Immunization with live, virulence-attenuated Listeria monocytogenes provides newborn mice with long-term protection against asthma

• Main Author: Segeritz, Charis-Patricia
• Language: English
• Published: University of British Columbia 2011
• Online Access: http://hdl.handle.net/2429/33954

Asthma is a chronic respiratory disorder that leads to inflammation and narrowing of the airways. The global prevalence, morbidity, mortality and economic cost associated with asthma have been on the rise since the 1960’s and continue to increase dramatically by 50% every decade. Today, over 300 million people across all ages, genders and ethnic backgrounds suffer from asthma. In short, asthma has reached epidemic levels. Current treatment options either alleviate symptoms only temporarily, burden the asthmatic with life-long controller medication, or rely on environmental control measures. Children are disproportionally affected by asthma, indicating that asthma most often is initiated early in life. A vaccination strategy able to prevent or cure asthma early in life is therefore urgently needed. We have successfully developed a novel vaccine platform based on the live, attenuated, intracellular bacterium Listeria monocytogenes. We hypothesized that this vaccine platform would induce a sustained anti-allergic Th1 immune response after only one dose given to newborn mice, thus preventing asthma upon future challenge with the allergen. To test our hypothesis, neonatal mice immunized intraperitoneally with different Listeria monocytogenes vaccine strains were compared to negative and positive controls. We examined the protective effects of the following vaccines: the live vaccine strain Lm (trpS actA)/pSPOPShlyOVA, synthesizing ovalbumin proteins, 2) the same yet heatkilled vaccine strain HKLm (trpS actA)/pSPO-PShlyOVA and 3) the live vaccine strain Lm (trpS actA)/pSPO expressing no specific antigens. Subsequent sensitization and intranasal challenge with ovalbumin to induce asthma was followed by a detailed analysis of asthma severity. This analysis included the total number and types of cells in the bronchoalveolar lavage fluid, as well as histology of lung tissue identifying goblet cell metaplasia and cell infiltration of the airway epithelium. Serum antibody levels and cytokine profiles were also examined, as was airway resistance. We found that only neonatal mice immunized with the live Listeria monocytogenes strains were protected from asthma. This protection did not appear to be mediated by shifts in the Th1/Th2 responses and was found even in the absence of specific antigen expression by Listeria monocytogenes. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate