Cellular Vacuoles Induced by Mycoplasma pneumoniae CARDS Toxin Originate from Rab9-Associated Compartments

Johnson, Coreen; Kannan, Thirumalai R; Baseman, Joel B.

doi:10.1371/journal.pone.0022877

Cited by 39 publications

(54 citation statements)

References 56 publications

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“…The aforementioned results are consistent with CARDS TX interaction with SP-A, which is abundant in mouse lung and baboon tracheal rings; however, recombinant CARDS TX carries out ADP-ribosylating and vacuolating activities in mammalian cell lines that lack SP-A, suggesting that it uses alternative receptors (18,19). Using recombinant CARDS TX as bait, AnxA2 was isolated from the membrane fraction of A549 airway cells (19).…”

Section: Significancesupporting

confidence: 73%

“…HeLa cells expressing dominant-negative Rab9 demonstrate reduced vacuole formation, whereas those expressing dominantnegative Rab7 do not. These data suggest that Rab9 is involved in CARDS TX-mediated vacuole formation (18), although how CARDS TX influences Rab9 association with vacuoles is unclear.…”

Section: Significancementioning

confidence: 91%

“…The acidic vacuoles induced by CARDS TX originate from Rab9-associated compartments and are derived from the endocytic pathway (18). The V-ATPase inhibitor bafilomycin A1 and the ionophore monesin inhibit vacuole formation.…”

Section: Significancementioning

confidence: 99%

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Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae

Becker¹,

Kannan²,

Taylor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mycoplasma pneumoniae (Mp) infections cause tracheobronchitis and "walking" pneumonia, and are linked to asthma and other reactive airway diseases. As part of the infectious process, the bacterium expresses a 591-aa virulence factor with both mono-ADP ribosyltransferase (mART) and vacuolating activities known as Community-Acquired Respiratory Distress Syndrome Toxin (CARDS TX). CARDS TX binds to human surfactant protein A and annexin A2 on airway epithelial cells and is internalized, leading to a range of pathogenetic events. Here we present the structure of CARDS TX, a triangular molecule in which N-terminal mART and C-terminal tandem β-trefoil domains associate to form an overall architecture distinct from other well-recognized ADP-ribosylating bacterial toxins. We demonstrate that CARDS TX binds phosphatidylcholine and sphingomyelin specifically over other membrane lipids, and that cell surface binding and internalization activities are housed within the C-terminal β-trefoil domain. The results enhance our understanding of Mp pathogenicity and suggest a novel avenue for the development of therapies to treat Mp-associated asthma and other acute and chronic airway diseases. mycoplasma cytotoxin | single-crystal X-ray diffraction | ADP-ribosyltransferase | vacuolation | reactive airway disease

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Section: Significancesupporting

confidence: 73%

Section: Significancementioning

confidence: 91%

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Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae

Becker¹,

Kannan²,

Taylor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…rCARDS Toxin rCARDS toxin was produced as described (6,7,9), and bioactivity was determined by vacuolization of HeLa cells (6,8) with carrier fluid (CF) as a control.…”

Section: Methodsmentioning

confidence: 99%

“…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)(7)(8)(9).…”

mentioning

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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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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Clinical and histologic features of Mycoplasma pneumoniae –related erythema multiforme: A single-center series of 33 cases compared with 100 cases induced by other causes

Amode

Ingen‐Housz‐Oro

Ortonne

et al. 2018

Journal of the American Academy of Dermatology

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Cellular Vacuoles Induced by Mycoplasma pneumoniae CARDS Toxin Originate from Rab9-Associated Compartments

Cited by 39 publications

References 56 publications

Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae

Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae

Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

Clinical and histologic features of Mycoplasma pneumoniae –related erythema multiforme: A single-center series of 33 cases compared with 100 cases induced by other causes

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