Immunologic Aspects of Experimental Mycoplasma pneumoniae Infection

Fernald, Gerald W.

doi:10.1093/infdis/119.3.255

Cited by 51 publications

(43 citation statements)

References 26 publications

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“…These events were followed by progressive coalescence of cytoplasmic vacuoles and distortion of the cytoplasm, resulting in extensive cellular fragmentation and sloughing (28,(30)(31)(32). Although it was proposed that mycoplasma adherence to host target cells and active mycoplasma metabolic function, including peroxide secretion, contributed to M. pneumoniae-mediated pathogenicity (33), no differences in these properties were demonstrable between virulent or attenuated mycoplasmas (28,34). At that time, we postulated that unknown M. pneumoniae ''dose-dependent toxic factors'' mediated the observed host cell dysfunction and CPE (27).…”

Section: Discussionmentioning

confidence: 99%

ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens

Kannan

Baseman

2006

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

198

278

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Unlike many bacterial pathogens, Mycoplasma pneumoniae is not known to produce classical toxins, and precisely how M. pneumoniae injures the respiratory epithelium has remained a mystery for >50 years. Here, we report the identification of a virulence factor (MPN372) possibly responsible for airway cellular damage and other sequelae associated with M. pneumoniae infections in humans. We show that M. pneumoniae MPN372 encodes a 68-kDa protein that possesses ADP-ribosyltransferase (ART) activity. Within its N terminus, MPN372 contains key amino acids associated with NAD binding and ADP-ribosylating activity, similar to pertussis toxin (PTX) S1 subunit (PTX-S1). Interestingly, MPN372 ADP ribosylates both identical and distinct mammalian proteins when compared with PTX-S1. Remarkably, MPN372 elicits extensive vacuolization and ultimate cell death of mammalian cells, including distinct and progressive patterns of cytopathology in tracheal rings in organ culture that had been previously ascribed to infection with WT virulent M. pneumoniae. We observed dramatic seroconversion to MPN372 in patients diagnosed with M. pneumoniae-associated pneumonia, indicating that this toxin is synthesized in vivo and possesses highly immunogenic epitopes.ADP ribosylation ͉ community-acquired respiratory distress syndrome toxin ͉ vacuolization T he earliest reports of mycoplasmas as infectious agents in humans appeared in the 1940s (1). Definitive studies in the early 1960s established Mycoplasma pneumoniae as the singular cause of cold agglutinin-associated primary atypical pneumonia (2, 3). Today, M. pneumoniae is the best known of the human mycoplasmas (4). These bacteria are most unusual, lacking typical cell walls possessed by other prokaryotes, using UGA to encode tryptophan, and requiring cholesterol for growth and maintenance of membrane function and integrity. Much has been learned about the role of M. pneumoniae as a respiratory tract pathogen (5). M. pneumoniae infections constitute 20-40% of all community-acquired pneumonia and are frequently associated with other airway disorders, such as tracheobronchitis and pharyngitis. Extrapulmonary manifestations, such as hematopoietic, dermatologic, joint, central nervous system, liver, pancreas, kidney, and cardiovascular syndromes are considered sequelae of primary M. pneumoniae infections. Also, M. pneumoniae has been linked to fulminant disease, with multiorgan involvement (6). Therefore, M. pneumoniae causes a wide spectrum of pathologies, with more extensive complications than previously recognized (6), yet no single virulence determinant has been associated with these clinical signs and symptoms. In addition, definitive diagnosis and therapeutic decisions relative to M. pneumoniae infections are often delayed or lacking because of the long incubation period (average 1-2 weeks) before clinical symptoms can be observed. Further, direct isolation of M. pneumoniae from patients frequently fails, and, when successful, broth or colony growth requires 10-21 days.The early stages of t...

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Section: Discussionmentioning

confidence: 99%

ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens

Kannan

Baseman

2006

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

198

278

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Section: Plate Xi1mentioning

confidence: 99%

“…However, the M. pneumoniae-infected Syrian hamster is a useful model, not only because this is one of the few small animals that can be successfully infected, but also because the histological characteristics of the pneumonia and the temporal development of antibody are similar to these features in man (Dajani, Clyde and Denny, 1965;Fernald, 1969).Pneumonia in hamsters infected with M. pneumoniae consists of peribronchial and perivascular cuffing by lymphocytes, and this suggests that it is the result of a delayed hypersensitivity response in the lung. However, immunoglobulin is associated with many of the cells (Fernald, Clyde and Bienenstock, 1972), indicating that the response may not be a pure delayed hypersensitivity reaction.…”

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confidence: 99%

Reduction in the Severity of Mycoplasma Pneumoniae-Induced Pneumonia in Hamsters by Immunosuppressive Treatment with Anti-Thymocyte Sera

