
Respiratory Pathogen ◽  
High Dose ◽  
Disease Symptoms ◽  
Content Type ◽  
Airway Pathology

ABSTRACTThroughout infection, pathogenic bacteria induce dramatic changes in host transcriptional repertoires. An understanding of how bacterial factors influence host reprogramming will provide insight into disease pathogenesis. In the human respiratory pathogenBordetella pertussis, the causative agent of whooping cough, pertussis toxin (PT) is a key virulence factor that promotes colonization, suppresses innate immune responses during early infection, and causes systemic disease symptoms. To determine the full extent of PT-associated gene regulation in the airways through the peak of infection, we measured global transcriptional profiles in the lungs of BALB/c mice infected with wild-type (WT) or PT-deficient (ΔPT)B. pertussis. ΔPT bacteria were inoculated at a dose equivalent to the WT dose and at a high dose (ΔPThigh) to distinguish effects caused by higher bacterial loads achieved in WT infection from effects associated with PT. The results demonstrated that PT was associated with a significant upregulation of immune and inflammatory response genes as well as several other genes implicated in airway pathology. In contrast to the early, transient responses observed for ΔPThighinfection, WT infection induced a prolonged expression of inflammatory genes and increased the extent and duration of lung histopathology. In addition, the administration of purified PT to ΔPThigh-infected mice 1 day after bacterial inoculation exacerbated and prolonged inflammatory responses and airway pathology. These data indicate that PT not only is associated with exacerbated host airway responses during peakB. pertussisinfection but also may inhibit host mechanisms of attenuating and resolving inflammation in the airways, suggesting possible links between PT and pertussis disease symptoms.

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 Identification of Pneumococcal Factors Affecting Pneumococcal Shedding Shows that thedltLocus Promotes Inflammation and Transmission

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
M. Ammar Zafar ◽  
Alexandria J. Hammond ◽  
Shigeto Hamaguchi ◽  
Weisheng Wu ◽  
Masamitsu Kono ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Capsular Polysaccharide ◽  
Inflammatory Responses ◽  
Transposon Mutagenesis ◽  
Respiratory Pathogen ◽  
Invasive Infection ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Upper Respiratory

ABSTRACTHost-to-host transmission is a necessary but poorly understood aspect of microbial pathogenesis. Herein, we screened a genomic library of mutants of the leading respiratory pathogenStreptococcus pneumoniaegenerated by mariner transposon mutagenesis (Tn-Seq) to identify genes contributing to its exit or shedding from the upper respiratory tract (URT), the limiting step in the organism’s transmission in an infant mouse model. Our analysis focused on genes affecting the bacterial surface that directly impact interactions with the host. Among the multiple factors identified was thedltlocus, which addsd-alanine onto lipoteichoic acids (LTA) and thereby increases Toll-like receptor 2-mediated inflammation and resistance to antimicrobial peptides. The more robust proinflammatory response in the presence ofd-alanylation promotes secretions that facilitate pneumococcal shedding and allows for transmission. Expression of thedltlocus is controlled by the CiaRH system, which senses cell wall stress in response to antimicrobial activity, including in response to lysozyme, the most abundant antimicrobial along the URT mucosa. Accordingly, in alysM−/−host, there was no longer an effect of thedltlocus on pneumococcal shedding. Thus, our findings demonstrate how a pathogen senses the URT milieu and then modifies its surface characteristics to take advantage of the host response for transit to another host.IMPORTANCEStreptococcus pneumoniae(the pneumococcus) is a common cause of respiratory tract and invasive infection. The overall effectiveness of immunization with the organism’s capsular polysaccharide depends on its ability to block colonization of the upper respiratory tract and thereby prevent host-to-host transmission. Because of the limited coverage of current pneumococcal vaccines, we carried out an unbiasedin vivotransposon mutagenesis screen to identify pneumococcal factors other than its capsular polysaccharide that affect transmission. One such candidate was expressed by thedltlocus, previously shown to addd-alanine onto the pneumococcal lipoteichoic acid present on the bacterial cell surface. This modification protects against host antimicrobials and augments host inflammatory responses. The latter increases secretions and bacterial shedding from the upper respiratory tract to allow for transmission. Thus, this study provides insight into a mechanism employed by the pneumococcus to successfully transit from one host to another.

scholarly journals Increased Persistence of Salmonella enterica Serovar Typhi in the Presence of Acanthamoeba castellanii

