Otitis media (OM) is the most common childhood bacterial infection and the leading cause of hearing loss. It remains a major health problem and a substantial socioeconomic burden. S. pneumoniae (Sp) is a major gram-positive bacteria causing OM. Current vaccine has a limited impact on OM and inappropriate antibiotic use increased antibiotic-resistance. To date there have been no effective non-antibiotic therapeutic agents available for OM due to poor understanding of Sp pathogenesis. Appropriate innate immune response is critical for host defense in children. However, if uncontrolled, excessive inflammatory response often results in immunopathology and impaired function of middle ear. Thus, innate inflammatory response must be tightly controlled. However, the key regulators and the underlying mechanisms remain largely unknown. Our long-term goal is to understand the molecular mechanisms underlying the tight control of innate inflammatory & host defense response in Sp-induced OM pathogenesis and develop novel non-antibiotic therapeutics. We previously showed that MAP kinase ERK1 positively mediates pathological responses whereas deubiquitinase CYLD and phosphatase MKP-1 act as key negative regulators of pathological responses. Thus, we hypothesized that CYLD and MKP-1 may tightly regulate Sp-induced inflammation and host defense via inhibiting ERK1 by deubiquitinating and dephosphorylating it, and up-regulating CYLD and MKP-1 may represent an ideal and novel therapeutic strategy to inhibit excessive inflammation and maintain an appropriate host defense. Indeed, our preliminary studies demonstrate that CYLD and MKP-1 act as negative regulators for Sp-induced inflammation, but positive regulators for antimicrobial -defensin, likely via inhibiting ERK1; Excitingly, systemic and CPE-mediated ototopical administration of Vinpocetine, an existing drug for neurological diseases, suppressed inflammation, improved hearing loss and enhanced -defensin induction and bacterial clearance likely via up-regulating CYLD and MKP-1. Vinpocetine also inhibited inflammation and improved hearing in a well-established model of chronic OM. These exciting preliminary data have thus laid a solid foundation for us to further investigate the mechanisms underlying tight regulation of Sp-induced innate inflammatory & host defense responses and evaluate the therapeutic potential of Vinpocetine in OM.
Our specific aims are:
Aim 1. Determine how Sp-induced innate inflammatory & host defense responses are tightly controlled by inhibiting ERK1.
Aim 2. Determine how Vinpocetine inhibits Sp-induced inflammation and enhances host defense.
Aim 3. Determine the therapeutic potential of oral and ototopical administration of Vinpocetine in suppressing Sp-induced inflammation and enhancing host defense in acute and chronic OM animal models. Overall, the proposed studies will advance our understanding of molecular pathogenesis of Sp-induced OM and may lead to novel therapeutic strategy to suppress overactive inflammation, improve middle ear hearing function and enhance host defense for Sp-induced OM (Impact & Significance).

Public Health Relevance

Otitis media (OM), the most common childhood bacterial infection and the leading cause of hearing loss, remains a major health problem and a substantial socioeconomic burden, accounting for 24.5 million visits and costing over $5 billion annually. Current pneumococcal vaccine has a limited impact on OM, inappropriate antibiotic use increased antibiotic-resistance, and to date there have been no effective non-antibiotic therapeutic agents available for OM due to poor understanding of its pathogenesis. The proposed studies will advance our understanding of molecular pathogenesis of Sp-induced OM and lead to new therapeutic strategy to suppress innate inflammatory response without compromising host defense for Sp-induced OM.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC013833-03
Application #
9273905
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Watson, Bracie
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Georgia State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Zhang, Yi-Shuai; Li, Jian-Dong; Yan, Chen (2018) An update on vinpocetine: New discoveries and clinical implications. Eur J Pharmacol 819:30-34
Konduru, Anuhya Sharma; Matsuyama, Shingo; Lee, Byung-Cheol et al. (2017) Curcumin Inhibits NTHi-Induced MUC5AC Mucin Overproduction in Otitis Media via Upregulation of MAPK Phosphatase MKP-1. Int J Inflam 2017:4525309
Luo, Wenwei; Yi, Hong; Taylor, Jeannette et al. (2017) Cilia distribution and polarity in the epithelial lining of the mouse middle ear cavity. Sci Rep 7:45870
Wu, Mei-Ping; Zhang, Yi-Shuai; Xu, Xiangbin et al. (2017) Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis. Cardiovasc Drugs Ther 31:157-166
Harusato, A; Abo, H; Ngo, V L et al. (2017) IL-36? signaling controls the induced regulatory T cell-Th9 cell balance via NF?B activation and STAT transcription factors. Mucosal Immunol 10:1455-1467
Raji, Idris; Yadudu, Fatima; Janeira, Emily et al. (2017) Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase. Bioorg Med Chem 25:1202-1218
Andrews, Carla S; Matsuyama, Shingo; Lee, Byung-Cheol et al. (2016) Resveratrol suppresses NTHi-induced inflammation via up-regulation of the negative regulator MyD88 short. Sci Rep 6:34445
Lee, Byung-Cheol; Miyata, Masanori; Lim, Jae Hyang et al. (2016) Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88. Proc Natl Acad Sci U S A 113:E165-71
Konduru, Anuhya S; Lee, Byung-Cheol; Li, Jian-Dong (2016) Curcumin suppresses NTHi-induced CXCL5 expression via inhibition of positive IKK? pathway and up-regulation of negative MKP-1 pathway. Sci Rep 6:31695
Shuto, Tsuyoshi; Kamei, Shunsuke; Nohara, Hirofumi et al. (2016) Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases. Sci Rep 6:39305

Showing the most recent 10 out of 19 publications