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Nicholas Carbonetti
University of Maryland School of Medicine

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Preprint content
Published: 25 September 2020
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Whooping cough is caused byBordetella pertussisthat releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, the role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is characterized in detail. PTS1 specifically and directly interacts with chaperonesin vitroand in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing cytosolic PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.

ACS Style

Katharina Ernst; Ann-Katrin Mittler; Veronika Winkelmann; Nina Eberhardt; Anna Anastasia; Michael Sonnabend; Robin Lochbaum; Jan Wirsching; Ciaran Skerry; Nicholas H. Carbonetti; Manfred Frick; Holger Barth. Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo. 2020, 1 .

AMA Style

Katharina Ernst, Ann-Katrin Mittler, Veronika Winkelmann, Nina Eberhardt, Anna Anastasia, Michael Sonnabend, Robin Lochbaum, Jan Wirsching, Ciaran Skerry, Nicholas H. Carbonetti, Manfred Frick, Holger Barth. Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo. . 2020; ():1.

Chicago/Turabian Style

Katharina Ernst; Ann-Katrin Mittler; Veronika Winkelmann; Nina Eberhardt; Anna Anastasia; Michael Sonnabend; Robin Lochbaum; Jan Wirsching; Ciaran Skerry; Nicholas H. Carbonetti; Manfred Frick; Holger Barth. 2020. "Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo." , no. : 1.

Journal article
Published: 09 March 2020 in The Journal of Immunology
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Type I and III IFNs play diverse roles in bacterial infections, being protective for some but deleterious for others. Using RNA-sequencing transcriptomics we investigated lung gene expression responses to Bordetella pertussis infection in adult mice, revealing that type I and III IFN pathways may play an important role in promoting inflammatory responses. In B. pertussis–infected mice, lung type I/III IFN responses correlated with increased proinflammatory cytokine expression and with lung inflammatory pathology. In mutant mice with increased type I IFN receptor (IFNAR) signaling, B. pertussis infection exacerbated lung inflammatory pathology, whereas knockout mice with defects in type I IFN signaling had lower levels of lung inflammation than wild-type mice. Curiously, B. pertussis–infected IFNAR1 knockout mice had wild-type levels of lung inflammatory pathology. However, in response to infection these mice had increased levels of type III IFN expression, neutralization of which reduced lung inflammation. In support of this finding, B. pertussis–infected mice with a knockout mutation in the type III IFN receptor (IFNLR1) and double IFNAR1/IFNLR1 knockout mutant mice had reduced lung inflammatory pathology compared with that in wild-type mice, indicating that type III IFN exacerbates lung inflammation. In marked contrast, infant mice did not upregulate type I or III IFNs in response to B. pertussis infection and were protected from lethal infection by increased type I IFN signaling. These results indicate age-dependent effects of type I/III IFN signaling during B. pertussis infection and suggest that these pathways represent targets for therapeutic intervention in pertussis.

ACS Style

Jeremy Ardanuy; Karen Scanlon; Ciaran Skerry; Serge Y. Fuchs; Nicholas H. Carbonetti. Age-Dependent Effects of Type I and Type III IFNs in the Pathogenesis of Bordetella pertussis Infection and Disease. The Journal of Immunology 2020, 204, 2192 -2202.

AMA Style

Jeremy Ardanuy, Karen Scanlon, Ciaran Skerry, Serge Y. Fuchs, Nicholas H. Carbonetti. Age-Dependent Effects of Type I and Type III IFNs in the Pathogenesis of Bordetella pertussis Infection and Disease. The Journal of Immunology. 2020; 204 (8):2192-2202.

Chicago/Turabian Style

Jeremy Ardanuy; Karen Scanlon; Ciaran Skerry; Serge Y. Fuchs; Nicholas H. Carbonetti. 2020. "Age-Dependent Effects of Type I and Type III IFNs in the Pathogenesis of Bordetella pertussis Infection and Disease." The Journal of Immunology 204, no. 8: 2192-2202.

