The role of the inflammasome in virus- and pollutant-induced asthma exacerbation



Rebecca Bauer

Rebecca Bauer

Research Mentor:

Dr. Ilona Jaspers, PhD


Clinical Co-Mentor;

Dr. Terry  Noah, MD

Department Toxicology
Project Description Respiratory viral infections, as caused by influenza A virus (IAV), and the inhalation of oxidant air pollutants, such as O3, are the leading causes of asthma exacerbation, as typified by airway inflammation, hyperresponsiveness, and airway obstruction. The respiratory epithelium is the first line of defense against the inhaled environment. Viral infections and oxidant pollutants damage airway epithelial cells (AECs) and induce the production of soluble mediators that attract nearby immune cells and activate innate immune pathways. The communication between AECs and immune cells, such as macrophages, is essential for a balanced innate immune response which permits the appropriate response to pathogens or pollutants while controlling for excess inflammation that can lead to airway injury. Chronic airway inflammation, as caused by asthma, has been shown to upset this balance, resulting in altered innate immune responses to pathogens and pollutants and asthma pathogenesis. The objective of this study is to compare and contrast the mechanisms by which IAV and O3 induce asthma pathogenesis, and whether the same or different pathways mediate these responses. Recently, several NLRs, which oligomerize with caspase-1 and PYCARD to form the inflammasome complex, have been implicated in the innate immune response to pathogens and pollutants. Formation of the inflammasome complex induces activation caspase-1, which can then mediate the processing and release of pro-IL-1β and pro-IL-18. IL-1β is a potent neutrophil chemoattractant which has been long associated with asthma pathogenesis. Both O3 and IAV stimulate the production of IL-1β, suggesting that the inflammasome may be a shared pathway by which O3 and IAV induce allergic inflammation. We hypothesize that the chronic inflammatory state caused by asthma modifies inflammasome signaling and the interaction between macrophages and AECs, resulting in altered innate response to pathogens and pollutants and enhanced pathogenesis. Using a translational research design, with both in vivo and in vitro analysis of the innate immune and inflammasome pathways in asthmatic and non-asthmatic populations, we will address the following three specific aims: (1) Compare IAV-induced activation of the inflammasome and innate immune responses in AECs from asthmatics and non-asthmatics; (2) Determine the role of caspase-1 in the development and exacerbation of asthma using a murine model of acute allergic sensitization; and (3) Elucidate the effects of asthma on O3 -induced innate immune and inflammasome responses in AECs and macrophages using an in vitro co-culture. Asthma exacerbation is a serious public health and economic concern, yet the mechanisms mediating asthma pathogenesis are not understood. With the continued increase in urbanization and the recent worldwide IAV pandemic, determining the mechanisms responsible for IAV- and O3- induced asthma exacerbation is of high importance for the development of therapeutic strategies to mitigate these effects.