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

ABSTRACT: 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 ?-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 ?-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.

SUBMITTER: Becker A

PROVIDER: S-EPMC4413325 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Becker Argentina A Kannan T R TR Taylor Alexander B AB Pakhomova Olga N ON Zhang Yanfeng Y Somarajan Sudha R SR Galaleldeen Ahmad A Holloway Stephen P SP Baseman Joel B JB Hart P John PJ

Proceedings of the National Academy of Sciences of the United States of America 20150406 16

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 ...[more]

PMID: 25848012

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Project description:RationaleMycoplasma pneumoniae was recently discovered to produce an ADP-ribosylating and vacuolating cytotoxin, designated CARDS toxin, which is hypothesized to be a primary pathogenic mechanism responsible for M. pneumoniae-induced pulmonary inflammation. It is unknown if cytotoxin production varies with M. pneumoniae strain or if variation in cytotoxin production affects pulmonary disease severity.ObjectivesTo examine the production of CARDS toxin by various strains of M. pneumoniae and compare the disease manifestations elicited by these strains in an experimental model of M. pneumoniae respiratory infection.MethodsBALB/c mice were inoculated once intranasally with SP4 broth (negative control) or three different M. pneumoniae strains: M129-B7, M129-B9, or S1. Mice were assessed at 1, 2, 4, 7, 10, and 14 days after inoculation. Outcome variables included comparisons among M. pneumoniae strains relative to bronchoalveolar lavage (BAL) M. pneumoniae quantitative culture, CARDS toxin-based PCR, and CARDS toxin protein determinations, as well as cytokine and chemokine concentrations. Graded lung histopathologic score (HPS) was also assessed.Measurements and main resultsCARDS toxin concentrations were significantly increased in mice inoculated with strain S1 compared with mice inoculated with M129-B7 or M129-B9 strains. Quantitative M. pneumoniae culture and polymerase chain reaction were also significantly greater in mice infected with S1 strain compared with the other two strains, as were lung HPS and concentrations of IFN-?, IL-12, IL-1?, macrophage inflammatory protein-1?, and keratinocyte-derived chemokine. In addition, a significant positive correlation was found between CARDS toxin concentration and lung HPS.ConclusionsCARDS toxin concentrations in BAL are directly linked to the ability of specific M. pneumoniae strains to colonize, replicate, and persist, and elicit lung histopathology. This variation among strains may predict the range in severity of pulmonary disease observed among patients.

Dataset Information

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

Publications

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

Similar Datasets

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