Chronic rhinosinusitis with polyps (CRSwNP) is a significant health problem in the United States. This disorder, which is often particularly recalcitrant to medical and surgical therapy, is characterized by persistent eosinophilic inflammation of the sinonasal mucosa, with thickened secretions that are frequently colonized with bacteria and/or fungi. The cellular and molecular mechanisms that underlie CRSwNP remain poorly understood. Epithelial cells of the sinonasal tract play important roles in host immune defense of the upper airway. They express pattern recognition receptors and produce anti-microbial effectors in response to inhaled pathogens. Innate immune pathways of sinonasal epithelial cells (SNECs) also promote Th1-like inflammation to target bacteria, viruses, and fungi. However, there are no identified innate immune programs of SNECs that generate Th2-like inflammation. Our preliminary studies strongly suggest that such an innate immune pathway exists in SNECs and, importantly, that activation of this pathway down-regulates innate anti-microbial activity in CRSwNP. We hypothesize that SNECs in CRSwNP are influenced by local Th2 cytokines and particular lumenal pathogen-associated molecules to adopt an """"""""anti-parasite"""""""" innate immune program, characterized by expression of pro-eosinophilic mediators and suppression of anti-microbial function, thus promoting the cardinal features of CRSwNP. To further explore this hypothesis, we will initially, in aim 1, examine tissue samples from control subjects and well-characterized patients with chronic rhinosinusitis with and without nasal polyps, to fully characterize the anti-parasite pattern of gene expression in vivo. We will explore in vitro whether this phenotype results in reduced anti-microbial responses by SNECs to toll-like receptor agonists.
In aim 2, we will use an air-liquid interface cell culture system to drive SNECs to the anti-parasite phenotype through exposure to Th2 cytokines and putative parasite-associated molecules. We will utilize this model to characterize the effect on innate anti-microbial function and identify underlying molecular mechanisms. Finally, in aim 3 we will create a genetically-modified mouse model of inducible Th2 sinonasal inflammation. We will examine whether our mouse model recapitulates important features of the human disease, and study whether chronic sinonasal Th2 inflammation in vivo leads to impaired innate anti-microbial function. Development of this model will provide the first transgenic animal model of chronic rhinosinusitis, which will have great potential to further a wide range of future CRSwNP research. These combined studies described in the proposal will significantly advance current knowledge about CRSwNP and potentially lead to innovative therapies for this debilitating and costly medical condition.
|Wohlgemuth, Nicholas; Ye, Yang; Fenstermacher, Katherine J et al. (2017) The M2 protein of live, attenuated influenza vaccine encodes a mutation that reduces replication in human nasal epithelial cells. Vaccine 35:6691-6699|
|Kohanski, Michael A; Tharakan, Anuj; London, Nyall R et al. (2017) Bactericidal antibiotics promote oxidative damage and programmed cell death in sinonasal epithelial cells. Int Forum Allergy Rhinol 7:359-364|
|London Jr, Nyall R; Lane, Andrew P (2016) Innate immunity and chronic rhinosinusitis: What we have learned from animal models. Laryngoscope Investig Otolaryngol 1:49-56|
|Peretz, Jackye; Pekosz, Andrew; Lane, Andrew P et al. (2016) Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors. Am J Physiol Lung Cell Mol Physiol 310:L415-25|
|Kohanski, Michael A; Tharakan, Anuj; Lane, Andrew P et al. (2016) Bactericidal antibiotics promote reactive oxygen species formation and inflammation in human sinonasal epithelial cells. Int Forum Allergy Rhinol 6:191-200|
|Kohanski, Michael A; Lane, Andrew P (2015) Sinonasal epithelial cell response to Staphylococcus aureus burden in chronic rhinosinusitis. JAMA Otolaryngol Head Neck Surg 141:341-9|
|Cho, Seok Hyun; Oh, Sun Young; Lane, Andrew P et al. (2014) Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways. PLoS One 9:e103685|
|Paris, Gina; Pozharskaya, Tatyana; Asempa, Tomefa et al. (2014) Damage-associated molecular patterns stimulate interleukin-33 expression in nasal polyp epithelial cells. Int Forum Allergy Rhinol 4:15-21|
|Sultan, Babar; Ramanathan Jr, Murugappan; Lee, Joan et al. (2013) Sinonasal epithelial cells synthesize active vitamin D, augmenting host innate immune function. Int Forum Allergy Rhinol 3:26-30|
|Liang, Jonathan; Lane, Andrew P (2013) Topical Drug Delivery for Chronic Rhinosinusitis. Curr Otorhinolaryngol Rep 1:51-60|
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