Chapter
Published: 03 August 2019 in Advances in Experimental Medicine and Biology
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Bordetella pertussis produces several toxins that affect host-pathogen interactions. Of these, the major toxins that contribute to pertussis infection and disease are pertussis toxin, adenylate cyclase toxin-hemolysin and tracheal cytotoxin. Pertussis toxin is a multi-subunit protein toxin that inhibits host G protein-coupled receptor signaling, causing a wide array of effects on the host. Adenylate cyclase toxin-hemolysin is a single polypeptide, containing an adenylate cyclase enzymatic domain coupled to a hemolysin domain, that primarily targets phagocytic cells to inhibit their antibacterial activities. Tracheal cytotoxin is a fragment of peptidoglycan released by B. pertussis that elicits damaging inflammatory responses in host cells. This chapter describes these three virulence factors of B. pertussis, summarizing background information and focusing on the role of each toxin in infection and disease pathogenesis, as well as their role in pertussis vaccination.

ACS Style

Karen Scanlon; Ciaran Skerry; Nicholas Carbonetti. Role of Major Toxin Virulence Factors in Pertussis Infection and Disease Pathogenesis. Advances in Experimental Medicine and Biology 2019, 1183, 35 -51.

AMA Style

Karen Scanlon, Ciaran Skerry, Nicholas Carbonetti. Role of Major Toxin Virulence Factors in Pertussis Infection and Disease Pathogenesis. Advances in Experimental Medicine and Biology. 2019; 1183 ():35-51.

Chicago/Turabian Style

Karen Scanlon; Ciaran Skerry; Nicholas Carbonetti. 2019. "Role of Major Toxin Virulence Factors in Pertussis Infection and Disease Pathogenesis." Advances in Experimental Medicine and Biology 1183, no. : 35-51.

Review
Published: 27 June 2019 in Toxins
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Pertussis, caused by respiratory tract infection with the bacterial pathogen Bordetella pertussis, has long been considered to be a toxin-mediated disease. Bacteria adhere and multiply extracellularly in the airways and release several toxins, which have a variety of effects on the host, both local and systemic. Predominant among these toxins is pertussis toxin (PT), a multi-subunit protein toxin that inhibits signaling through a subset of G protein-coupled receptors in mammalian cells. PT activity has been linked with severe and lethal pertussis disease in young infants and a detoxified version of PT is a common component of all licensed acellular pertussis vaccines. The role of PT in typical pertussis disease in other individuals is less clear, but significant evidence supporting its contribution to pathogenesis has been accumulated from animal model studies. In this review we discuss the evidence indicating a role for PT in pertussis disease, focusing on its contribution to severe pertussis in infants, modulation of immune and inflammatory responses to infection, and the characteristic paroxysmal cough of pertussis.

ACS Style

Karen Scanlon; Ciaran Skerry; Nicholas Carbonetti. Association of Pertussis Toxin with Severe Pertussis Disease. Toxins 2019, 11, 373 .

AMA Style

Karen Scanlon, Ciaran Skerry, Nicholas Carbonetti. Association of Pertussis Toxin with Severe Pertussis Disease. Toxins. 2019; 11 (7):373.

Chicago/Turabian Style

Karen Scanlon; Ciaran Skerry; Nicholas Carbonetti. 2019. "Association of Pertussis Toxin with Severe Pertussis Disease." Toxins 11, no. 7: 373.

Journal article
Published: 01 November 2017 in Infection and Immunity
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In infants, Bordetella pertussis can cause severe disease, manifested as pronounced leukocytosis, pulmonary hypertension, and even death. The exact cause of death remains unknown, and no effective therapies for treating fulminant pertussis exist. In this study, a neonatal mouse model of critical pertussis is characterized, and a central role for pertussis toxin (PT) is described. PT promoted colonization, leukocytosis, T cell phenotypic changes, systemic pathology, and death in neonatal but not adult mice. Surprisingly, PT inhibited lung inflammatory pathology in neonates, a result which contrasts dramatically with observed PT-promoted pathology in adult mice. Infection with a PT-deficient strain induced severe pulmonary inflammation but not mortality in neonatal mice, suggesting that death in these mice was not associated with impaired lung function. Dissemination of infection beyond the lungs was also detected in neonatal mice, which may contribute to the observed systemic effects of PT. We propose that it is the systemic activity of pertussis toxin and not pulmonary pathology that promotes mortality in critical pertussis. In addition, we observed transmission of infection between neonatal mice, the first report of B. pertussis transmission in mice. This model will be a valuable tool to investigate causes of pertussis pathogenesis and identify potential therapies for critical pertussis.

