Persistence of Community-Acquired Respiratory Distress Syndrome Toxin-Producing Mycoplasma pneumoniae in Refractory Asthma

Peters, Jay I.; Singh, Harjinder; Brooks, Edward G.; Diaz, Joseph D.; Kannan, Thirumalai R; Coalson, Jacqueline J.; Baseman, Janet; Cagle, Marianna P.; Baseman, Joel B.

doi:10.1378/chest.11-0221

Cited by 50 publications

(59 citation statements)

References 24 publications

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“…However, what is becoming clearer is the link between M. pneumoniae infection, CARDS toxin activity, and asthma (6,8,10,11,15,17,22,23). Recently, we reported a case series where we detected the prolonged presence (up to18 mo) of CARDS toxin protein in the respiratory secretions of a subset of patients with refractory asthma (41). These data are in good agreement with the current literature where emerging experimental and clinical data strongly links M. pneumoniae and M. pneumoniae-associated virulence factors to wheezing and exacerbation asthma (19, 21-25, 39, 42, 43).…”

Section: Discussionmentioning

confidence: 97%

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Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

Medina¹,

Coalson²,

Brooks

et al. 2012

Am J Respir Cell Mol Biol

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Mycoplasma pneumoniae causes acute and chronic lung infections in humans, leading to a variety of pulmonary and extrapulmonary sequelae. Of the airway complications of M. pneumoniae infection, M. pneumoniae-associated exacerbation of asthma and pediatric wheezing are emerging as significant sources of human morbidity. However, M. pneumoniae products capable of promoting allergic inflammation are unknown. Recently, we reported that M. pneumoniae produces an ADP-ribosylating and vacuolating toxin termed the community-acquired respiratory distress syndrome (CARDS) toxin. Here we report that naive mice exposed to a single dose of recombinant CARDS (rCARDS) toxin respond with a robust inflammatory response consistent with allergic disease. rCARDS toxin induced 30-fold increased expression of the Th-2 cytokines IL-4 and IL-13 and 70-to 80-fold increased expression of the Th-2 chemokines CCL17 and CCL22, corresponding to a mixed cellular inflammatory response comprised of a robust eosinophilia, accumulation of T cells and B cells, and mucus metaplasia. The inflammatory responses correlate temporally with toxin-dependent increases in airway hyperreactivity characterized by increases in airway restriction and decreases in lung compliance. Furthermore, CARDS toxin-mediated changes in lung function and histopathology are dependent on CD4 1 T cells. Altogether, the data suggest that rCARDS toxin is capable of inducing allergic-type inflammation in naive animals and may represent a causal factor in M. pneumoniae-associated asthma.Keywords: Mycoplasma pneumoniae; asthma; rCARDS toxin; eosinophilia; T cell Mycoplasma pneumoniae is a common human bacterial pathogen that causes acute and chronic infections of the respiratory tract and extrapulmonary pathology (1, 2). With the exception of mycoplasma adherence to the host epithelium, molecular mechanisms of virulence associated with the pathogenesis of M. pneumoniae infection are not well understood (1, 3). M. pneumoniae is predominantly an extracellular pathogen that binds to respiratory epithelial cells using a polarized tip organelle (1, 3-5). Interaction of M. pneumoniae with the respiratory epithelium results in significant cytopathology in cell culture and in vivo (4, 5). Previously, the cytopathology was attributed in part to the cytotoxic effects of hydrogen peroxides produced by M. pneumoniae (3). However, recently, we identified an ADP-ribosylating and vacuolating toxin produced by M. pneumoniae that is capable of inducing cytopathology in vitro and in vivo and that reproduces the infectious process (6-9).The community-acquired respiratory distress syndrome (CARDS) toxin encoded by the MPN372 gene was functionally identified as a human surfactant protein A binding protein (7). Upon further investigation, we discovered that CARDS toxin possesses structurally and functionally important regions of identity to the pertussis toxin S1 protein. Furthermore, highly purified rCARDS toxin causes extensive dose-dependent cytopathology in mammalian cell and organ culture, suggestin...

