There is only limited information about the newly described type 2 innate lymphoid cell (ILC2) population in the lung, the regulation of these cells, and their impact on protection against acute respiratory infections. We have now found that IFN-? negatively regulates ILC2 immune function and that animals deficient in IFN-? expression demonstrate increased resistance to both primary H1N1 pandemic virus infection as well as secondary pneumococcal infection. Enhanced ILC2 activity in viral-infected IFN-?-/- mice is accompanied by decreased lung tissue inflammation and increased expression of pulmonary IL-5, amphiregulin, and eosinophils, but no change in viral burden. Importantly, the increased protection seen after IFN-? neutralization is not observed in ILC2-deficient mice. Studies in this proposal are designed to now determine the unique role of ILC2s in resistance to influenza and secondary bacterial infections. Based on our preliminary data, we hypothesize that IFN-? signaling diminishes ILC2 innate effector function and leads to decreased tissue homeostasis and host survival. To test this concept, we will exploit several unique resources, including novel strains of mice that are deficient in ILC2s, eosinophil expression, and TGF-?IIR signaling, as well as our extensive experience in studying host-pathogen interactions.
The aims are to determine for the first time: 1) the role of ILC2s in mediating resistance to CA04 influenza infection; and 2) the role of ILC2s in regulating susceptibility to secondary bacterial infections following influenza. The ultimate goal is to obtain an understanding of the processes responsible for protection against acute respiratory infection and to exploit the information obtained in order to influence clinical approaches for prevention and treatment of influenza and associated secondary bacterial infections.
This study focuses on understanding the mechanisms responsible for protection against influenza and secondary bacterial infections which represent a significant cause of morbidity and mortality in humans. The results obtained from this study will provide a comprehensive model for understanding microbial interactions in the pulmonary tract and thus provide important insight into the development of effective therapeutics for human use.
|Califano, Danielle; Furuya, Yoichi; Metzger, Dennis W (2018) Effects of Influenza on Alveolar Macrophage Viability Are Dependent on Mouse Genetic Strain. J Immunol 201:134-144|