Chronic Rhinosinusitis (CRS) is one of the most frequently reported chronic diseases in the U.S. Even with aggressive medical and surgical therapies, many CRS patients have persistent disease. The pathogenesis of CRS is not well understood, and the etiology, classification, and assessment of disease severity remain controversial. Human airways are constantly exposed to environmental fungal spores, often at higher levels than the levels of allergenic pollens. During the past funding period, peripheral blood immune cells from CRS patients reacted to these common fungi, and a product(s) of an environmental fungus, Alternaria, showed a unique immunostimulatory activity. These findings led to a novel hypothesis;namely, CRS is caused or exacerbated by an exaggerated immune response to airborne fungi, such as Alternaria. Airway immune cells in CRS patients produce vigorous immune and inflammatory responses to fungi and fungal products, especially to protease(s) and a glycolytic enzyme(s), resulting in uncontrolled Th1 and Th2 cytokine production, persistent eosinophilic inflammation, tissue damage and remodeling. To test this hypothesis, the immune responses in CRS patients to common airborne fungi will be characterized by in vitro and in vivo approaches (Aim 1). Immune responses from both innate and acquired immune cells in blood and sinus tissues of CRS patients will be compared to the responses in allergic and nonallergic controls. The product(s) of Alternaria, which triggers profound Th2-like inflammation in vitro in human airway cells and in vivo in murine airways, will be identified and characterized (Aim 2). After proteomic identification, the recombinant molecule(s) and gene knockout fungus will be examined for their biological activities in human airway and immune cells in vitro and in mice in vivo. This application involves a multidisciplinary team of immunologists, allergy physicians, otorhinolaryngology surgeons, and functional genomic scientists. Elucidation of the mechanisms of persistent airway inflammation in CRS will advance the field and help to provide specific and effective therapies for this common, costly, and incapacitating disorder. Relevance: This proposal will investigate why patients with chronic rhinosinusitis have such persistent health problems. It will use advanced biotechnological methods to examine common environmental agents that may cause or intensify this disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Togias, Alkis
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Divekar, Rohit; Hagan, John; Rank, Matthew et al. (2016) Diagnostic Utility of Urinary LTE4 in Asthma, Allergic Rhinitis, Chronic Rhinosinusitis, Nasal Polyps, and Aspirin Sensitivity. J Allergy Clin Immunol Pract 4:665-70
Divekar, Rohit; Kita, Hirohito (2015) Recent advances in epithelium-derived cytokines (IL-33, IL-25, and thymic stromal lymphopoietin) and allergic inflammation. Curr Opin Allergy Clin Immunol 15:98-103
Ponikau, Jens U; Winter, Laurie A; Kephart, Gail M et al. (2015) An immunologic test for chronic rhinosinusitis based on free intranasal eosinophilic major basic protein. Int Forum Allergy Rhinol 5:28-35
Kobayashi, Takehito; Soma, Tomoyuki; Noguchi, Toru et al. (2015) ATP drives eosinophil effector responses through P2 purinergic receptors. Allergol Int 64 Suppl:S30-6
Drake, Li Yin; Iijima, Koji; Hara, Kenichiro et al. (2015) B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens. PLoS One 10:e0121660
Divekar, R D; Samant, S; Rank, M A et al. (2015) Immunological profiling in chronic rhinosinusitis with nasal polyps reveals distinct VEGF and GM-CSF signatures during symptomatic exacerbations. Clin Exp Allergy 45:767-78
Iijima, Koji; Kobayashi, Takao; Hara, Kenichiro et al. (2014) IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure. J Immunol 193:1549-59
Likness, Micah M; Pallanch, John F; Sherris, David A et al. (2014) Computed tomography scans as an objective measure of disease severity in chronic rhinosinusitis. Otolaryngol Head Neck Surg 150:305-11
Hara, Kenichiro; Iijima, Koji; Elias, Martha K et al. (2014) Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa. J Immunol 192:4032-42
Drake, L Y; Iijima, K; Kita, H (2014) Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy 69:1300-7

Showing the most recent 10 out of 48 publications