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Section: Discussionmentioning

confidence: 97%

“…The ability of rCARDS toxin to promote allergic inflammation may have a profound impact on the exacerbation of human asthma. A direct role for CARDS toxin in human asthma has not been proven, but it would not be unreasonable to predict a role for CARDS toxin in human lung disease (41,45).…”

Section: Discussionmentioning

confidence: 99%

Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

Medina¹,

Coalson²,

Brooks

et al. 2012

Am J Respir Cell Mol Biol

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“…, 2008, Waites & Talkington, 2004). Evidence linking the organism to reactive airway diseases, such as asthma, is rapidly accumulating (Esposito et al , 2000, Kraft, 2000, Biscardi et al , 2004, Nisar et al , 2007, Sutherland & Martin, 2007, Peters et al. , 2011).…”

Section: Introductionmentioning

confidence: 99%

Functional mapping of community‐acquired respiratory distress syndrome (CARDS) toxin of Mycoplasma pneumoniae defines regions with ADP‐ribosyltransferase, vacuolating and receptor‐binding activities

Kannan

Krishnan

Ramasamy

et al. 2014

Molecular Microbiology

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SUMMARY Community-acquired respiratory distress syndrome (CARDS) toxin from Mycoplasma pneumoniae is a 591 amino acid virulence factor with ADP-ribosyltransferase (ADPRT) and vacuolating activities. It is expressed at low levels during in vitro growth and at high levels during colonization of the lung. Exposure of experimental animals to purified recombinant CARDS toxin alone is sufficient to recapitulate the cytopathology and inflammatory responses associated with M. pneumoniae infection in humans and animals. Here, by molecular modeling, serial truncations and site-directed mutagenesis, we show that the N-terminal region is essential for ADP-ribosylating activity. Also, by systematic truncation and limited proteolysis experiments we identified a portion of the C-terminal region that mediates toxin binding to mammalian cell surfaces and subsequent internalization. In addition, the C-terminal region alone induces vacuolization in a manner similar to full-length toxin. Together, these data suggest that CARDS toxin has a unique architecture with functionally separable N-terminal and C-terminal domains.

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“…For example, we reported that M. pneumoniae was detected in 52% of the respiratory secretions from a cohort of refractory asthmatics. Among the M. pneumoniae -positive refractory asthmatic patients, all tested positive for CARDS toxin by antigen capture indicating the presence of the toxin in the airway and suggesting an important role of CARDS toxin in asthmatic lung disease [14]. Additionally, Wood et al showed a strong correlation between poor asthma control and testing positive for CARDS toxin by antigen capture suggesting that M. pneumoniae infection and CARDS toxin can worsen asthma symptom severity and control [15].…”

Section: Introductionmentioning

confidence: 99%

Mycoplasma pneumoniae CARDS Toxin Exacerbates Ovalbumin-Induced Asthma-Like Inflammation in BALB/c Mice

et al. 2014

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Mycoplasma pneumoniae causes a range of airway and extrapulmonary pathologies in humans. Clinically, M. pneumoniae is associated with acute exacerbations of human asthma and a worsening of experimentally induced asthma in mice. Recently, we demonstrated that Community Acquired Respiratory Distress Syndrome (CARDS) toxin, an ADP-ribosylating and vacuolating toxin synthesized by M. pneumoniae, is sufficient to induce an asthma-like disease in BALB/cJ mice. To test the potential of CARDS toxin to exacerbate preexisting asthma, we examined inflammatory responses to recombinant CARDS toxin in an ovalbumin (OVA) murine model of asthma. Differences in pulmonary inflammatory responses between treatment groups were analyzed by histology, cell differentials and changes in cytokine and chemokine concentrations. Additionally, assessments of airway hyperreactivity were evaluated through direct pulmonary function measurements. Analysis of histology revealed exaggerated cellular inflammation with a strong eosinophilic component in the CARDS toxin-treated group. Heightened T-helper type-2 inflammatory responses were evidenced by increased expression of IL-4, IL-13, CCL17 and CCL22 corresponding with increased airway hyperreactivity in the CARDS toxin-treated mice. These data demonstrate that CARDS toxin can be a causal factor in the worsening of experimental allergic asthma, highlighting the potential importance of CARDS toxin in the etiology and exacerbation of human asthma.

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Persistence of Community-Acquired Respiratory Distress Syndrome Toxin-Producing Mycoplasma pneumoniae in Refractory Asthma

Cited by 50 publications

References 24 publications

Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

Functional mapping of community‐acquired respiratory distress syndrome (CARDS) toxin of Mycoplasma pneumoniae defines regions with ADP‐ribosyltransferase, vacuolating and receptor‐binding activities

Mycoplasma pneumoniae CARDS Toxin Exacerbates Ovalbumin-Induced Asthma-Like Inflammation in BALB/c Mice

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