ACS Style

Karen M. Scanlon; Yael G. Snyder; Ciaran Skerry; Nicholas H. Carbonetti. Fatal Pertussis in the Neonatal Mouse Model Is Associated with Pertussis Toxin-Mediated Pathology beyond the Airways. Infection and Immunity 2017, 85, 1 .

AMA Style

Karen M. Scanlon, Yael G. Snyder, Ciaran Skerry, Nicholas H. Carbonetti. Fatal Pertussis in the Neonatal Mouse Model Is Associated with Pertussis Toxin-Mediated Pathology beyond the Airways. Infection and Immunity. 2017; 85 (11):1.

Chicago/Turabian Style

Karen M. Scanlon; Yael G. Snyder; Ciaran Skerry; Nicholas H. Carbonetti. 2017. "Fatal Pertussis in the Neonatal Mouse Model Is Associated with Pertussis Toxin-Mediated Pathology beyond the Airways." Infection and Immunity 85, no. 11: 1.

Journal article
Published: 03 November 2016 in Journal of Infectious Diseases
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Recent data have demonstrated the potential of sphingosine 1-phosphate (S1P) receptor (S1PR) agonism in the treatment of infectious diseases. A previous study used a murine model of Bordetella pertussis infection to demonstrate that treatment with the S1PR agonist AAL-R reduces pulmonary inflammation during infection. In the current study, we showed that this effect is mediated via the S1PR1 on LysM+ (myeloid) cells. Signaling via this receptor results in reduced lung inflammation and cellular recruitment as well as reduced morbidity and mortality in a neonatal mouse model of disease. Despite the fact that S1PRs are pertussis toxin–sensitive G protein-coupled receptors, the effects of AAL-R were pertussis toxin insensitive in our model. Furthermore, our data demonstrate that S1PR agonist administration may be effective at therapeutic time points. These results indicate a role for S1P signaling in B. pertussis–mediated pathology and highlight the possibility of host-targeted therapy for pertussis.

ACS Style

Ciaran Skerry; Karen Scanlon; Jeremy Ardanuy; Drew Roberts; Li Zhang; Hugh Rosen; Nicholas H. Carbonetti. Therapeutic treatment with sphingosine-1-phosphate receptor 1 ligands reduces pertussis inflammatory pathology by a pertussis toxin-insensitive mechanism. Journal of Infectious Diseases 2016, 215, 278 -286.

AMA Style

Ciaran Skerry, Karen Scanlon, Jeremy Ardanuy, Drew Roberts, Li Zhang, Hugh Rosen, Nicholas H. Carbonetti. Therapeutic treatment with sphingosine-1-phosphate receptor 1 ligands reduces pertussis inflammatory pathology by a pertussis toxin-insensitive mechanism. Journal of Infectious Diseases. 2016; 215 (2):278-286.

Chicago/Turabian Style

Ciaran Skerry; Karen Scanlon; Jeremy Ardanuy; Drew Roberts; Li Zhang; Hugh Rosen; Nicholas H. Carbonetti. 2016. "Therapeutic treatment with sphingosine-1-phosphate receptor 1 ligands reduces pertussis inflammatory pathology by a pertussis toxin-insensitive mechanism." Journal of Infectious Diseases 215, no. 2: 278-286.

Spotlight
Published: 21 September 2016 in Clinical and Vaccine Immunology
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Pertussis is a severe respiratory disease caused by infection with the bacterial pathogenBordetella pertussis. The disease affects individuals of all ages but is particularly severe and sometimes fatal in unvaccinated young infants. OtherBordetellaspecies cause diseases in humans, animals, and birds. Scientific, clinical, public health, vaccine company, and regulatory agency experts on these pathogens and diseases gathered in Buenos Aires, Argentina from 5 to 8 April 2016 for the 11th InternationalBordetellaSymposium to discuss recent advances in our understanding of the biology of these organisms, the diseases they cause, and the development of new vaccines and other strategies to prevent these diseases. Highlights of the meeting included pertussis epidemiology in developing nations, genomic analysis ofBordetellabiology and evolution, regulation of virulence factor expression, new model systems to studyBordetellabiology and disease, effects of different vaccines on immune responses, maternal immunization as a strategy to prevent newborn disease, and novel vaccine development for pertussis. In addition, the group approved the formation of an InternationalBordetellaSociety to promote research and information exchange on bordetellae and to organize future meetings. A new Bordetella.org website will also be developed to facilitate these goals.