2011 ◽  
Vol 77 (21) ◽  
pp. 7640-7646 ◽  
Author(s):  
Frédéric Douesnard-Malo ◽  
France Daigle
Keyword(s):  
Salmonella Enterica ◽  
Pathogenic Bacteria ◽  
Systemic Disease ◽  
Acanthamoeba Castellanii ◽  
Selective Advantage ◽  
Viable Count ◽  
Physical Contact ◽  
Content Type ◽  
Contaminated Food ◽  
Cultured Bacteria

ABSTRACTSalmonella entericaserovar Typhi (S. Typhi) is the etiological agent of the systemic disease typhoid fever. Transmission occurs via ingestion of contaminated food or water.S. Typhi is specific to humans, and no animal or environmental reservoirs are known. As the free-living amoebaAcanthamoeba castellaniiis an environmental host for many pathogenic bacteria, this study investigates interactions betweenS. Typhi andA. castellaniiby using cocultures. Growth of both organisms was estimated by cell count, viable count, flow cytometry, and fluorescence microscopy. Results indicate thatS. Typhi can survive at least 3 weeks when grown withA. castellanii, as opposed to less than 10 days when grown as singly cultured bacteria under the same conditions. Interestingly, growth rates of amoebae after 14 days were similar in cocultures or when amoebae were singly cultured, suggesting thatS. Typhi is not cytotoxic toA. castellanii. Bacteria surviving in coculture were not intracellular and did not require a physical contact with amoebae for their survival. These results suggest thatS. Typhi may have a selective advantage when it is associated withA. castellaniiand that amoebae may contribute toS. Typhi persistence in the environment.

scholarly journals Modulation of Pertussis and Adenylate Cyclase Toxins by Sigma Factor RpoE in Bordetella pertussis

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Mariette Barbier ◽  
Dylan T. Boehm ◽  
Emel Sen-Kilic ◽  
Claire Bonnin ◽  
Theo Pinheiro ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Mutant Strain ◽  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Sigma Factor ◽  
Negative Regulator ◽  
Host Cells ◽  
Sequencing Analysis ◽  
Western Blots ◽  
Content Type

ABSTRACT Bordetella pertussis is a human pathogen that can infect the respiratory tract and cause the disease known as whooping cough. B. pertussis uses pertussis toxin (PT) and adenylate cyclase toxin (ACT) to kill and modulate host cells to allow the pathogen to survive and persist. B. pertussis encodes many uncharacterized transcription factors, and very little is known about their functions. RpoE is a sigma factor which, in other bacteria, responds to oxidative, heat, and other environmental stresses. RseA is a negative regulator of RpoE that sequesters the sigma factor to regulate gene expression based on conditions. In B. pertussis, deletion of the rseA gene results in high transcriptional activity of RpoE and large amounts of secretion of ACT. By comparing parental B. pertussis to an rseA gene deletion mutant (PM18), we sought to characterize the roles of RpoE in virulence and determine the regulon of genes controlled by RpoE. Despite high expression of ACT, the rseA mutant strain did not infect the murine airway as efficiently as the parental strain and PM18 was killed more readily when inside phagocytes. RNA sequencing analysis was performed and 263 genes were differentially regulated by RpoE, and surprisingly, the rseA mutant strain where RpoE activity was elevated expressed very little pertussis toxin. Western blots and proteomic analysis corroborated the inverse relationship of PT to ACT expression in the high-RpoE-activity rseA deletion strain. Our data suggest that RpoE can modulate PT and ACT expression indirectly through unidentified mechanisms in response to conditions.

scholarly journals A Unique Reverse Adaptation Mechanism Assists Bordetella pertussis in Resistance to Both Scarcity and Toxicity of Manganese

mBio ◽  
2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Jan Čapek ◽  
Ilona Procházková ◽  
Tomáš Matoušek ◽  
David Hot ◽  
Branislav Večerek
Keyword(s):  
Bordetella Pertussis ◽  
Respiratory Pathogen ◽  
Loss Of Function ◽  
Adaptation Mechanism ◽  
Content Type

Bordetella pertussis , a respiratory pathogen restricted to humans, continuously adapts its genome to its exclusive host. We show that speciation of this reemerging pathogen was accompanied by loss of function of the manganese exporter.

scholarly journals In Vivo Transcriptional Profiling of Yersinia pestis Reveals a Novel Bacterial Mediator of Pulmonary Inflammation

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Roger D. Pechous ◽  
Christopher A. Broberg ◽  
Nikolas M. Stasulli ◽  
Virginia L. Miller ◽  
William E. Goldman
Keyword(s):  
Yersinia Pestis ◽  
Inflammatory Responses ◽  
Severe Pneumonia ◽  
Sudden Onset ◽  
Host Factors ◽  
Respiratory Pathogen ◽  
Bacterial Survival ◽  
Pneumonic Plague ◽  
Content Type