Taylor¹,

Taylor‐Robinson²,

Fernald³

1974

Journal of Medical Microbiology

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PLATE XI1THE pathogenesis of pneumonia in man caused by Mycoplasma pnewnoniae is poorly understood. However, the M. pneumoniae-infected Syrian hamster is a useful model, not only because this is one of the few small animals that can be successfully infected, but also because the histological characteristics of the pneumonia and the temporal development of antibody are similar to these features in man (Dajani, Clyde and Denny, 1965;Fernald, 1969).Pneumonia in hamsters infected with M. pneumoniae consists of peribronchial and perivascular cuffing by lymphocytes, and this suggests that it is the result of a delayed hypersensitivity response in the lung. However, immunoglobulin is associated with many of the cells (Fernald, Clyde and Bienenstock, 1972), indicating that the response may not be a pure delayed hypersensitivity reaction. Nevertheless, other observations suggest that delayed hypersensitivity develops during M. pneumoniae infection. Thus, guinea-pigs and man develop skin hypersensitivity (Fernald, 1971 ;Mizutani et al., 1971). Furthermore, lymphocytes from previously infected human subjects and guinea-pigs can be stimulated in vitro by M. pneumoniae antigens to undergo blast transformation (Leventhal et al., 1969;Fernald, 1971; Biberfeld, 1972;Fernald, 1972), and the migration of macrophages can be inhibited by M. pneumoniae antigen (Arai et al., 1971). Nevertheless, these in-vitro demonstrations of delayed hypersensitivity may not be relevant in vivo. However, with regard to the latter situation, Denny, Taylor-Robinson and Allison (1972) demonstrated that mice, immunosuppressed by thymectomy and X-irradiation and infected intranasally with M. pulmonis, developed lung lesions that were much less severe than those observed in infected but immunologically normal mice. Although the lung lesions in these mice and in M. pneumoniae-infected hamsters appear similar, this does not necessarily mean that thymusdependent mechanisms are also important in the development of hamster lung lesions.Because we are particularly interested in the hamster as a model for the human disease, the effect of thymus-dependent lymphocyte depletion on the development of M. pneumoniae-induced lung lesions in hamsters was investigated. Immunosuppression was effected by the use of anti-thymocyte serum. The present report records findings obtained with this model in two laboratories. MATERIALS AND METHODSMycoplasma pneumoniae strains. Virulent M. pneumoniae strains P1-104166, B8-Ml29 and P5-427AY known to produce pneumonia in hamsters were used. The mycoplasmas

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“…M. pneumoniae pneumonia responds satisfactorily to the appropriate antibiotics, but the organisms are not effectively eradicated from the respiratory tract (14,23). Efforts have been directed toward the development of a vaccine for prophylaxis (7,10,12,17,25).Resistance of humans to M. pneumoniae infection has been reported to be correlated directly with the presence of serum antibodies (7,20,22,28). In hamsters, a high level of serum antibody produced by parenteral vaccination with killed M. pneumoniae was not accompanied by protection (l 0) .…”

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confidence: 99%

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Immunological Responses of Hamsters in the Acquired Immune State to Mycoplasma pneumoniae Infection

Hayatsu

Kawakubo

Yayoshi

et al. 1981

Microbiology and Immunology

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Protective effects of vaccination of hamsters against Mycoplasma pneumoniae infection, evaluated according to the recovery of mycoplasmas and histopathological changes in the respiratory tract after challenge infection, persisted for at least 6 months after the final vaccination. Serum antibody levels reached a maximum in the second week after the last vaccination and decreased markedly between the first and the third months, but increased again in sera obtained from animals given booster injections. Metabolism-inhibiting antibodies were detected in bronchial washings of animals showing high resistance obtained by vaccinal or passive immunization. Antiserum transfer was also effective for protection but cell-mediated immune responses were not demonstrated in any animals up to 6 months after the vaccination. Even after 10 months, suppression of both mycoplasmal proliferation and lung lesions was apparent, and a single dose of the vaccine induced a significant booster effect. These findings suggest that (I) humoral immunity is more important than cell-mediated immunity in resistance of hamsters to M. pneumoniae pneumonia, and (2) the antibody secreted in the respiratory tract may be involved in the local defense mechanisms.Mycoplasma pneumoniae, a respiratory tract pathogen, causes bronchitis and pneumonia in children and young adults. Epidemiological problems have been raised, especially in closed populations such as kindergartens, primary schools, and military forces (1,6,15,26,29). M. pneumoniae pneumonia responds satisfactorily to the appropriate antibiotics, but the organisms are not effectively eradicated from the respiratory tract (14,23). Efforts have been directed toward the development of a vaccine for prophylaxis (7,10,12,17,25).Resistance of humans to M. pneumoniae infection has been reported to be correlated directly with the presence of serum antibodies (7,20,22,28). In hamsters, a high level of serum antibody produced by parenteral vaccination with killed M. pneumoniae was not accompanied by protection (l 0) . On the other hand, 1255

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Immunologic Aspects of Experimental Mycoplasma pneumoniae Infection

Cited by 51 publications

References 26 publications

ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens

ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens

Reduction in the Severity of Mycoplasma Pneumoniae-Induced Pneumonia in Hamsters by Immunosuppressive Treatment with Anti-Thymocyte Sera

Immunological Responses of Hamsters in the Acquired Immune State to Mycoplasma pneumoniae Infection

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