ACS Style

Nicholas H. Carbonetti; Carl Heinz Wirsing Von König; Ruiting Lan; Francoise Jacob-Dubuisson; Peggy A. Cotter; Rajendar Deora; Tod J. Merkel; Cécile A. Van Els; Camille Locht; Daniela Hozbor; Maria E. Rodriguez. Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development. Clinical and Vaccine Immunology 2016, 23, 842 -850.

AMA Style

Nicholas H. Carbonetti, Carl Heinz Wirsing Von König, Ruiting Lan, Francoise Jacob-Dubuisson, Peggy A. Cotter, Rajendar Deora, Tod J. Merkel, Cécile A. Van Els, Camille Locht, Daniela Hozbor, Maria E. Rodriguez. Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development. Clinical and Vaccine Immunology. 2016; 23 (11):842-850.

Chicago/Turabian Style

Nicholas H. Carbonetti; Carl Heinz Wirsing Von König; Ruiting Lan; Francoise Jacob-Dubuisson; Peggy A. Cotter; Rajendar Deora; Tod J. Merkel; Cécile A. Van Els; Camille Locht; Daniela Hozbor; Maria E. Rodriguez. 2016. "Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development." Clinical and Vaccine Immunology 23, no. 11: 842-850.

Historical article
Published: 07 September 2016 in Pathogens and Disease
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The significant and sometimes dramatic rise in the number of circulating white blood cells (leukocytosis) in infants suffering from pertussis (whooping cough) has been recognized for over a century. Although pertussis is a disease that afflicts people of all ages, it can be particularly severe in young infants, and these are the individuals in whom leukocytosis is most pronounced. Very high levels of leukocytosis are associated with poor outcome in infants hospitalized with pertussis and modern treatments are often aimed at reducing the number of leukocytes. Pertussis leukocytosis is caused by pertussis toxin, a soluble protein toxin released by Bordetella pertussis during infection, but the exact mechanisms by which this occurs are still unclear. In this minireview, I discuss the history of clinical and experimental findings on pertussis leukocytosis, possible contributing mechanisms causing this condition and treatments aimed at reducing leukocytosis in hospitalized infants. Since recent studies have detailed significant associations between specific levels of pertussis leukocytosis and fatal outcome, this is a timely review that may stimulate new thinking on how to understand and combat this problem.

ACS Style

Nicholas H. Carbonetti. Pertussis leukocytosis: mechanisms, clinical relevance and treatment. Pathogens and Disease 2016, 74, 1 .

AMA Style

Nicholas H. Carbonetti. Pertussis leukocytosis: mechanisms, clinical relevance and treatment. Pathogens and Disease. 2016; 74 (7):1.

Chicago/Turabian Style

Nicholas H. Carbonetti. 2016. "Pertussis leukocytosis: mechanisms, clinical relevance and treatment." Pathogens and Disease 74, no. 7: 1.

Journal article
Published: 30 June 2016 in Pathogens and Disease
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The active subunit (S1) of pertussis toxin (PT), a major virulence factor of Bordetella pertussis, ADP-ribosylates Gi proteins in the mammalian cell cytosol to inhibit GPCR signaling. The intracellular pathway of PT includes endocytosis and retrograde transport to the trans-Golgi network (TGN) and endoplasmic reticulum (ER). Subsequent translocation of S1 to the cytosol is presumably preceded by dissociation from the holotoxin. In vitro, such dissociation is stimulated by interaction of PT with ATP. To investigate the role of this interaction in cellular events, we engineered a form of PT (PTDM) with changes to two amino acids involved in the interaction with ATP. PTDM was reduced in (1) binding to ATP, (2) dissociability by interaction with ATP, (3) in vitro enzymatic activity and (4) cellular ADP-ribosylation activity. In cells treated with PTDM carrying target sequences for organelle-specific modifications, normal transport to the TGN and ER occurred, but N-glycosylation patterns of the S1 and S4 subunits were consistent with an inability of PTDM to dissociate in the ER. These results indicate a requirement for interaction with ATP for PT dissociation in the ER and cellular activity. They also indicate that the retrograde transport route is the cellular intoxication pathway for PT.

