scholarly journals Suppression of Serum Antibody Responses by Pertussis Toxin after Respiratory Tract Colonization by Bordetella pertussis and Identification of an Immunodominant Lipoprotein

2004 ◽  
Vol 72 (6) ◽  
pp. 3350-3358 ◽  
Author(s):  
Nicholas H. Carbonetti ◽  
Galina V. Artamonova ◽  
Charlotte Andreasen ◽  
Edward Dudley ◽  
R. Michael Mays ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Tract Infection ◽  
Antibody Response ◽  
Respiratory Tract ◽  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Low Molecular Weight ◽  
Respiratory Tract Colonization

ABSTRACT Pertussis toxin (PT), a virulence factor secreted by Bordetella pertussis, contributes to respiratory tract infection and disease caused by this pathogen. By comparing a wild-type (WT) B. pertussis strain to a mutant strain with an in-frame deletion of the ptx genes encoding PT (ΔPT), we recently found that the lack of PT confers a significant defect in respiratory tract colonization in mice after intranasal inoculation. In this study, we analyzed serum antibody responses in mice infected with the WT or ΔPT strain and found that infection with the ΔPT strain elicited greater responses to several B. pertussis antigens than did infection with the WT, despite the lower colonization level achieved by the ΔPT strain. The same enhanced antibody response was observed after infection with a strain expressing an enzymatically inactive PT; but this response was not observed after infection with B. pertussis mutant strains lacking filamentous hemagglutinin or adenylate cyclase toxin, nor when purified PT was administered with the ΔPT inoculum, indicating a specific role for PT activity in this immunosuppressive effect. In particular, there were consistent strong serum antibody responses to one or more low-molecular-weight antigens after infection with the ΔPT strain. These antigens were Bvg independent, membrane localized, and also expressed by the closely related pathogens Bordetella parapertussis and Bordetella bronchiseptica. Two-dimensional gel electrophoresis and mass spectrometry were used to identify one of the immunodominant low-molecular-weight antigens as a protein with significant sequence homology to peptidoglycan-associated lipoprotein in several other gram-negative bacterial species. However, a serum antibody response to this protein alone did not protect mice against respiratory tract infection by B. pertussis.

scholarly journals Mucosally Induced Immunoglobulin E-Associated Inflammation in the Respiratory Tract

2000 ◽  
Vol 68 (2) ◽  
pp. 672-679 ◽  
Author(s):  
Jerry W. Simecka ◽  
Raymond J. Jackson ◽  
Hiroshi Kiyono ◽  
Jerry R. McGhee
Keyword(s):  
Antibody Response ◽  
Respiratory Tract ◽  
Immunoglobulin E ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Th2 Cells ◽  
Inflammatory Reactions ◽  
Interleukin 5 ◽  
Nasal Immunization ◽  
Igg1 Subclass

ABSTRACT The purpose of the present study was to determine the immunologic responses, particularly immunopathologic reactions, associated with nasal immunization with the mucosal adjuvant, cholera toxin (CT). BALB/c mice were nasally immunized with tetanus toxoid (TT) combined with CT, and the responses of these mice were determined. After nasal immunization, mice produce a serum antibody response, primarily of the immunoglobulin G (IgG) isotype of predominantly IgG1 subclass, against both TT and CT. Along with the antibody responses, we also found that inflammatory reactions, which could be potentially fatal, developed within the lung. Furthermore, IgE responses were also induced after nasal immunization, and these responses were associated with the detection of interleukin 5 in the serum. Thus, nasal immunization with TT plus CT likely results in the activation of Th2 cells, which may contribute to serious immunopathologic reactions in the lung.

scholarly journals Pertussis Toxin Targets Airway Macrophages To Promote Bordetella pertussis Infection of the Respiratory Tract

2007 ◽  
Vol 75 (4) ◽  
pp. 1713-1720 ◽  
Author(s):  
Nicholas H. Carbonetti ◽  
Galina V. Artamonova ◽  
Nico Van Rooijen ◽  
Victor I. Ayala
Keyword(s):  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Intranasal Administration ◽  
Protein Modification ◽  
Target Cells ◽  
Bacterial Inoculation ◽  
Enhancing Effect

ABSTRACT Pertussis toxin (PT), a secreted virulence factor of Bordetella pertussis, ADP ribosylates mammalian Gi proteins and plays an important early role in respiratory tract infection by this pathogen in a mouse intranasal infection model. To test the hypothesis that PT targets resident airway macrophages (AM) to promote this infection, we depleted AM by intranasal administration of liposome-encapsulated clodronate prior to bacterial inoculation. This treatment enhanced respiratory tract infection by B. pertussis, even though it also induced a rapid influx of neutrophils to the airways. Strikingly, AM depletion also enhanced infection by mutant strains deficient in PT production or activity to the same level as the wild-type infection, indicating that AM may be the primary target cells for PT in promoting infection. The enhancing effect of clodronate-liposome treatment on infection (i) was shown to be due to macrophage depletion rather than neutrophil influx; (ii) was observed for both tracheal infection and lung infection; (iii) was observed during the early and peak phases of the infection but was lost by day 14 postinoculation, during clearance of the infection; (iv) persisted for at least 1 week (prior to bacterial inoculation); and (v) was equivalent in magnitude to the effect of PT pretreatment and the effects were not additive, consistent with the idea that PT targets AM. We found that PT efficiently ADP ribosylated AM G proteins both in vitro and after intranasal administration of PT in mice and that the duration of G protein modification in vivo was equivalent to the duration of the enhancing effect of PT treatment on the bacterial infection. Collectively, these observations indicate that PT targets AM to promote early infection of the respiratory tract by B. pertussis.