ABSTRACTInhalation ofYersinia pestisresults in primary pneumonic plague, a highly lethal and rapidly progressing necrotizing pneumonia. The disease begins with a period of extensive bacterial replication in the absence of disease symptoms, followed by the sudden onset of inflammatory responses that ultimately prove fatal. Very little is known about the bacterial and host factors that contribute to the rapid biphasic progression of pneumonic plague. In this work, we analyzed thein vivotranscription kinetics of 288 bacterial open reading frames previously shown by microarray analysis to be dynamically regulated in the lung. Using this approach combined with bacterial genetics, we were able to identify five Y. pestis genes that contribute to the development of pneumonic plague. Deletion of one of these genes,ybtX, did not alter bacterial survival but attenuated host inflammatory responses during late-stage disease. Deletion ofybtXin another lethal respiratory pathogen,Klebsiella pneumoniae, also resulted in diminished host inflammation during infection. Thus, ourin vivotranscriptional screen has identified an important inflammatory mediator that is common to two Gram-negative bacterial pathogens that cause severe pneumonia.IMPORTANCEYersinia pestis is responsible for at least three major pandemics, most notably the Black Death of the Middle Ages. Due to its pandemic potential, ease of dissemination by aerosolization, and a history of its weaponization, Y. pestis is categorized by the Centers for Disease Control and Prevention as a tier 1 select agent most likely to be used as a biological weapon. To date, there is no licensed vaccine against Y. pestis. Importantly, an early “silent” phase followed by the rapid onset of nondescript influenza-like symptoms makes timely treatment of pneumonic plague difficult. A more detailed understanding of the bacterial and host factors that contribute to pathogenesis is essential to understanding the progression of pneumonic plague and developing or enhancing treatment options.

scholarly journals Bordetella Dermonecrotic Toxin Is a Neurotropic Virulence Factor That Uses CaV3.1 as the Cell Surface Receptor

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Shihono Teruya ◽  
Yukihiro Hiramatsu ◽  
Keiji Nakamura ◽  
Aya Fukui-Miyazaki ◽  
Kentaro Tsukamoto ◽  
...  
Keyword(s):  
Nervous System ◽  
Adenylate Cyclase ◽  
Virulence Factor ◽  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Neural Cells ◽  
Intracerebral Injection ◽  
Content Type ◽  
Voltage Gated ◽  
Dermonecrotic Toxin

ABSTRACT Dermonecrotic toxin (DNT) is one of the representative toxins produced by Bordetella pertussis, but its role in pertussis, B. pertussis infection, remains unknown. In this study, we identified the T-type voltage-gated Ca2+ channel CaV3.1 as the DNT receptor by CRISPR-Cas9-based genome-wide screening. As CaV3.1 is highly expressed in the nervous system, the neurotoxicity of DNT was examined. DNT affected cultured neural cells and caused flaccid paralysis in mice after intracerebral injection. No neurological symptoms were observed by intracerebral injection with the other major virulence factors of the organisms, pertussis toxin and adenylate cyclase toxin. These results indicate that DNT has aspects of the neurotropic virulence factor of B. pertussis. The possibility of the involvement of DNT in encephalopathy, which is a complication of pertussis, is also discussed. IMPORTANCE Bordetella pertussis, which causes pertussis, a contagious respiratory disease, produces three major protein toxins, pertussis toxin, adenylate cyclase toxin, and dermonecrotic toxin (DNT), for which molecular actions have been elucidated. The former two toxins are known to be involved in the emergence of some clinical symptoms and/or contribute to the establishment of bacterial infection. In contrast, the role of DNT in pertussis remains unclear. Our study shows that DNT affects neural cells through specific binding to the T-type voltage-gated Ca2+ channel that is highly expressed in the central nervous system and leads to neurological disorders in mice after intracerebral injection. These data raise the possibility of DNT as an etiological agent for pertussis encephalopathy, a severe complication of B. pertussis infection.

scholarly journals Complete Genome Sequences of Bordetella pertussis Isolates with Novel Pertactin-Deficient Deletions

2017 ◽  
Vol 5 (37) ◽  
Author(s):  
Michael R. Weigand ◽  
Yanhui Peng ◽  
Pamela K. Cassiday ◽  
Vladimir N. Loparev ◽  
Taccara Johnson ◽  
...  
Keyword(s):  
United States ◽  
Bordetella Pertussis ◽  
Complete Genome ◽  
The United States ◽  
Clinical Isolates ◽  
Respiratory Pathogen ◽  
Genome Sequences ◽  
Vaccine Immunogen ◽  
Content Type ◽  
Acellular Vaccine