ACS Style

Roger Plaut; Karen M. Scanlon; Michael Taylor; Ken Teter; Nicholas H. Carbonetti. Intracellular disassembly and activity of pertussis toxin require interaction with ATP. Pathogens and Disease 2016, 74, 1 .

AMA Style

Roger Plaut, Karen M. Scanlon, Michael Taylor, Ken Teter, Nicholas H. Carbonetti. Intracellular disassembly and activity of pertussis toxin require interaction with ATP. Pathogens and Disease. 2016; 74 (6):1.

Chicago/Turabian Style

Roger Plaut; Karen M. Scanlon; Michael Taylor; Ken Teter; Nicholas H. Carbonetti. 2016. "Intracellular disassembly and activity of pertussis toxin require interaction with ATP." Pathogens and Disease 74, no. 6: 1.

Review
Published: 01 June 2016 in Current Opinion in Infectious Diseases
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Purpose of review The purpose of this review is to summarize and discuss recent findings and selected topics of interest in Bordetella pertussis virulence and pathogenesis and treatment of pertussis. It is not intended to cover issues on immune responses to B. pertussis infection or problems with currently used pertussis vaccines. Recent findings Studies on the activities of various B. pertussis virulence factors include the immunomodulatory activities of filamentous hemagglutinin, fimbriae, and adenylate cyclase toxin. Recently emerging B. pertussis strains show evidence of genetic selection for vaccine escape mutants, with changes in vaccine antigen-expressing genes, some of which may have increased the virulence of this pathogen. Severe and fatal pertussis in young infants continues to be a problem, with several studies highlighting predictors of fatality, including the extreme leukocytosis associated with this infection. Treatments for pertussis are extremely limited, though early antibiotic intervention may be beneficial. Neutralizing pertussis toxin activity may be an effective strategy, as well as targeting two host proteins, pendrin and sphingosine-1-phosphate receptors, as novel potential therapeutic interventions. Summary Pertussis is reemerging as a major public health problem and continued basic research is revealing information on bacterial virulence and disease pathogenesis, as well as potential novel strategies for vaccination and targets for therapeutic intervention.

ACS Style

Nicholas H. Carbonetti. Bordetella pertussis. Current Opinion in Infectious Diseases 2016, 29, 287 -294.

AMA Style

Nicholas H. Carbonetti. Bordetella pertussis. Current Opinion in Infectious Diseases. 2016; 29 (3):287-294.

Chicago/Turabian Style

Nicholas H. Carbonetti. 2016. "Bordetella pertussis." Current Opinion in Infectious Diseases 29, no. 3: 287-294.

Review
Published: 21 September 2015 in Pathogens and Disease
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Pertussis toxin (PT) is a multisubunit protein toxin secreted by Bordetella pertussis, the bacterial agent of the disease pertussis or whooping cough. PT in detoxified form is a component of all licensed acellular pertussis vaccines, since it is considered to be an important virulence factor for this pathogen. PT inhibits G protein-coupled receptor signaling through Gi proteins in mammalian cells, an activity that has led to its widespread use as a cell biology tool. But how does this activity of PT contribute to pertussis, including the severe respiratory symptoms of this disease? In this minireview, the contribution of PT to the pathogenesis of pertussis disease will be considered based on evidence from both human infections and animal model studies. Although definitive proof of the role of PT in humans is lacking, substantial evidence supports the idea that PT is a major contributor to pertussis pathology, including the severe respiratory symptoms associated with this disease.

ACS Style

Nicholas H. Carbonetti. Contribution of pertussis toxin to the pathogenesis of pertussis disease: Graphical Abstract Figure. Pathogens and Disease 2015, 73, ftv073 .

AMA Style

Nicholas H. Carbonetti. Contribution of pertussis toxin to the pathogenesis of pertussis disease: Graphical Abstract Figure. Pathogens and Disease. 2015; 73 (8):ftv073.

Chicago/Turabian Style

Nicholas H. Carbonetti. 2015. "Contribution of pertussis toxin to the pathogenesis of pertussis disease: Graphical Abstract Figure." Pathogens and Disease 73, no. 8: ftv073.

