Asthma and atopic diseases are major health burdens in the westernized world. The mechanism(s) responsible for the development and exacerbation of these diseases are not well understood. Respiratory viral infections have been implicated in development and exacerbation of atopic disease. We have utilized a mouse model of paramyxoviral infection where infection with Sendai virus (SeV) leads to a long-lasting post-viral atopic disease with airway hyperreactivity and mucous cell metaplasia. This pro-atopic paradigm depends upon recruitment of CD49d expressing neutrophils (PMN), which, through an unknown mechanism, drive expression of the high-affinity receptor for IgE on lung dendritic cells. Anti-SeV IgE is made which crosslinks this receptor, ultimately leading to recruitment of IL13 producing Th2 cells. Whether modulation of the PMN subsets can impact disease is not known, nor is it clear what role IgE plays during the antiviral immune response. We hypothesize that specific components of the pulmonary immune response to viruses (i.e., CD49d+ PMN and IgE) drive development of atopic disease, and can be modulated to reduce the atopic disease risk. To test this hypothesis we propose these specific aims: 1) Determine if manipulation of CD49d expressing PMN can prevent post-viral atopic disease. 2) Determine the mechanism through which CD49d expressing PMN induce cDC FceRI. 3) Determine the functional relevance of IgE during the antiviral immune response. Upon completion of this project, we will have determined how CD49d+ PMN differ from CD49d- PMN, whether modulation of their recruitment affects the development of post-viral atopic disease, and whether similar cells exist in humans. The mechanism through which CD49d+ PMN drive dendritic cell expression of FceRI will be known, and we will have determined the functional relevance of IgE in the antiviral immune response. Together, these studies will help us refine and focus potential therapeutic interventions in the future to prevent the development and exacerbation of post-viral atopic disease.
These studies will determine how neutrophil subsets can be manipulated to prevent asthma and allergic disease, how these cells influence the development of asthma after a viral infection and the role IgE plays in the antiviral immune response. Ultimately, this work will lead to development of new therapeutic strategies to prevent or treat post viral-induced allergic diseases, like asthma.
| Hussain, Syed-Rehan A; Mejias, Asuncion; Ramilo, Octavio et al. (2018) Post-viral atopic airway disease: pathogenesis and potential avenues for intervention. Expert Rev Clin Immunol :1-10 |
| Cheung, Dorothy S; Sigua, Jerome A; Simpson, Pippa M et al. (2018) Cysteinyl leukotriene receptor 1 expression identifies a subset of neutrophils during the antiviral response that contributes to postviral atopic airway disease. J Allergy Clin Immunol 142:1206-1217.e5 |
| Martorano, Lisa M; Grayson, Mitchell H (2018) Respiratory viral infections and atopic development: From possible mechanisms to advances in treatment. Eur J Immunol 48:407-414 |
| Grayson, Mitchell H; Camarda, Lauren E; Hussain, Syed-Rehan A et al. (2018) Intestinal Microbiota Disruption Reduces Regulatory T Cells and Increases Respiratory Viral Infection Mortality Through Increased IFN? Production. Front Immunol 9:1587 |
| Scherzer, Rebecca; Grayson, Mitchell H (2018) Heterogeneity and the origins of asthma. Ann Allergy Asthma Immunol 121:400-405 |
| Tam, Jonathan S; Grayson, Mitchell H (2017) IgE and antiviral immune response in asthma. J Allergy Clin Immunol 139:1717 |
| Kelly, Brian T; Grayson, Mitchell H (2016) Immunoglobulin E, what is it good for? Ann Allergy Asthma Immunol 116:183-7 |
| Tam, Jonathan S; Jackson, William T; Hunter, Desire et al. (2013) Rhinovirus specific IgE can be detected in human sera. J Allergy Clin Immunol 132:1241-3 |
| Cheung, Dorothy S; Grayson, Mitchell H (2012) Role of viruses in the development of atopic disease in pediatric patients. Curr Allergy Asthma Rep 12:613-20 |
| Vasudev, Monica; Cheung, Dorothy S; Pincsak, Hannah et al. (2012) Expression of high-affinity IgE receptor on human peripheral blood dendritic cells in children. PLoS One 7:e32556 |
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