scholarly journals Pertussis Toxin Plays an Early Role in Respiratory Tract Colonization by Bordetella pertussis

2003 ◽  
Vol 71 (11) ◽  
pp. 6358-6366 ◽  
Author(s):  
Nicholas H. Carbonetti ◽  
Galina V. Artamonova ◽  
R. Michael Mays ◽  
Zoe E. V. Worthington
Keyword(s):  
Respiratory Tract ◽  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Type Strain ◽  
Wild Type Strain ◽  
Saline Control ◽  
Control Analysis ◽  
Wild Type ◽  
Respiratory Tract Colonization ◽  
Infection Experiments

ABSTRACT In this study, we sought to determine whether pertussis toxin (PT), an exotoxin virulence factor produced exclusively by Bordetella pertussis, is important for colonization of the respiratory tract by this pathogen by using a mouse intranasal infection model. By comparing a wild-type Tohama I strain to a mutant strain with an in-frame deletion of the ptx genes encoding PT (ΔPT), we found that the lack of PT confers a significant peak (day 7) colonization defect (1 to 2 log10 units) over a range of bacterial inoculum doses and that this defect was apparent within 1 to 2 days postinoculation. In mixed-strain infection experiments, the ΔPT strain showed no competitive disadvantage versus the wild-type strain and colonized at higher levels than in the single-strain infection experiments. To test the hypothesis that soluble PT produced by the wild-type strain in mixed infections enhanced respiratory tract colonization by ΔPT, we coadministered purified PT with the ΔPT inoculum and found that colonization was increased to wild-type levels. This effect was not observed when PT was coadministered via a systemic route. Intranasal administration of purified PT up to 14 days prior to inoculation with ΔPT significantly increased bacterial colonization, but PT administration 1 day after bacterial inoculation did not enhance colonization versus a phosphate-buffered saline control. Analysis of bronchoalveolar lavage fluid samples from mice infected with either wild-type or ΔPT strains at early times after infection revealed that neutrophil influx to the lungs 48 h postinfection was significantly greater in response to ΔPT infection, implicating neutrophil chemotaxis as a possible target of PT activity promoting B. pertussis colonization of the respiratory tract.

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.

scholarly journals Pertussis Toxin and Adenylate Cyclase Toxin Provide a One-Two Punch for Establishment of Bordetella pertussis Infection of the Respiratory Tract

2005 ◽  
Vol 73 (5) ◽  
pp. 2698-2703 ◽  
Author(s):  
Nicholas H. Carbonetti ◽  
Galina V. Artamonova ◽  
Charlotte Andreasen ◽  
Nicholas Bushar
Keyword(s):  
Adenylate Cyclase ◽  
Respiratory Tract ◽  
Pertussis Toxin ◽  
Bordetella Pertussis ◽  
Type Strain ◽  
Wild Type Strain ◽  
Infection Model ◽  
Wild Type ◽  
Adenylate Cyclase Toxin ◽  
Tract Infections

ABSTRACT Previously we found that pertussis toxin (PT), an exotoxin virulence factor produced by Bordetella pertussis, plays an important early role in colonization of the respiratory tract by this pathogen, using a mouse intranasal infection model. In this study, we examined the early role played by another exotoxin produced by this pathogen, adenylate cyclase toxin (ACT). By comparing a wild-type strain to a mutant strain (ΔCYA) with an in-frame deletion of the cyaA gene encoding ACT, we found that the lack of ACT confers a significant peak (day 7) colonization defect (1 to 2 log10). In mixed-infection experiments, the ΔCYA strain was significantly outcompeted by the wild-type strain, and intranasal administration of purified ACT did not increase colonization by ΔCYA. These data suggest that ACT benefits the bacterial cells that produce it and, unlike PT, does not act as a soluble factor benefiting the entire infecting bacterial population. Comparison of lower respiratory tract infections over the first 4 days after inoculation revealed that the colonization defect of the PT deletion strain was apparent earlier than that of ΔCYA, suggesting that PT plays an earlier role than ACT in the establishment of B. pertussis infection. Examination of cells in the bronchoalveolar lavage fluid of infected mice revealed that, unlike PT, ACT does not appear to inhibit neutrophil influx to the respiratory tract early after infection but may combat neutrophil activity once influx has occurred.

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