Review
Published: 21 September 2015 in Pathogens and Disease
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Whooping cough, or pertussis, incidence has reached levels not seen since the 1950s. Previous studies have shown that antibiotics fail to improve the course of disease unless diagnosed early. Early diagnosis is complicated by the non-diagnostic presentation of disease early in infection. This review focuses on previous attempts at developing novel host-directed therapies for the treatment of pertussis. In addition, two novel approaches from our group are discussed. Manipulation of the signaling pathway of sphingosine-1-phosphate, a lipid involved in many immune processes, has shown great promise, but is in its infancy. Pendrin, a host epithelial anion exchanger upregulated in the airways with B. pertussis infection, appears to drive mucus production and dysregulation of airway surface liquid pH and salinity. In addition to detailing these potential new therapeutic targets, the need for greater focus on the neonatal model of disease is highlighted.

ACS Style

Karen M. Scanlon; Ciaran Skerry; Nicholas. H. Carbonetti. Novel therapies for the treatment of pertussis disease. Pathogens and Disease 2015, 73, ftv074 .

AMA Style

Karen M. Scanlon, Ciaran Skerry, Nicholas. H. Carbonetti. Novel therapies for the treatment of pertussis disease. Pathogens and Disease. 2015; 73 (8):ftv074.

Chicago/Turabian Style

Karen M. Scanlon; Ciaran Skerry; Nicholas. H. Carbonetti. 2015. "Novel therapies for the treatment of pertussis disease." Pathogens and Disease 73, no. 8: ftv074.

Journal article
Published: 23 December 2014 in Journal of Infectious Diseases
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Recent pertussis resurgence represents a major public health concern. Currently, there are no effective treatments for critical pertussis in infants. Recent data have demonstrated the potential of sphingosine-1-phosphate receptor (S1PR) agonism in the treatment of infectious diseases. We used the murine Bordetella pertussis model to test the hypothesis that treatment with S1PR agonist AAL-R reduces pulmonary inflammation during infection. AAL-R treatment resulted in reduced expression of inflammatory cytokines and chemokines and attenuated lung pathology in infected mice. These results demonstrate a role for sphingosine-1-phosphate (S1P) signaling in B. pertussis-mediated pathology and highlight the possibility of host-targeted therapy for pertussis.

ACS Style

Ciaran Skerry; Karen Scanlon; Hugh Rosen; Nicholas H. Carbonetti. Sphingosine-1-phosphate Receptor Agonism Reduces Bordetella pertussis-mediated Lung Pathology. Journal of Infectious Diseases 2014, 211, 1883 -6.

AMA Style

Ciaran Skerry, Karen Scanlon, Hugh Rosen, Nicholas H. Carbonetti. Sphingosine-1-phosphate Receptor Agonism Reduces Bordetella pertussis-mediated Lung Pathology. Journal of Infectious Diseases. 2014; 211 (12):1883-6.

Chicago/Turabian Style

Ciaran Skerry; Karen Scanlon; Hugh Rosen; Nicholas H. Carbonetti. 2014. "Sphingosine-1-phosphate Receptor Agonism Reduces Bordetella pertussis-mediated Lung Pathology." Journal of Infectious Diseases 211, no. 12: 1883-6.

Journal article
Published: 28 July 2014 in Infection and Immunity
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Pertussis 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.

ACS Style

Karen M. Scanlon; Yael Gau; Jingsong Zhu; Ciaran Skerry; Susan M. Wall; Manoocher Soleimani; Nicholas H. Carbonetti. Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection. Infection and Immunity 2014, 82, 4212 -4221.

AMA Style

Karen M. Scanlon, Yael Gau, Jingsong Zhu, Ciaran Skerry, Susan M. Wall, Manoocher Soleimani, Nicholas H. Carbonetti. Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection. Infection and Immunity. 2014; 82 (10):4212-4221.

Chicago/Turabian Style

Karen M. Scanlon; Yael Gau; Jingsong Zhu; Ciaran Skerry; Susan M. Wall; Manoocher Soleimani; Nicholas H. Carbonetti. 2014. "Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection." Infection and Immunity 82, no. 10: 4212-4221.