<i>Mycoplasma pneumoniae</i> Induces Host-Dependent Pulmonary Inflammation and Airway Obstruction in Mice

Fonseca-Aten, Mónica; Ríos, Ana María; Mejías, Asunción; Chávez-Bueno, Susana; Katz, Kathy; Gómez, Ana M.; McCracken, George H.; Hardy, R. Doug

doi:10.1165/rcmb.2004-0197oc

Cited by 62 publications

(78 citation statements)

References 60 publications

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“…These results reconfirm the findings of recent investigations that have shown a significant role for IL-12 and IFN-g in the immunopathogenesis of inflammation in Mycoplasma respiratory infection (27,28,(32)(33)(34)(35). It should be noted that the cytokine immunopathogenesis of M. pneumoniae infection appears to be different between hosts with and without allergic sensitization of the airways, especially regarding pulmonary IL-4 (36).…”

Section: Discussionsupporting

confidence: 89%

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Variation in Colonization, ADP-Ribosylating and Vacuolating Cytotoxin, and Pulmonary Disease Severity among Mycoplasma pneumoniae Strains

Techasaensiri¹,

Tagliabue²,

Cagle³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Mycoplasma 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. Objectives: To 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. Methods: BALB/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 Results: CARDS 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-g, IL-12, IL-1a, macrophage inflammatory protein-1a, and keratinocytederived chemokine. In addition, a significant positive correlation was found between CARDS toxin concentration and lung HPS. Conclusions: CARDS 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.Keywords: Mycoplasma pneumoniae; toxin; pneumonia; asthma; ADPribosylating Mycoplasma pneumoniae is a common respiratory bacterial pathogen that affects both the upper and lower respiratory tracts of children and adults (1-9). More recent data demonstrate an association between M. pneumoniae respiratory infection and reactive airway disease and asthma (10-15). Although M. pneumoniae has been recognized as a significant clinical pathogen for decades, its virulence determinants have only been partially deciphered. M. pneumoniae is believed to primarily act as an extracellular parasite, with its pathogenicity dependent on its attachment to respiratory epithelium and subsequent initiation of injury to the host. Much investigation has been directed at understanding the mechanisms responsible for the essential process of extracellular attachment (16)(17)(18)(19). In addition, M. pneumoniae has been reported to possess invasive and intracellular survival capabilities. However, the microbial factors responsible f...

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Section: Discussionsupporting

confidence: 89%

“…The objective of this study was to examine the production of CARDS toxin by various strains of M. pneumoniae and to compare the disease manifestations elicited by these strains in an established experimental model of M. pneumoniae respiratory infection (27)(28)(29).…”

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confidence: 99%

Variation in Colonization, ADP-Ribosylating and Vacuolating Cytotoxin, and Pulmonary Disease Severity among Mycoplasma pneumoniae Strains

Techasaensiri¹,

Tagliabue²,

Cagle³

et al. 2010

Am J Respir Crit Care Med

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“…A number of studies have highlighted the importance of IL-12 and IFN-g and Th-1 type T-cell responses during the pathogenesis of M. pneumoniae infection in mouse models of pneumonia (8,(12)(13)(14). However, if the host is sensitized to allergen before infection, M. pneumoniae can worsen asthma-like disease in mouse models, leading to airway remodeling, mucus metaplasia, and changes in pulmonary function (15,16).…”

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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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“…It has been previously described that the levels of total immunoglobulins, immunoglobulin A (IgA), IgM, and IgG, in serum increase during the convalescent phase of the disease (19) and that there is production of IgE specific to M. pneumoniae during infection (18). The bronchoalveolar lavage cytokine data suggest a predominant Th2-like cytokine response in M. pneumoniae infections, thus representing a favorable condition for IgE production (7), although other results suggest a Th1 cytokine response predominance (5,21).…”

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confidence: 99%

Humoral and Cellular Immunity in Children withMycoplasma pneumoniaeInfection: a 1-Year Prospective Study

Stelmach¹,

Podsiadłowicz-Borzęcka²,

Grzelewski³

et al. 2005

Clin Vaccine Immunol

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To determine whether children have persistent abnormalities in cellular and humoral immunity development after acute Mycoplasma pneumoniae infection, serum immunoglobulin G (IgG), IgA, IgM, and IgE levels and lymphocyte phenotypes were determined. There were no changes in the levels of IgG, IgM, IgA, or CD4 ؉ or CD19؉ lymphocytes that were measured in M. pneumoniae-positive patients after 3 months or after 12 months, but there were increases in these in M. pneumoniae-negative patients. Serum IgE increased in M. pneumoniae-positive patients. We have shown alterations in immunity development after M. pneumoniae infection.Mycoplasma pneumoniae is a common pathogen of children's respiratory tracts (8), and its abilities to act as a polyclonal activator of lymphocytes and autoantibodies to various tissues and immune complexes are well known (2, 16). CD4 ϩ T cells, B cells, and plasma cells infiltrate the lungs, which is followed by further amplification of the immune response, namely, proliferation of lymphocytes, production of immunoglobulins, and release of proinflammatory cytokines (3,14). It has been previously described that the levels of total immunoglobulins, immunoglobulin A (IgA), IgM, and IgG, in serum increase during the convalescent phase of the disease (19) and that there is production of IgE specific to M. pneumoniae during infection (18). The bronchoalveolar lavage cytokine data suggest a predominant Th2-like cytokine response in M. pneumoniae infections, thus representing a favorable condition for IgE production (7), although other results suggest a Th1 cytokine response predominance (5, 21).Previous studies are confined to the acute phase of M. pneumoniae infection and do not answer questions about the possible duration of the humoral and cellular imbalance after M. pneumoniae infection in children. In this study, we hypothesized that children may have persistent abnormalities in cellular and humoral immunity development after acute M. pneumoniae infection.The study participants included 110 patients (52 male and 58 female) aged 1 to 5 years, all suffering from recurrent respiratory tract infections, defined according to Ribeiro (15). The diagnosis of M. pneumoniae infection was based on clinical symptoms (12,20) and the presence of IgM, determined by enzyme-linked immunosorbent assay (ELISA) and confirmed by PCR. Children diagnosed with M. pneumoniae infection were treated with clarithromycin (4). None of the patients had previously suffered from allergic disease or immunodeficiency syndrome. The characteristics of the patients are presented in Table 1.There were five study visits. At the first visit, patients were informed about the purpose of the study and were told that the second visit would occur after 3 months or earlier (in the case of respiratory tract infection). The patient's medical history was recorded, a physical examination was done, and blood samples for IgG, IgA, IgM, and IgE serum levels and lymphocyte phenotypes were taken at each visit. During the second visit, a blood sample was ...

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Mycoplasma pneumoniae Induces Host-Dependent Pulmonary Inflammation and Airway Obstruction in Mice

Cited by 62 publications

References 60 publications

Variation in Colonization, ADP-Ribosylating and Vacuolating Cytotoxin, and Pulmonary Disease Severity among Mycoplasma pneumoniae Strains

Variation in Colonization, ADP-Ribosylating and Vacuolating Cytotoxin, and Pulmonary Disease Severity among Mycoplasma pneumoniae Strains

Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

Humoral and Cellular Immunity in Children withMycoplasma pneumoniaeInfection: a 1-Year Prospective Study

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