ABSTRACT Clinical isolates of the respiratory pathogen Bordetella pertussis in the United States have become predominantly deficient for the acellular vaccine immunogen pertactin through various independent mutations. Here, we report the complete genome sequences for four B. pertussis isolates that harbor novel deletions responsible for pertactin deficiency.

scholarly journals Identification of Highly Pathogenic Microorganisms by Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry: Results of an Interlaboratory Ring Trial

2015 ◽  
Vol 53 (8) ◽  
pp. 2632-2640 ◽  
Author(s):  
Peter Lasch ◽  
Tara Wahab ◽  
Sandra Weil ◽  
Bernadett Pályi ◽  
Herbert Tomaso ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Mass Spectra ◽  
Pathogenic Bacteria ◽  
Identification Accuracy ◽  
High Dose ◽  
Highly Pathogenic ◽  
Content Type ◽  
Microbial Identification ◽  
First Case ◽  
Strain Collection

In the case of a release of highly pathogenic bacteria (HPB), there is an urgent need for rapid, accurate, and reliable diagnostics. MALDI-TOF mass spectrometry is a rapid, accurate, and relatively inexpensive technique that is becoming increasingly important in microbiological diagnostics to complement classical microbiology, PCR, and genotyping of HPB. In the present study, the results of a joint exercise with 11 partner institutions from nine European countries are presented. In this exercise, 10 distinct microbial samples, among them five HPB,Bacillus anthracis,Brucella canis,Burkholderia mallei,Burkholderia pseudomallei, andYersinia pestis, were characterized under blinded conditions. Microbial strains were inactivated by high-dose gamma irradiation before shipment. Preparatory investigations ensured that this type of inactivation induced only subtle spectral changes with negligible influence on the quality of the diagnosis. Furthermore, pilot tests on nonpathogenic strains were systematically conducted to ensure the suitability of sample preparation and to optimize and standardize the workflow for microbial identification. The analysis of the microbial mass spectra was carried out by the individual laboratories on the basis of spectral libraries available on site. All mass spectra were also tested against an in-house HPB library at the Robert Koch Institute (RKI). The averaged identification accuracy was 77% in the first case and improved to >93% when the spectral diagnoses were obtained on the basis of the RKI library. The compilation of complete and comprehensive databases with spectra from a broad strain collection is therefore considered of paramount importance for accurate microbial identification.

scholarly journals Pertussis Toxin Inhibits Early Chemokine Production To Delay Neutrophil Recruitment in Response to Bordetella pertussis Respiratory Tract Infection in Mice

2008 ◽  
Vol 76 (11) ◽  
pp. 5139-5148 ◽  
Author(s):  
Charlotte Andreasen ◽  
Nicholas H. Carbonetti
Keyword(s):  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Inflammatory Responses ◽  
Neutrophil Migration ◽  
Neutrophil Recruitment ◽  
Chemokine Production ◽  
Neutrophil Influx

ABSTRACT Pertussis is an acute respiratory disease of humans caused by the bacterium Bordetella pertussis. Pertussis toxin (PT) plays a major role in the virulence of this pathogen, including important effects that it has soon after inoculation. Studies in our laboratory and other laboratories have indicated that PT inhibits early neutrophil influx to the lungs and airways in response to B. pertussis respiratory tract infection in mice. Previous in vitro and in vivo studies have shown that PT can affect neutrophils directly by ADP ribosylating Gi proteins associated with surface chemokine receptors, thereby inhibiting neutrophil migration in response to chemokines. However, in this study, by comparing responses to wild-type (WT) and PT-deficient strains, we found that PT has an indirect inhibitory effect on neutrophil recruitment to the airways in response to infection. Analysis of lung chemokine expression indicated that PT suppresses early neutrophil recruitment by inhibiting chemokine upregulation in alveolar macrophages and other lung cells in response to B. pertussis infection. Enhancement of early neutrophil recruitment to the airways in response to WT infection by addition of exogenous keratinocyte-derived chemokine, one of the dominant neutrophil-attracting chemokines in mice, further revealed an indirect effect of PT on neutrophil chemotaxis. Additionally, we showed that intranasal administration of PT inhibits lipopolysaccharide-induced chemokine gene expression and neutrophil recruitment to the airways, presumably by modulation of signaling through Toll-like receptor 4. Collectively, these results demonstrate how PT inhibits early inflammatory responses in the respiratory tract, which reduces neutrophil influx in response to B. pertussis infection, potentially providing an advantage to the pathogen in this interaction.

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