Respiratory syncytial virus (RSV) is a major cause of disease, with an especially high burden in infants. Disease severity is variable;it can range from mild upper respiratory tract infections to debilitating bronchiolitis, viral pneumonia, respiratory collapse, and death. While nearly all children will be infected by the age of 3, our ability to tret RSV is very limited. The treatment options are primarily supportive to prevent respiratory failure or major organ dysfunction. Widely available, cost-effective preventative options are also lacking. The only FDA-approved prevention for RSV infection is palivizumab, a monoclonal antibody directed against the RSV fusion protein. While effective, this therapy is prohibitively expensive for general use. Due to the frequency and severity of infection, the development of new therapeutics is of high importance. Many of the hallmark clinical features associated with severe disease may actually be due to inappropriate immune responses to the virus. Therefore, successful rational design of new therapeutics and preventative treatments is dependent upon a more comprehensive understanding of the immune response to RSV. Specifically, both mucus production and increased airway responsiveness, primary culprits in airway obstruction and respiratory failure, are mediated by interleukin 13 (IL-13) signaling. A major source of IL-13 is T helper 2 (Th2) cells. During RSV infection, mature IL-13-producingTh2 cells begin to populate the lungs around one week post infection. However, preliminary data show significant IL-13 accumulation in the lungs as early as 4 days after infection, suggesting involvement of additional sources of IL-13. In other pulmonary disease models that are characterized by mucus production and airway responsiveness, such as asthma, group 2 innate lymphoid cells (ILC2) have been implicated as a major early source of IL-13. Preliminary data demonstrate a 10-fold increase in the total number of lung ILC2s 4 days after RSV infection. Lung ILC2s can be stimulated by the cytokine interleukin 33 (IL-33) signaling through its receptor ST2. Preliminary data show significant, early increases in IL-33 protein and mRNA in the lungs after RSV infection. Collectively, these data strongly suggest a role for IL-33-stimulated ILC2s in contributing to airway dysfunction during RSV infection. Experiments using mice deficient in either IL- 33 or its receptor ST2 will be used to determine the effect of this signaling axis on ILC2 proliferation and IL-13 expression. Additionally, the capacity of RSV-infected human airway epithelial cells to produce IL-33 will be determined to provide a direct translational component to this work. Finally, experiments using various depletions of Th2 and/or ILC2s will be performed to evaluate the ability of ILC2s to contribute to mucus production and airway responsiveness. These proposed studies will determine a previously unknown role for IL-33 and ILC2s in RSV-induced airway dysfunction. This knowledge will be paradigm-shifting in the field of RSV immunology and will suggest new targetable pathways for RSV therapeutics.
Respiratory syncytial virus is the leading cause of infant hospitalization and bronchiolitis in the United States. Clinical manifestations of severe RSV disease, including obstructed airways and respiratory failure, are caused by excessively strong or inappropriately directed immune responses to the virus. This study aims to determine the role of group 2 innate lymphoid cells-a newly discovered, highly active immune cell population in the lungs-in respiratory syncytial virus-induced airway dysfunction.
|Stier, Matthew T; Zhang, Jian; Goleniewska, Kasia et al. (2018) IL-33 promotes the egress of group 2 innate lymphoid cells from the bone marrow. J Exp Med 215:263-281|
|Stier, Matthew T; Peebles Jr, R Stokes (2017) Innate lymphoid cells and allergic disease. Ann Allergy Asthma Immunol 119:480-488|
|Stier, Matthew T; Bloodworth, Melissa H; Toki, Shinji et al. (2016) Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J Allergy Clin Immunol 138:814-824.e11|