RESUMEN
The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness.
Asunto(s)
Células Epiteliales Alveolares/efectos de los fármacos , Carbunco/patología , Antígenos Bacterianos/toxicidad , Bacillus anthracis/patogenicidad , Toxinas Bacterianas/toxicidad , Infecciones del Sistema Respiratorio/patología , Actinas/metabolismo , Células Epiteliales Alveolares/citología , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/microbiología , Animales , Carbunco/microbiología , Antígenos Bacterianos/genética , Bacillus anthracis/genética , Bacillus anthracis/metabolismo , Toxinas Bacterianas/genética , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Células Cultivadas , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Receptores de Péptidos/genética , Receptores de Péptidos/metabolismo , Infecciones del Sistema Respiratorio/microbiología , VirulenciaRESUMEN
BACKGROUND: Neurotrophins have been implicated in the pathogenesis of asthma because of their ability to induce airway inflammation and to promote hyperreactivity of sensory neurons, which reflects an important mechanism in the pathogenesis of airway hyperreactivity. Neurotrophins use a dual-receptor system consisting of Trk-receptor tyrosine kinases and the structurally unrelated p75NTR. Previous studies revealed an important role of p75NTR in the pathogenesis of allergic asthma. OBJECTIVES: The aim of the study was to investigate the precise mechanisms of neurotrophins in neuroimmune interaction, which can lead to both airway inflammation and sensory nerve hyperreactivity in vivo. METHODS: Mice selectively expressing p75NTR in immune cells or nerves, respectively, were generated. After sensitization and allergen provocation, hyperreactivity of sensory nerves was tested in response to capsaicin. Airway inflammation was analyzed on the basis of differential cell counts and cytokine levels in bronchoalveolar lavage fluids. RESULTS: Allergic mice selectively expressing p75NTR in immune cells showed normal inflammation but no sensory nerve hyperreactivity, whereas mice selectively expressing p75NTR in nerve cells had a diminished inflammation and a distinct sensory nerve hyperreactivity. CONCLUSION: Our data indicate that p75NTR plays a dual role by promoting hyperreactivity of sensory nerves and airway inflammation. Additionally, our study provides experimental evidence that development of sensory nerve hyperreactivity depends on an established airway inflammation in asthma. In contrast, development of airway inflammation seems to be independent from sensory nerve hyperreactivity. CLINICAL IMPLICATIONS: Because of its dual function, antagonization of p75NTR-mediated signals might be a novel approach in asthma therapy.