High-Resolution Magic Angle Spinning NMR-Based Metabolomics Revealing Metabolic Changes in Lung of Mice Infected with P. aeruginosa Consistent with the Degree of Disease Severity.

Pseudomonas aeruginosa is a critical pathogen for human health, due to increased resistances to antibiotics and to nosocomial infections. There is an urgent need for tools allowing for better understanding mechanisms underlying the disease processes and for evaluating new therapeutic strategies with animal models. Here, we used a novel approach, applying high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HRMAS NMR) directly to lung biopsies of mice to better understand the impact of infection on the tissue at a molecular level. Mice were infected with two P. aeruginosa strains of different virulence levels. Statistical analysis applied to HRMAS NMR data allowed us to build a multivariate discriminant model to distinguish the lungs' metabolic profiles of mice, infected or not. Moreover, a second model was built to appreciate the degree of severity of infection, demonstrating sufficient sensitivity of HRMAS NMR-based metabolomics to investigate this type of infection. The metabolic features that discriminate infection statuses are dominated by some key differentially expressed metabolites that are related, respectively, to bacterial carbon metabolism (glycerophosphocholine) and to septic hypoxic stress response of host (succinate). Finally, to get closer to clinical and diagnosis issues, we proposed to build simple logistic regression models to predict the infection status on the basis of only one metabolite intensity. Thus, we have demonstrated that succinate intensity could discriminate the infected/noninfected status infection with a sensibility of 89% and a specificity of 95%, and leucine/isoleucine intensity could predict the severe/not severe status of infection with a sensibility of 100% and a specificity of 95%. We also looked for the interest of this model in order to predict the efficacy of anti- P. aeruginosa treatment. By HRMAS metabolomics analysis of lungs infected with P. aeruginosa after vaccination, we demonstrated that this model could be a useful tool to predict the efficacy of new anti- P. aeruginosa drugs. This metabolomics approach could therefore be useful both for the definition of biomarkers of severity of infection and for an earlier characterization of therapeutic efficacy.

Killed but metabolically active Pseudomonas aeruginosa-based vaccine induces protective humoral- and cell-mediated immunity against Pseudomonas aeruginosa pulmonary infections.

Pseudomonas aeruginosa (Pa) is a significant cause of morbidity and mortality, especially in cystic fibrosis patients. Its eradication is difficult due to a wide phenotypic adaptability and an increase of its resistance to antibiotics. After the failure of several recombinant vaccines which mainly triggered humoral response, live-attenuated vaccines received attention thanks to their ability to elicit a broad immunity with both humoral- and cell-mediated responses, essential to fight this pathogen. In this study, we developed an innovative and safer live-attenuated Pa vaccine based on a Killed But Metabolically Active (KBMA) attenuation method. KBMA Pa has been further rationally designed to overexpress beneficial effectors like the type 3 secretion system apparatus. We demonstrated that KBMA Pa elicits a high and broad humoral response in mice against several antigens of particular interest such as OprF and PcrV proteins. Moreover, we assessed cytokines in the serum of immunized mice and showed that KBMA Pa elicits Th1, Th2 and especially Th17 pathways of cell-mediated immune responses. Th17 pathway involvement was also confirmed after specific stimulation of helper T cells in immunized mice. Finally, we showed that this vaccine is safe and has a protective effect in a murine acute pulmonary infectious challenge. In conclusion, KBMA Pa is a new platform with high potential for the development of a vaccine against Pa.

Atypical response to erlotinib in a patient with metastatic lung adenocarcinoma: a case report.

INTRODUCTION: Tyrosine kinase inhibitors are widely prescribed in thoracic oncology and have excellent responses as a first-line treatment for locally advanced or metastatic lung cancer with epidermal growth factor receptor mutations. The side effects of tyrosine kinase inhibitors are mostly gastrointestinal and dermatological, and are usually resolved after symptomatic treatment. However, new complications have now arisen due to increased use of these drugs. Here we report a side effect of erlotinib that has not been described previously: that is, metastatic lung tumor nodules were transformed into cysts, which ruptured the pleura and were responsible for bilateral life-threatening pneumothorax. CASE PRESENTATION: We report the case of a 35-year-old Caucasian woman with metastatic adenocarcinoma and a deletion in epidermal growth factor receptor exon 19 (del E746-A750). She was treated with erlotinib for metastatic lung adenocarcinoma. Treatment with erlotinib resulted in the replacement of pulmonary tumor nodules with air-containing cysts. These cysts ruptured in the pleura causing a life-threatening bilateral pneumothorax. To the best of our knowledge, this tumor-cystic response after erlotinib therapy has not been previously described. CONCLUSIONS: Tyrosine kinase inhibitors are widely prescribed in thoracic oncology, and managing toxicities must be optimal in order to improve adherence. Transformation of pulmonary nodules into cysts must be known and clinicians should be aware of this potential complication, which can lead to life-threatening pneumothorax.