Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

Abstract

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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