Following the common cold, otitis media (OM), or inflammation of the middle ear, is the most frequent illness resulting in visits to physicians and the most common cause of hearing impairment and dizziness in children. The recent pathogenic shift of OM by S. pneumoniae vaccination emphasizes the clinical importance of nontypeable Haemophilus influenzae (NTHi), which is the focus of this proposal. In recent years, an alarming increase in antibiotic resistance has been observed worldwide among pathogens. Thus, there is an urgent need to develop new and innovative non-antibiotic approaches to prevent and manage OM. To this end, it is imperative to understand the molecular mechanisms that control the expression of antimicrobial innate immune molecules (AIIMs), which comprise the tubotympanum's first line of defense and determine if these mechanisms can be exploited to prevent or manage OM. Of the AIIMs tested to date, 2-defensin 2 (DEFB4) is the most effective antimicrobial molecule against OM pathogens. However, current understanding of the molecular mechanisms involved in the regulation of the 2-defensin 2 expression by NTHi is limited. The long-term goal of this project is to elucidate the role of innate immunity in OM pathogenesis, focusing on 2-defensin 2, a potent and inducible AIIM and to develop AIIMs-based approaches to prevent or treat OM. Our overall hypotheses are: a) NOD2- and TLR2-mediated activation of NF-:B is required for NTHi- induced 2-defensin 2 up-regulation and contributes to NTHi clearance from the middle ear;b) NTHi-induced IL- 10 negatively regulates NTHi-induced 2-defensin 2 up-regulation and impairs NTHi clearance from the middle ear;and c) Exogenous and over-expressed 2-defensin 2 may have therapeutic potential in the prevention and the management of OM. To evaluate our hypotheses, we will: 1) identify the signaling network(s) involved in NTHi-induced 2-defensin 2 up-regulations (Specific Aim 1);2) determine the role of IL-10 as a negative regulator of NTHi-induced 2-defensin 2 expression (Specific Aim 2);and 3) determine the therapeutic potential of 2-defensin 2 in the prevention and the management of OM (Specific Aim 3). The significance of this study is: 1) to provide insight into understanding how antimicrobial innate immune molecules (AIIMs) produced by the host protect the middle ear from invading pathogens, and 2) to facilitate the application of AIIMs, particularly 2-defensin 2, in the prevention of OM (using a gene-based approach), and the management of OM (using synthetic AIIMs). Otitis media (OM), or middle ear infection, is one of the most frequent illnesses affecting young children and the most frequent reason for antibiotic prescriptions. The rapid increase in antibiotic resistance among OM pathogens has become a major global health concern. The goal of this proposal is to understand the interaction between bacteria and host and to develop innovative new approaches in preventing and managing OM, without antibiotics, using natural antimicrobial molecules produced by the host.

Public Health Relevance

Otitis media (OM), or middle ear infection, is one of the most frequent illnesses affecting young children and the most frequent reason for antibiotic prescriptions. The rapid increase in antibiotic resistance among OM pathogens has become a major global health concern. The goal of this proposal is to understand the interaction between bacteria and host and to develop innovative new approaches in preventing and managing OM, without antibiotics, using natural antimicrobial molecules produced by the host.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
7R01DC005025-12
Application #
8787258
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2001-09-10
Project End
2014-06-30
Budget Start
2013-10-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$275,001
Indirect Cost
$96,436
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Woo, Jeong-Im; Oh, Sejo; Webster, Paul et al. (2014) NOD2/RICK-dependent ?-defensin 2 regulation is protective for nontypeable Haemophilus influenzae-induced middle ear infection. PLoS One 9:e90933
Woo, Jeong-Im; Kil, Sung-Hee; Pan, Huiqi et al. (2014) Distal NF-kB binding motif functions as an enhancer for nontypeable H. influenzae-induced DEFB4 regulation in epithelial cells. Biochem Biophys Res Commun 443:1035-40
Li, Jian-Dong; Hermansson, Ann; Ryan, Allen F et al. (2013) Panel 4: Recent advances in otitis media in molecular biology, biochemistry, genetics, and animal models. Otolaryngol Head Neck Surg 148:E52-63
Oh, Sejo; Woo, Jeong-Im; Lim, David J et al. (2012) ERK2-dependent activation of c-Jun is required for nontypeable Haemophilus influenzae-induced CXCL2 upregulation in inner ear fibrocytes. J Immunol 188:3496-505
Woo, Jeong-Im; Pan, Huiqi; Oh, Sejo et al. (2010) Spiral ligament fibrocyte-derived MCP-1/CCL2 contributes to inner ear inflammation secondary to nontypeable H. influenzae-induced otitis media. BMC Infect Dis 10:314
Shimada, Jun; Moon, Sung K; Lee, Haa-Yung et al. (2008) Lysozyme M deficiency leads to an increased susceptibility to Streptococcus pneumoniae-induced otitis media. BMC Infect Dis 8:134
Lee, Haa-Yung; Takeshita, Tamotsu; Shimada, Jun et al. (2008) Induction of beta defensin 2 by NTHi requires TLR2 mediated MyD88 and IRAK-TRAF6-p38MAPK signaling pathway in human middle ear epithelial cells. BMC Infect Dis 8:87
Moon, Sung K; Linthicum Jr, Fred H; Yang, Hae Dong et al. (2008) Activities of matrix metalloproteinases and tissue inhibitor of metalloproteinase-2 in idiopathic hemotympanum and otitis media with effusion. Acta Otolaryngol 128:144-50
Moon, Sung K; Woo, Jeong-Im; Lee, Haa-Yung et al. (2007) Toll-like receptor 2-dependent NF-kappaB activation is involved in nontypeable Haemophilus influenzae-induced monocyte chemotactic protein 1 up-regulation in the spiral ligament fibrocytes of the inner ear. Infect Immun 75:3361-72
So, Hongseob; Kim, HyungJin; Lee, Jeong-Han et al. (2007) Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-kappaB. J Assoc Res Otolaryngol 8:338-55

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